Trial Outcomes & Findings for 48 Weeks, Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO) (NCT NCT03845075)

Last Updated: 2024-02-13

Results Overview

Number and percentage of deviations from normal range (as defined by the investigational site's laboratory) for hemoglobin, platelet counts, white cells count, differential counts at baseline, week 12 and week 24 in each of the two treatment arms

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

21 participants

Primary outcome timeframe

from Baseline to week 24

Results posted on

2024-02-13

Participant Flow

A total of 35 subjects with HIO were screened; 13 subjects were screen failures. A total of 21 unique subjects were assigned 22 randomization numbers. One subject was a screen failure who was randomized in error, and withdrawn after receiving 1 dose of tesofensine/metoprolol; this subject was later rescreened and rerandomized to placebo. This subject is summarized for both tesofensine/metoprolol and placebo (ie, considered as 2 independent subjects).

Participant milestones

Participant milestones
Measure	Tesofensine/Metoprolol Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo Subjects were randomized to receive matching placebo tesofensine and placebo metoprolol once daily for 24 weeks during Part 1.	Tesofensine/Metoprolol -> Tesofensine/Metoprolol Subjects who received co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1 and continued to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.	Placebo -> Tesofensine/Metoprolol Subjects who received matching placebo tesofensine and placebo metoprolol once daily for 24 weeks during Part 1 and were switched to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.
Part 1 - DB STARTED	14	8	0	0
Part 1 - DB COMPLETED	12	6	0	0
Part 1 - DB NOT COMPLETED	2	2	0	0
Part 2 - OLE STARTED	0	0	12	6
Part 2 - OLE COMPLETED	0	0	12	6
Part 2 - OLE NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tesofensine/Metoprolol Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo Subjects were randomized to receive matching placebo tesofensine and placebo metoprolol once daily for 24 weeks during Part 1.
Part 1 - DB Withdrawal by Subject	1	1
Part 1 - DB Adverse Event	0	1
Part 1 - DB Screen failure, but received 1 dose of study drug in error	1	0

Baseline Characteristics

48 Weeks, Study to Evaluate Overall Safety and Tolerability of Co-administration of Tesofensine and Metoprolol in Subjects With Hypothalamic Injury-induced Obesity (HIO)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.	Total n=22 Participants Total of all reporting groups
Age, Continuous	45.4 years STANDARD_DEVIATION 13.3 • n=5 Participants	44.4 years STANDARD_DEVIATION 18.3 • n=7 Participants	45.0 years STANDARD_DEVIATION 14.9 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	6 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	14 Participants n=5 Participants	8 Participants n=7 Participants	22 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Denmark	14 Participants n=5 Participants	8 Participants n=7 Participants	22 Participants n=5 Participants
Weight	114.34 kg STANDARD_DEVIATION 18.14 • n=5 Participants	112.16 kg STANDARD_DEVIATION 27.04 • n=7 Participants	113.55 kg STANDARD_DEVIATION 21.18 • n=5 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos)

Number and percentage of participants with adverse events in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Number of Participants With Treatment Emergent Adverse Events	12 Participants	7 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos)

Number and percentage of participants with mild, moderate or severe adverse events in each of the two treatment arms.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Number of Participants With at Least One Mild, Moderate or Severe Adverse Event At least one mild AE	11 Participants	7 Participants
Number of Participants With at Least One Mild, Moderate or Severe Adverse Event At least one moderate AE	10 Participants	5 Participants
Number of Participants With at Least One Mild, Moderate or Severe Adverse Event At least one severe AE	2 Participants	2 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos)

Number and percentage of participants with at least one serious adverse event, indicating type, in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Participants (Number and Percentage) With and Type of Serious Adverse Events At least one SAE	2 Participants	1 Participants
Participants (Number and Percentage) With and Type of Serious Adverse Events Preferred Term: Anxiety	1 Participants	0 Participants
Participants (Number and Percentage) With and Type of Serious Adverse Events Preferred Term: Craniopharyngioma	1 Participants	0 Participants
Participants (Number and Percentage) With and Type of Serious Adverse Events Preferred Term: Hyponatraemia	0 Participants	1 Participants
Participants (Number and Percentage) With and Type of Serious Adverse Events Preferred Term: Post procedural complication	1 Participants	0 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Systolic blood pressure in mmHg measured at each visit in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=13 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Systolic Blood Pressure [mmHg] Baseline	124.0 mmHg Standard Deviation 9	134.5 mmHg Standard Deviation 16
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 4	126.6 mmHg Standard Deviation 12	131.8 mmHg Standard Deviation 17
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 8	129.2 mmHg Standard Deviation 17	126.3 mmHg Standard Deviation 23
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 12	126.3 mmHg Standard Deviation 13	126.2 mmHg Standard Deviation 14
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 16	123.9 mmHg Standard Deviation 14	126.0 mmHg Standard Deviation 17
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 20	127.3 mmHg Standard Deviation 12	129.2 mmHg Standard Deviation 18
Safety as Assessed by Systolic Blood Pressure [mmHg] Week 24	125.3 mmHg Standard Deviation 16	130.5 mmHg Standard Deviation 22

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Diastolic blood pressure in mmHg measured at each visit in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=13 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Diastolic Blood Pressure [mmHg] Baseline	83.2 mmHg Standard Deviation 14	85.9 mmHg Standard Deviation 8
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 4	84.2 mmHg Standard Deviation 8	86.8 mmHg Standard Deviation 8
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 8	84.5 mmHg Standard Deviation 9	86.0 mmHg Standard Deviation 9
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 12	81.5 mmHg Standard Deviation 10	86.5 mmHg Standard Deviation 8
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 16	81.4 mmHg Standard Deviation 9	80.3 mmHg Standard Deviation 13
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 20	84.3 mmHg Standard Deviation 9	85.7 mmHg Standard Deviation 9
Safety as Assessed by Diastolic Blood Pressure [mmHg] Week 24	83.1 mmHg Standard Deviation 9	84.2 mmHg Standard Deviation 13

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Heart rate measured in beats per minute (bpm) at each visit in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=13 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Heart Rate [Bpm] Baseline	75.5 bpm Standard Deviation 8	78.9 bpm Standard Deviation 11
Safety as Assessed by Heart Rate [Bpm] Week 4	71.9 bpm Standard Deviation 9	75.9 bpm Standard Deviation 12
Safety as Assessed by Heart Rate [Bpm] Week 8	72.7 bpm Standard Deviation 8	76.0 bpm Standard Deviation 13
Safety as Assessed by Heart Rate [Bpm] Week 12	74.2 bpm Standard Deviation 10	73.3 bpm Standard Deviation 8
Safety as Assessed by Heart Rate [Bpm] Week 16	73.8 bpm Standard Deviation 13	74.8 bpm Standard Deviation 6
Safety as Assessed by Heart Rate [Bpm] Week 20	74.8 bpm Standard Deviation 11	77.2 bpm Standard Deviation 13
Safety as Assessed by Heart Rate [Bpm] Week 24	73.6 bpm Standard Deviation 10	71.5 bpm Standard Deviation 9

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Hematology Parameters Hemoglobin: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Hemoglobin: Baseline - High	0 Participants	1 Participants
Safety as Assessed by Hematology Parameters Hemoglobin: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Hemoglobin: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Hemoglobin: Week 24 - Low	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Hemoglobin: Week 24 - High	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Baseline - High	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Week 12 - High	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Platelets: Week 24 - High	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters WBC: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters WBC: Baseline - High	3 Participants	2 Participants
Safety as Assessed by Hematology Parameters WBC: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters WBC: Week 12 - High	5 Participants	1 Participants
Safety as Assessed by Hematology Parameters WBC: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters WBC: Week 24 - High	0 Participants	1 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Baseline - Low	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Baseline - High	1 Participants	1 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Week 12 - High	4 Participants	1 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Week 24 - Low	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Neutrophils: Week 24 - High	1 Participants	1 Participants
Safety as Assessed by Hematology Parameters Monocytes: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Monocytes: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Monocytes: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Monocytes: Week 12 - High	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Monocytes: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Monocytes: Week 24 - High	1 Participants	0 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Baseline - Low	0 Participants	1 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Baseline - High	1 Participants	2 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Week 12 - Low	0 Participants	1 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Hematology Parameters Lymphocytes: Week 24 - High	1 Participants	0 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Number and percentage of deviations from normal range (as defined by the investigational site's laboratory) for sodium, potassium, creatinine at each visit in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Electrolytes and Creatinine Sodium: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Baseline - High	2 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 4 - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 4 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 8 - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 8 - High	1 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 12 - High	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 16 - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 16 - High	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 20 - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 20 - High	2 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 24 - Low	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Sodium: Week 24 - High	0 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Baseline - High	0 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 4 - Low	2 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 4 - High	0 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 8 - Low	2 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 8 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 12 - Low	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 16 - Low	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 16 - High	0 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 20 - Low	1 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 20 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 24 - Low	0 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Potassium: Week 24 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Baseline - Low	3 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 4 - Low	2 Participants	4 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 4 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 8 - Low	2 Participants	3 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 8 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 12 - Low	2 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 16 - Low	3 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 16 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 20 - Low	4 Participants	2 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 20 - High	0 Participants	0 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 24 - Low	3 Participants	1 Participants
Safety as Assessed by Electrolytes and Creatinine Creatinine: Week 24 - High	0 Participants	0 Participants

PRIMARY outcome

Timeframe: from Baseline to week 24

Population: Safety Analysis Set: all subjects who took at least one dose of the IMPs (active substances or placebos). Subjects with an assessment at given timepoint.

Number and percentage of deviations from normal range (as defined by the investigational site's laboratory) for gamma glutamyl transferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), glomerular filtration rate (GFR), and urea at baseline, week 12, and week 24 in each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Safety as Assessed by Liver and Kidney Function Tests GGT: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GGT: Baseline - High	5 Participants	1 Participants
Safety as Assessed by Liver and Kidney Function Tests GGT: Week 12 - Low	0 Participants	1 Participants
Safety as Assessed by Liver and Kidney Function Tests GGT: Week 12 - High	5 Participants	2 Participants
Safety as Assessed by Liver and Kidney Function Tests GGT: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GGT: Week 24 - High	4 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests AST: Week 24 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Week 12 - High	1 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALT: Week 24 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Baseline - High	1 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Week 12 - High	2 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests ALP: Week 24 - High	1 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Baseline - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Week 12 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Week 24 - Low	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests GFR: Week 24 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Baseline - Low	1 Participants	1 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Baseline - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Week 12 - Low	2 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Week 12 - High	0 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Week 24 - Low	1 Participants	0 Participants
Safety as Assessed by Liver and Kidney Function Tests Urea: Week 24 - High	0 Participants	0 Participants

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Population: Modified Intention-to-treat (mITT) Population: all subjects who entered Part 2 (open-label extension) and had nonmissing baseline assessments and at least 1 post-Part 1 assessment. Last observation carried forward (LOCF) approach.

Change in satiety and appetite using the CSS from Baseline to week 24, from Baseline to week 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms Full name of the scale: composite satiety score (CSS), sometimes referred to as "appetite suppression score". Range of values is 0-100; lower the value, hungrier a person is. CSS = (satiety + fullness + \[100 - hunger\] + \[100 - prospective food consumption\]) / 4. The four variables included are measured by visual analog scales (0-100 mm)

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Composite Satiety Score (CSS) Baseline to Week 24	4.5 score on a scale Standard Deviation 20.6	6.5 score on a scale Standard Deviation 19.3
Composite Satiety Score (CSS) Baseline to Week 48	4.2 score on a scale Standard Deviation 15.1	11.2 score on a scale Standard Deviation 14.3
Composite Satiety Score (CSS) Week 24 to Week 48	-0.3 score on a scale Standard Deviation 14.4	4.7 score on a scale Standard Deviation 12.5

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in body weight from baseline to week 24, from baseline to 48 and from week 24 to week 48 measured at each visit for each of the two treatment arms

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Body Weight Baseline to Week 24	-7.93 kg Standard Deviation 6.59	-0.15 kg Standard Deviation 4.74
Body Weight Baseline to Week 48	-6.53 kg Standard Deviation 7.36	-5.65 kg Standard Deviation 8.90
Body Weight Week 24 to Week 48	1.40 kg Standard Deviation 4.05	-5.50 kg Standard Deviation 6.20

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Population: Modified Intention-to-treat (mITT) Population: all subjects who entered Part 2 (open-label extension) and had nonmissing baseline assessments and at least 1 post-Part 1 assessment.

Change in body fat mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Body Composition - Fat Mass Baseline to Week 24	-5.31 kg Standard Deviation 5.34	-1.04 kg Standard Deviation 3.75
Body Composition - Fat Mass Baseline to Week 48	-4.87 kg Standard Deviation 5.31	-3.77 kg Standard Deviation 5.81
Body Composition - Fat Mass Week 24 to Week 48	0.44 kg Standard Deviation 3.50	-2.73 kg Standard Deviation 3.37

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Population: Modified Intention-to-treat (mITT) Population: all subjects who entered Part 2 (open-label extension) and had nonmissing baseline assessments and at least 1 post-Part 1 assessment.

Change in lean body mass as measured in kg by DXA scan measured at baseline, week 24 and week 48 for each of the two treatment arms. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Body Composition - Lean Body Mass Baseline to Week 24	-2.85 kg Standard Deviation 1.88	0.55 kg Standard Deviation 1.32
Body Composition - Lean Body Mass Baseline to Week 48	-1.81 kg Standard Deviation 2.18	-1.87 kg Standard Deviation 3.36
Body Composition - Lean Body Mass Week 24 to Week 48	1.04 kg Standard Deviation 1.18	-2.42 kg Standard Deviation 3.51

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Population: Modified Intention-to-treat (mITT) Population: all subjects who entered Part 2 (open-label extension) and had nonmissing baseline assessments and at least 1 post-Part 1 assessment.

Change in HbA1c from baseline to week 24, baseline to week 48 and week 24 to week 48 for each of the two treatment arms. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Glycemic Control - HbA1c Week 24 to Week 48	0.67 mmol/mol Standard Deviation 1.30	0.00 mmol/mol Standard Deviation 0.63
Glycemic Control - HbA1c Baseline to Week 24	-6.00 mmol/mol Standard Deviation 15.39	-0.17 mmol/mol Standard Deviation 2.40
Glycemic Control - HbA1c Baseline to Week 48	-5.33 mmol/mol Standard Deviation 14.79	-0.17 mmol/mol Standard Deviation 2.23

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Population: Modified Intention-to-treat (mITT) Population: all subjects who entered Part 2 (open-label extension) and had nonmissing baseline assessments and at least 1 post-Part 1 assessment.

Change in fasting plasma glucose from baseline to week 24, baseline to week 48 and week 24 to week 48 measured at each visit for each of the two treatments arms. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Glycemic Control - Fasting Plasma Glucose Baseline to Week 24	-0.29 mmol/L Standard Deviation 0.64	-0.28 mmol/L Standard Deviation 0.57
Glycemic Control - Fasting Plasma Glucose Baseline to Week 48	-0.11 mmol/L Standard Deviation 0.53	0.08 mmol/L Standard Deviation 0.37
Glycemic Control - Fasting Plasma Glucose Week 24 to Week 48	0.18 mmol/L Standard Deviation 0.46	0.37 mmol/L Standard Deviation 0.59

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in craving for something sweet, salty, meat/fish, or fatty by the use of visual analogue scales (VAS) from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The VAS consisted of a 100-mm horizontal line; subjects placed a vertical line on the VAS to indicate the level of intensity of their food craving. The VAS value is the distance in mm (0-100 mm) from the left end of the line to the subject's vertical line (higher value represents less craving). mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something sweet from baseline to week 24	9.0 score on a scale Standard Deviation 36.6	16.2 score on a scale Standard Deviation 30.8
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something sweet from baseline to week 48	2.1 score on a scale Standard Deviation 35.8	35.3 score on a scale Standard Deviation 32.9
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something sweet from week 24 to week 48	-6.9 score on a scale Standard Deviation 20.2	19.2 score on a scale Standard Deviation 30.7
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something salty from baseline to week 24	-2.3 score on a scale Standard Deviation 27.9	13.2 score on a scale Standard Deviation 21.5
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something salty from baseline to week 48	-3.4 score on a scale Standard Deviation 28.8	33.3 score on a scale Standard Deviation 30.9
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something salty from week 24 to week 48	-1.2 score on a scale Standard Deviation 8.5	20.2 score on a scale Standard Deviation 22.7
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for meat/fish from baseline to week 24	7.3 score on a scale Standard Deviation 42.6	8.8 score on a scale Standard Deviation 34.0
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for meat/fish from baseline to week 48	14.0 score on a scale Standard Deviation 44.1	35.0 score on a scale Standard Deviation 34.6
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for meat/fish from week 24 to week 48	6.8 score on a scale Standard Deviation 18.6	26.2 score on a scale Standard Deviation 34.2
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something fatty from baseline to week 24	18.2 score on a scale Standard Deviation 22.6	2.2 score on a scale Standard Deviation 11.3
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something fatty from baseline to week 48	5.2 score on a scale Standard Deviation 25.7	22.5 score on a scale Standard Deviation 26.3
Craving for Something Sweet, Salty, Meat/Fish, or Fatty Desire for something fatty from week 24 to week 48	-13.0 score on a scale Standard Deviation 15.6	20.3 score on a scale Standard Deviation 28.0

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in thirst by the use of a visual analog scale (VAS) from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The VAS consisted of a 100-mm horizontal line; subjects placed a vertical line on the VAS to indicate the level of intensity of their thirst. The VAS value is the distance in mm (0-100 mm) from the left end of the line to the subject's vertical line (higher value represents an increase in perception of thirst). mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Thirst From baseline to week 24	-2.4 score on a scale Standard Deviation 28.9	-18.8 score on a scale Standard Deviation 23.2
Thirst From baseline to week 48	-6.3 score on a scale Standard Deviation 25.8	-16.7 score on a scale Standard Deviation 18.8
Thirst From week 24 to week 48	-3.8 score on a scale Standard Deviation 16.5	2.2 score on a scale Standard Deviation 20.5

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in waist circumference from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Waist Circumference From baseline to week 24	-7.08 cm Standard Deviation 6.93	-1.17 cm Standard Deviation 4.40
Waist Circumference From baseline to week 48	-5.75 cm Standard Deviation 5.26	-3.00 cm Standard Deviation 6.51
Waist Circumference From week 24 to week 48	1.33 cm Standard Deviation 4.01	-1.83 cm Standard Deviation 2.64

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in lipid profile from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Lipid Profile Change in total cholesterol from baseline to week 24	-0.17 mmol/L Standard Deviation 0.46	-0.17 mmol/L Standard Deviation 0.45
Lipid Profile Change in total cholesterol from baseline to week 48	-0.01 mmol/L Standard Deviation 0.60	-0.22 mmol/L Standard Deviation 0.75
Lipid Profile Change in total cholesterol from week 24 to week 48	0.16 mmol/L Standard Deviation 0.48	-0.05 mmol/L Standard Deviation 0.69
Lipid Profile Change in HDL cholesterol from baseline to week 24	0.04 mmol/L Standard Deviation 0.21	-0.02 mmol/L Standard Deviation 0.37
Lipid Profile Change in HDL cholesterol from baseline to week 48	0.09 mmol/L Standard Deviation 0.26	0.03 mmol/L Standard Deviation 0.25
Lipid Profile Change in HDL cholesterol from week 24 to week 48	0.05 mmol/L Standard Deviation 0.24	0.05 mmol/L Standard Deviation 0.16
Lipid Profile Change in LDL cholesterol from baseline to week 24	-0.23 mmol/L Standard Deviation 0.39	-0.20 mmol/L Standard Deviation 0.43
Lipid Profile Change in LDL cholesterol from baseline to week 48	-0.15 mmol/L Standard Deviation 0.38	-0.32 mmol/L Standard Deviation 0.53
Lipid Profile Change in LDL cholesterol from week 24 to week 48	0.08 mmol/L Standard Deviation 0.28	-0.12 mmol/L Standard Deviation 0.45
Lipid Profile Change in triglycerides from baseline to week 24	-0.08 mmol/L Standard Deviation 0.77	-0.30 mmol/L Standard Deviation 0.76
Lipid Profile Change in triglycerides from baseline to week 48	-0.07 mmol/L Standard Deviation 0.77	-0.48 mmol/L Standard Deviation 0.28
Lipid Profile Change in triglycerides from week 24 to week 48	0.01 mmol/L Standard Deviation 0.69	-0.18 mmol/L Standard Deviation 0.66

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in quality of life by use of the Short Form 36 Health Survey (SF-36) scores from baseline to week 24, from baseline to week 48, and from week 24 to week 48 The physical component summary score includes the aggregated scores for scales of physical functioning, role-physical, bodily pain, and general health. The mental health component summary score includes the aggregated scores for scales of vitality, social functioning, role-emotional, and mental health. Scores range from 0 to 100; higher score indicates better health. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Quality of Life - SF-36 Physical component from baseline to week 24	0.90 score on a scale Standard Deviation 7.59	1.36 score on a scale Standard Deviation 3.74
Quality of Life - SF-36 Physical component from baseline to week 48	0.70 score on a scale Standard Deviation 5.98	2.41 score on a scale Standard Deviation 4.82
Quality of Life - SF-36 Physical component from week 24 to week 48	-0.21 score on a scale Standard Deviation 6.80	1.05 score on a scale Standard Deviation 3.64
Quality of Life - SF-36 Mental component from baseline to week 24	-3.08 score on a scale Standard Deviation 11.44	-0.49 score on a scale Standard Deviation 2.02
Quality of Life - SF-36 Mental component from baseline to week 48	-1.46 score on a scale Standard Deviation 7.74	0.49 score on a scale Standard Deviation 1.74
Quality of Life - SF-36 Mental component from week 24 to week 48	1.62 score on a scale Standard Deviation 11.46	0.98 score on a scale Standard Deviation 2.29

SECONDARY outcome

Timeframe: from week 24 to week 48

Population: One subject was excluded from safety analysis (in the Tesofensine/Metoprolol -\> Tesofensine/Metoprolol arm) since subject discontinued Tesomet treatment in Part 1 but continued in Part 2 without being dosed.

Number of participants with adverse event(s) and/or serious adverse event(s) reported from week 24 to week 48

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=11 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Infections and infestations	6 Participants	4 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Gastrointestinal disorders	5 Participants	3 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Musculoskeletal and connective tissue disorders	7 Participants	1 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Nervous system disorders	3 Participants	4 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension General disorders and administration site conditions	4 Participants	0 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Psychiatric disorders	2 Participants	2 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Cardiac disorders	0 Participants	3 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Injury, poisoning and procedural complications	1 Participants	1 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Vascular disorders	0 Participants	2 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Blood and lymphatic system disorders	1 Participants	0 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Investigations	1 Participants	0 Participants
Number of Participants With Adverse Event(s) and/or Serious Adverse Event(s) - Open-label Extension Respiratory, thoracic and mediastinal disorders	1 Participants	0 Participants

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in blood pressure from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Blood Pressure (Change) Change in Systolic BP from baseline to week 24	2.0 mmHg Standard Deviation 13	-4.2 mmHg Standard Deviation 8
Blood Pressure (Change) Change in Systolic BP from baseline to week 48	5.8 mmHg Standard Deviation 14	-9.7 mmHg Standard Deviation 13
Blood Pressure (Change) Change in Systolic BP from week 24 to wek 48	5.0 mmHg Standard Deviation 11	-5.5 mmHg Standard Deviation 14
Blood Pressure (Change) Change in Diastolic BP from baseline to week 24	2.8 mmHg Standard Deviation 11	-2.0 mmHg Standard Deviation 11
Blood Pressure (Change) Change in Diastolic BP from baseline to week 48	6.5 mmHg Standard Deviation 12	-1.0 mmHg Standard Deviation 13
Blood Pressure (Change) Change in Diastolic BP from week 24 to week 48	4.2 mmHg Standard Deviation 9	1.0 mmHg Standard Deviation 10

SECONDARY outcome

Timeframe: from baseline to week 12 and baseline to week 24

Population: Number of participants analyzed: Tesofensine/Metoprolol - Baseline/Week 12/Week 24: 14/12/9 Placebo - Baseline/Week 12/Week24: 8/6/5

Changes in 24 hours blood pressure from baseline to week 12 and baseline to week 24

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
24 Hours Blood Pressure Diastolic BP mean change from baseline to week 12	0.2 mmHg Standard Deviation 9	3.7 mmHg Standard Deviation 8
24 Hours Blood Pressure Systolic BP mean change from baseline to week 12	-8.0 mmHg Standard Deviation 20	0.7 mmHg Standard Deviation 14
24 Hours Blood Pressure Systolic BP mean change from baseline to week 24	2.3 mmHg Standard Deviation 20	-8.4 mmHg Standard Deviation 17
24 Hours Blood Pressure Diastolic BP mean change from baseline to week 24	3.7 mmHg Standard Deviation 8	-2.8 mmHg Standard Deviation 9

SECONDARY outcome

Timeframe: baseline to week 48

Population: The Placebo -\> Tesofensine/Metoprolol group did not start treatment before week 25

Plasma trough concentrations of tesofensine, metabolite NS2360 and metoprolol for the active arm (the first 24 weeks and then continuously up to week 48) and placebo arm (start of treatment at week 25 and then continuously up to week 48). mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=11 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Plasma Trough Concentrations Metoprolol Week 48	7.29 μg/L Geometric Coefficient of Variation 156.9	7.30 μg/L Geometric Coefficient of Variation 578.8
Plasma Trough Concentrations Tesofensine Week 12	12.03 μg/L Geometric Coefficient of Variation 38.6	—
Plasma Trough Concentrations Tesofensine Week 24	12.34 μg/L Geometric Coefficient of Variation 55.4	—
Plasma Trough Concentrations Tesofensine Week 36	11.01 μg/L Geometric Coefficient of Variation 54.4	19.10 μg/L Geometric Coefficient of Variation 56.1
Plasma Trough Concentrations Tesofensine Week 48	6.78 μg/L Geometric Coefficient of Variation 394.7	15.11 μg/L Geometric Coefficient of Variation 70.2
Plasma Trough Concentrations NS2360 metab. Week 12	3.39 μg/L Geometric Coefficient of Variation 48.5	—
Plasma Trough Concentrations NS2360 metab. Week 24	3.96 μg/L Geometric Coefficient of Variation 71.9	—
Plasma Trough Concentrations NS2360 metab. Week 36	3.39 μg/L Geometric Coefficient of Variation 57.1	6.51 μg/L Geometric Coefficient of Variation 56.3
Plasma Trough Concentrations NS2360 metab. Week 48	2.44 μg/L Geometric Coefficient of Variation 157.3	6.02 μg/L Geometric Coefficient of Variation 67.7
Plasma Trough Concentrations Metoprolol Week 12	10.83 μg/L Geometric Coefficient of Variation 120.8	—
Plasma Trough Concentrations Metoprolol Week 24	9.07 μg/L Geometric Coefficient of Variation 281.4	—
Plasma Trough Concentrations Metoprolol Week 36	8.97 μg/L Geometric Coefficient of Variation 309.6	10.62 μg/L Geometric Coefficient of Variation 206.0

SECONDARY outcome

Timeframe: baseline, week 12 and week 24

Population: 21 sub. were assign. 22 randomization no. 1 sub. was screen failure received 1 dose of Tesomet prior to being withdrawn at baseline. Sub. was re-screened and randomized as new sub. receiving PBO. As this sub. was assigned 2 randomization no., 1 under each arm, the sub. is summarized for both arms. The 2 randomization no. are considered as 2 sub. 14 sub. were randomized to receive Tesomet and 8 sub. received PBO. 4 sub. (2 Tesomet, 2 PBO) terminated study before end of 24W DB period.

For Part 1, 48 hours HR and QT interval from week 12 to week 24 were not recorded in the database and analysis of changes not evaluated. Instead, abnormal findings over visits were summarized. Abnormal ECG findings detected in the three Tesomet treated subjects are: * QTc prolongation (466 ms) * Bradycardia (56 bpm) * QTc prolongation (460 ms) All were considered not clinically significant.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=14 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation baseline · Normal	14 Participants	8 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation baseline · Abnormal	0 Participants	0 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation at week 12 · Normal	9 Participants	6 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation at week 12 · Abnormal	3 Participants	0 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation at week 24 · Normal	11 Participants	6 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 ECG interretation at week 24 · Abnormal	1 Participants	0 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at baseline · Normal	13 Participants	8 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at baseline · Abnormal	0 Participants	0 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at week 12 · Normal	10 Participants	6 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at week 12 · Abnormal	2 Participants	0 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at week 24 · Normal	12 Participants	6 Participants
48 Hours Heart Rate and QT Interval at Baseline, Week 12 and Week 24 48 hour heart rate at week 24 · Abnormal	0 Participants	0 Participants

SECONDARY outcome

Timeframe: from baseline to week 24, from baseline to week 48 and from week 24 to week 48

Change in heart rate from baseline to week 24, from baseline to week 48, and from week 24 to week 48. mITT observed values.

Outcome measures

Outcome measures
Measure	Tesofensine/Metoprolol n=12 Participants Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=6 Participants Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.
Heart Rate (Change) Change in Heart Rate from baseline to week 24	-2.4 bpm Standard Deviation 11	-7.0 bpm Standard Deviation 12
Heart Rate (Change) Change in Heart Rate from baseline to week 48	0.1 bpm Standard Deviation 7	0.7 bpm Standard Deviation 20
Heart Rate (Change) Change in Heart Rate from week 24 to week 48	4.2 bpm Standard Deviation 8	7.7 bpm Standard Deviation 10

Adverse Events

Tesofensine/Metoprolol

Serious events: 2 serious events

Other events: 12 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 7 other events

Deaths: 0 deaths

Tesofensine/Metoprolol -> Tesofensine/Metoprolol

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo -> Tesofensine/Metoprolol

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tesofensine/Metoprolol n=14 participants at risk Subjects were randomized to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1.	Placebo n=8 participants at risk Subjects were randomized to receive matching placebo tablets once daily for 24 weeks during Part 1.	Tesofensine/Metoprolol -> Tesofensine/Metoprolol n=11 participants at risk Subjects who received co-administration of 0.5 mg tesofensine/50 mg metoprolol (active medication) once daily for 24 weeks during Part 1 continued to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.	Placebo -> Tesofensine/Metoprolol n=6 participants at risk Subjects who received matching placebo tablets once daily for 24 weeks during Part 1 were switched to receive co-administration of 0.5 mg tesofensine/50 mg metoprolol once daily for an additional 24 weeks in Part 2.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/14 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/8 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	9.1% 1/11 • Number of events 1 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/6 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.
Injury, poisoning and procedural complications Post procedural complication	7.1% 1/14 • Number of events 1 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/8 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/11 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/6 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/14 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	12.5% 1/8 • Number of events 1 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/11 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/6 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Craniopharyngioma	7.1% 1/14 • Number of events 1 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/8 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/11 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/6 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.
Psychiatric disorders Anxiety	7.1% 1/14 • Number of events 1 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/8 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/11 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.	0.00% 0/6 • Part 1 (double-blind part): From the first dose of double-blind study drug during Part 1 until the last dose during Part 1 (24 weeks duration). Part 2 (open-label extension part): From the first dose of open-label study drug during Part 2 until the last dose during Part 2 (24 weeks duration). Part 1: Safety Analysis Set included all subjects who took at least 1 dose of study drug (active substances or matching placebos). Part 2: Safety Analysis Set included all subjects who took at least 1 dose of study drug in the open-label extension (active substances or matching placebos); 1 subject continued in Part 2 without being dosed and was therefore excluded from the Safety Analysis Set.

Other adverse events

Additional Information

Janus Schreiber Larsen

Saniona A/S

Phone: 7070 5225

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place