Diabetes, Diabetes Mellitus, Type 2, Healthy
Conditions
Brief summary
This trial is conducted in the United States of America (USA). The aim of this trial is to investigate the safety, tolerability and pharmacokinetics (exposure in the body) of liraglutide-depot in healthy subjects.
Interventions
DRUGliraglutide-depot
Subjects will be randomised to receive a single dose of liraglutide-depot, at increasing dose levels, injected s.c./subcutaneously (under the skin). Progression to next dose level (max. 8) will be based on safety evaluation.
DRUGplacebo
Subjects will be randomised to receive a single dose of liraglutide-depot placebo, at increasing dose levels, injected s.c./subcutaneously (under the skin).
Sponsors
Novo Nordisk A/S
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Body mass index (BMI) between 20 and 35 kg/m\^2 (both inclusive) with a body weight of at least 60 kg * Apart from being obese (BMI above 30 kg/m\^2) the subject has to be considered generally healthy
Exclusion criteria
* Medical history of, or presence of, cancer, diabetes or any clinically significant cardiovascular, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrine, haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders * Clinical or laboratory findings which suggest that the subject cannot be considered generally healthy * Prescription medicine and non-prescription medicine with few exceptions * Current and prior history of alcohol or drug abuse * Current smoking of more than 5 cigarettes per day * Mental incapacity, language barriers, or unwillingness to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Emergent Adverse Events (TEAEs) | Day 0 and up to 21 days after treatment | TEAEs: AEs from 1st exposure (exp) until follow-up (FU) or AEs with onset before 1st exp increasing in severity up to the FU. Mild AEs: no or transient symptoms, no interference (inf) with subject's daily activities. Moderate AEs: marked symptoms, moderate inf with subject's daily activities. Severe AEs: considerable inf with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in death/ a life-threatening experience/ in-subject hospitalization/prolongation of existing hospitalisation; or persistent/significant disability/incapacity/congenital anomaly/birth defect. |
Secondary
| Measure | Time frame |
|---|---|
| Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose |
| Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity | Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose |
| Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose |
| Area Under the Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects With Liraglutide 6 mg/ml Pre-treatment | 0 to 168 hours after dosing |
| Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Day 0 and Day 21 |
| Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment | 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168 hours post dose |
Countries
United States
Participant flow
Recruitment details
The trial was conducted at one site in Evansville, Indiana, USA.
Pre-assignment details
It was a Novo Nordisk business decision, and not a decision due to safety concerns, not to continue the development of liraglutide depot. Therefore cohorts with liraglutide pre-treatment were not initiated based on review of pharmacokinetic data, and hence no analysis was done. So no subjects were enrolled for the outcome measure 6.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1a: Lira-depot 2.25 mg In cohort 1a a single subcutaneous dose of 2.25 mg liraglutide-depot was administered. | 6 |
| Cohort 2a: Lira-depot 6.75 mg In cohort 2a a single subcutaneous dose of 6.75 mg liraglutide-depot was administered. | 6 |
| Cohort 3a: Lira-depot 15 mg In cohort 3a a single subcutaneous dose of 15 mg liraglutide-depot was administered. | 6 |
| Cohort 4a: Lira-depot 30 mg In cohort 4a a single subcutaneous dose of 30 mg liraglutide-depot was administered. | 5 |
| Placebo In the placebo group a corresponding volume of liraglutide-depot placebo was administered subcutaneous (s.c.). | 8 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Other | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1a: Lira-depot 2.25 mg | Cohort 2a: Lira-depot 6.75 mg | Cohort 3a: Lira-depot 15 mg | Cohort 4a: Lira-depot 30 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 39.8 years STANDARD_DEVIATION 11.4 | 30.0 years STANDARD_DEVIATION 12.6 | 29.8 years STANDARD_DEVIATION 7.7 | 39.0 years STANDARD_DEVIATION 8.4 | 28.5 years STANDARD_DEVIATION 7.9 | 32.9 years STANDARD_DEVIATION 10.3 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 8 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 6 | 3 / 6 | 3 / 6 | 5 / 5 | 5 / 8 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 8 |
Outcome results
Primary
Number of Treatment Emergent Adverse Events (TEAEs)
TEAEs: AEs from 1st exposure (exp) until follow-up (FU) or AEs with onset before 1st exp increasing in severity up to the FU. Mild AEs: no or transient symptoms, no interference (inf) with subject's daily activities. Moderate AEs: marked symptoms, moderate inf with subject's daily activities. Severe AEs: considerable inf with subject's daily activities, unacceptable. Serious AE: AE that at any dose results in death/ a life-threatening experience/ in-subject hospitalization/prolongation of existing hospitalisation; or persistent/significant disability/incapacity/congenital anomaly/birth defect.
Time frame: Day 0 and up to 21 days after treatment
Population: The safety analysis set includes all subjects who were exposed to at least one dose of trial product. Subjects in the safety analysis set contribute to the evaluation 'as treated'.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Total adverse events (AEs) | 3 events |
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Serious AE | 0 events |
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Severe AE | 0 events |
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate AE | 0 events |
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Mild AE | 3 events |
| Cohort 1a: Lira-depot 2.25 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Fatal AE | 0 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Mild AE | 3 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Fatal AE | 0 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Total adverse events (AEs) | 3 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Severe AE | 0 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate AE | 0 events |
| Cohort 2a: Lira-depot 6.75 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Serious AE | 0 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate AE | 0 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Mild AE | 4 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Total adverse events (AEs) | 4 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Severe AE | 0 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Serious AE | 0 events |
| Cohort 3a: Lira-depot 15 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Fatal AE | 0 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate AE | 9 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Serious AE | 0 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Severe AE | 1 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Fatal AE | 0 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Mild AE | 11 events |
| Cohort 4a: Lira-depot 30 mg | Number of Treatment Emergent Adverse Events (TEAEs) | Total adverse events (AEs) | 21 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Mild AE | 12 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Severe AE | 0 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Serious AE | 0 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Fatal AE | 0 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Moderate AE | 1 events |
| Placebo | Number of Treatment Emergent Adverse Events (TEAEs) | Total adverse events (AEs) | 13 events |
Secondary
Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment
Time frame: 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168 hours post dose
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment. 1 subject was not included for this evaluation in the cohort 1a arm due to insufficient data. Cohorts with liraglutide pre-treatment were not initiated based on review of pharmacokinetic data, and hence no analysis was done.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment | 37298 pmol.h/L | Geometric Coefficient of Variation 27 |
| Cohort 2a: Lira-depot 6.75 mg | Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment | 114101 pmol.h/L | Geometric Coefficient of Variation 20 |
| Cohort 3a: Lira-depot 15 mg | Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment | 316642 pmol.h/L | Geometric Coefficient of Variation 46 |
| Cohort 4a: Lira-depot 30 mg | Area Under the Liraglutide Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects Without Liraglutide 6 mg/ml Pre-treatment | 1363187 pmol.h/L | Geometric Coefficient of Variation 21 |
Secondary
Area Under the Plasma Concentration Curve in the First Week Following Liraglutide-depot Administration for Subjects With Liraglutide 6 mg/ml Pre-treatment
Time frame: 0 to 168 hours after dosing
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment. Cohorts with liraglutide pre-treatment were not initiated based on review of pharmacokinetic data, and hence no analysis was done.
Secondary
Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity
Time frame: Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment. 1 subject was not included for this evaluation in the cohort 1a arm due to insufficient data. This evaluation was not done on placebo cohort.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity | 43840 pmol.h/L | Geometric Coefficient of Variation 24 |
| Cohort 2a: Lira-depot 6.75 mg | Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity | 116935 pmol.h/L | Geometric Coefficient of Variation 20 |
| Cohort 3a: Lira-depot 15 mg | Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity | 360000 pmol.h/L | Geometric Coefficient of Variation 46 |
| Cohort 4a: Lira-depot 30 mg | Area Under the Plasma Concentration Curve in the Period From the Time of Liraglutide-depot Administration to Infinity | 1443038 pmol.h/L | Geometric Coefficient of Variation 22 |
Secondary
Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot
Time frame: Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment. This evaluation was not done on placebo cohort.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 690 pmol/L | Geometric Coefficient of Variation 52 |
| Cohort 2a: Lira-depot 6.75 mg | Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 2141 pmol/L | Geometric Coefficient of Variation 25 |
| Cohort 3a: Lira-depot 15 mg | Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 6977 pmol/L | Geometric Coefficient of Variation 62 |
| Cohort 4a: Lira-depot 30 mg | Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 40041 pmol/L | Geometric Coefficient of Variation 35 |
Secondary
Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up
Time frame: Day 0 and Day 21
Population: The safety analysis set includes all subjects who were exposed to at least one dose of trial product. Subjects in the safety analysis set contribute to the evaluation 'as treated'.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Positive | 0 participants |
| Cohort 1a: Lira-depot 2.25 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Negative | 6 participants |
| Cohort 2a: Lira-depot 6.75 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Negative | 6 participants |
| Cohort 2a: Lira-depot 6.75 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Positive | 0 participants |
| Cohort 3a: Lira-depot 15 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Positive | 0 participants |
| Cohort 3a: Lira-depot 15 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Negative | 6 participants |
| Cohort 4a: Lira-depot 30 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Positive | 0 participants |
| Cohort 4a: Lira-depot 30 mg | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Negative | 5 participants |
| Placebo | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Negative | 8 participants |
| Placebo | Number of Subjects With Antibodies (Positive) or Without Antibodies (Negative) Against Liraglutide Observed at Pre-dose and at Last Follow-up | Positive | 0 participants |
Secondary
Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot
Time frame: Day 0 through day 21 at 1,3,6,12,18, 24, 36, 48, 72, 96, 120, 168, 336, 504 hours post dose
Population: Full analysis set consisted of all subjects who were randomised and exposed to randomised treatment. This evaluation was not done on placebo cohort.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1a: Lira-depot 2.25 mg | Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 15.13 hours | Geometric Coefficient of Variation 92.28 |
| Cohort 2a: Lira-depot 6.75 mg | Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 8.09 hours | Geometric Coefficient of Variation 55.78 |
| Cohort 3a: Lira-depot 15 mg | Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 13.74 hours | Geometric Coefficient of Variation 22.13 |
| Cohort 4a: Lira-depot 30 mg | Time to Maximum Plasma Concentration of Liraglutide After a Single Dose of Liraglutide-depot | 10.46 hours | Geometric Coefficient of Variation 24.62 |