Obesity
Conditions
Brief summary
This study was being done to assess the stomach emptying effect of a maximum dose of 3 mg Liraglutide compared to placebo in subjects who are overweight or obese. Liraglutide is a medication approved by the Food and Drug Administration (FDA) for routine clinical use.
Detailed description
The objective of this study was to compare effects of liraglutide and placebo over 16 weeks on gastric motor functions, satiation, satiety and weight in obese patients. Subjects were randomized to liraglutide or placebo. Liraglutide or placebo was escalated by 0.6mg/day each week for 5 weeks and continued until week 16. At baseline and after 16 weeks' treatment, the investigators measured weight, gastric emptying of solids (GES), gastric volumes, satiation (maximum tolerated volume of liquid nutrient drink), and satiety. GES was also measured at 5 weeks. During the study, the subjects received standardized dietetic and behavioral advice for weight reduction therapy. All subjects were given a standard text for information and met with a behavioral psychologist who has expertise in obesity treatment at the baseline visit and at visits at weeks 4,8, and 12. Additionally, the subjects had brief contact with a member of the study team every 4 weeks to inquire about their adherence to study protocol, any difficulties they were experiencing, whether they were reading their text assignments, and to answer any additional questions.
Interventions
DRUGLiraglutide
Initiate at 0.6mg S.C. daily for 1 week; subjects will return to the Clinical Research Unit (CRU) each week until an increase by 0.6mg/day in weekly intervals to a dose of 3.0 mg/day is achieved (\ 4 weeks). Once maintenance dose of 3.0 mg is achieved, subjects will return approximately every 4 weeks to obtain new supply of study medication.
DRUGPlacebo
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Novo Nordisk A/S
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Overweight and obese adults (≥30 kg/m\^2 or ≥27 kg/m\^2 with an obesity-related co-morbidity). * Subjects residing within 125 miles of Mayo Clinic in Rochester, Minnesota. * Healthy individuals with no unstable psychiatric disease and not currently on treatment for cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, neurological, or endocrine (other than hyperglycemia type 2 diabetes mellitus on metformin) disorders. * Women of childbearing potential will be using an effective form of contraception, and have negative pregnancy tests within 48 hours of enrolment and before each radiation exposure. * Subjects must have the ability to provide informed consent before any trial-related activities.
Exclusion criteria
* Weight exceeding 137 kilograms (safety limit of camera for measuring gastric volumes). * Abdominal surgery other than appendectomy, Caesarian section or tubal ligation. * Positive history of chronic gastrointestinal diseases, systemic disease that could affect gastrointestinal motility, or use of medications that may alter gastrointestinal motility, appetite or absorption, e.g., orlistat. * Patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia-type 2. * Patients with a personal history of pancreatitis (acute or chronic) * Significant untreated psychiatric dysfunction based upon screening with the Hospital Anxiety and Depression Inventory, a self-administered alcoholism screening test (AUDIT-C), and the Questionnaire on Eating and Weight Patterns (binge eating disorders and bulimia). If such a dysfunction is identified by a Hospital Anxiety Depression (HAD) score \>8 or difficulties with substance or eating disorders, the participant will be excluded and given a referral letter to his/her primary care doctor for further appraisal and follow-up. * Intake of medication, whether prescribed or over the counter (except multivitamins), within 7 days of the study. Exceptions are birth control pill, estrogen replacement therapy, thyroxin replacement therapy and any medication administered for co-morbidities as long as they do not alter gastrointestinal motility including gastric emptying (GE) and gastric accommodation. For example, statins for hyperlipidemia, diuretics, β-adrenergic blockers,Angiotensin Converting Enzyme (ACE) inhibitors and angiotensin antagonists for hypertension, and metformin for type 2 diabetes mellitus or prediabetes are permissible. In contrast, resin sequestrants for hyperlipidemia \[which may reduce GE and reduce appetite, α2-adrenergic agonists for hypertension, or other glucagon-like peptide-1 receptor agonists (GLP-1) receptor agonists (exenatide) or amylin analogs (pramlintide) are not permissible because they significantly affect GE and/or gastric accommodation. * Hypersensitivity to the study medication, liraglutide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying of Solids Half-time (T1/2) at 5 Weeks | 5 weeks | Gastric emptying of solids was assessed by scintigraphy using a 320 Kcal 99mTc-radiolabeled egg, solid-liquid meal. Gastric Emptying Half-time was the linear interpretation of time to when 50% of radiolabeled meal emptied from the stomach. |
| Gastric Emptying of Solids Half-time (T1/2) at 16 Weeks | 16 weeks | Gastric emptying of solids was assessed by scintigraphy using a 320 Kcal 99mTc-radiolabeled egg, solid-liquid meal. Gastric Emptying Half-time was the linear interpretation of time to when 50% of radiolabeled meal emptied from the stomach. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Satiety by Buffet Meal, Total Calories Ingested at 16 Weeks | 16 weeks | Satiety (a measure of appetite) was appraised by free feeding buffet meal consisting of standard foods of known nutrient composition. The total amount of food consumed was analyzed by the study dietitian. |
| Satiation Volume to Fullness at 16 Weeks | 16 weeks | After drinking Ensure, participants recorded their sensations every 5 minutes using a numerical scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal and level 5 corresponding to the maximal tolerated volume (maximum or unbearable fullness/satiation). |
| Satiation Maximum Tolerated Volume at 16 Weeks | 16 weeks | After drinking Ensure, participants recorded their sensations every 5 minutes using a numerical scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal and level 5 corresponding to the maximal tolerated volume (maximum or unbearable fullness/satiation). |
| Weight Change at 5 Weeks | baseline, 5 weeks | Body weight in kg was measured at 5 weeks and compared to baseline. |
| Gastric Postprandial Volume at 16 Weeks | 16 weeks | Gastric fasting volume was measured by single photon emission computed tomography (SPECT) imaging of the stomach after intravenous injection of 99mTC-pertechnetate, which is taken up by the gastric mucosa. |
| Gastric Accommodation Volume at 16 Weeks | 16 weeks (approximately 1 hour after 99mTC injection) | Change between postprandial and fasting whole gastric volume by 99mTc-SPECT Imaging. A noninvasive SPECT method was used to measure gastric volume during fasting and 32 min after a liquid nutritional supplement meal. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. The first fasting scan was obtained, and the study medication was given s.c. After 10 min, a 2nd fasting post medication scan was obtained, and the meal consumed; then two serial postprandial scans were obtained. Each scan required 9-12 min. Tomographic images of the gastric wall were obtained throughout the long axis of the stomach using a dual-head gamma camera that rotates around the body. This allows assessment of the radiolabeled circumference of the gastric wall, rather than the intragastric content. |
| Gastric Fasting Volume at 16 Weeks | 16 weeks | Gastric fasting volume was measured by single photon emission computed tomography (SPECT) imaging of the stomach after intravenous injection of 99mTC-pertechnetate, which is taken up by the gastric mucosa. |
| Weight Change at 16 Weeks | baseline, 16 weeks | Body weight in kg was measured at 16 weeks and compared to baseline. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between December 18, 2015 and September 1, 2016 at the Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Saxenda initiated at 0.6mg S.C. daily for 1 week; subjects will return to the Clinical Research Unit (CRU) each week until an increase by 0.6 mg/day in weekly intervals to a dose of 3.0 mg/day is achieved. Once maintenance dose of 3.0 mg is achieved, subjects will return approximately every 4 weeks to obtain new supply of study medication. | 19 |
| Placebo Placebo initiated at 0.6mg S.C. daily for 1 week; subjects will return to the Clinical Research Unit (CRU) each week until an increase by 0.6 mg/day in weekly intervals to a dose of 3.0 mg/day is achieved. Once maintenance dose of 3.0 mg is achieved, subjects will return approximately every 4 weeks to obtain new supply of study medication. | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Liraglutide |
|---|---|---|---|
| Age, Continuous | 37.81 years STANDARD_DEVIATION 12.14 | 39.30 years STANDARD_DEVIATION 11.61 | 40.95 years STANDARD_DEVIATION 11.08 |
| Body Mass Index (BMI) | 34.6 kg/m^2 | 36.65 kg/m^2 | 37.2 kg/m^2 |
| Body Weight | 99.1 kg | 103 kg | 103.7 kg |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 19 Participants | 36 Participants | 17 Participants |
| Region of Enrollment United States | 21 Participants | 40 Participants | 19 Participants |
| Sex: Female, Male Female | 18 Participants | 35 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 |
| other Total, other adverse events | 17 / 19 | 14 / 21 |
| serious Total, serious adverse events | 0 / 19 | 0 / 21 |
Outcome results
Primary
Gastric Emptying of Solids Half-time (T1/2) at 16 Weeks
Gastric emptying of solids was assessed by scintigraphy using a 320 Kcal 99mTc-radiolabeled egg, solid-liquid meal. Gastric Emptying Half-time was the linear interpretation of time to when 50% of radiolabeled meal emptied from the stomach.
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Gastric Emptying of Solids Half-time (T1/2) at 16 Weeks | 142 minutes |
| Placebo | Gastric Emptying of Solids Half-time (T1/2) at 16 Weeks | 113 minutes |
Primary
Gastric Emptying of Solids Half-time (T1/2) at 5 Weeks
Gastric emptying of solids was assessed by scintigraphy using a 320 Kcal 99mTc-radiolabeled egg, solid-liquid meal. Gastric Emptying Half-time was the linear interpretation of time to when 50% of radiolabeled meal emptied from the stomach.
Time frame: 5 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Gastric Emptying of Solids Half-time (T1/2) at 5 Weeks | 180 minutes |
| Placebo | Gastric Emptying of Solids Half-time (T1/2) at 5 Weeks | 117 minutes |
Secondary
Gastric Accommodation Volume at 16 Weeks
Change between postprandial and fasting whole gastric volume by 99mTc-SPECT Imaging. A noninvasive SPECT method was used to measure gastric volume during fasting and 32 min after a liquid nutritional supplement meal. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. The first fasting scan was obtained, and the study medication was given s.c. After 10 min, a 2nd fasting post medication scan was obtained, and the meal consumed; then two serial postprandial scans were obtained. Each scan required 9-12 min. Tomographic images of the gastric wall were obtained throughout the long axis of the stomach using a dual-head gamma camera that rotates around the body. This allows assessment of the radiolabeled circumference of the gastric wall, rather than the intragastric content.
Time frame: 16 weeks (approximately 1 hour after 99mTC injection)
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Gastric Accommodation Volume at 16 Weeks | 453 mL |
| Placebo | Gastric Accommodation Volume at 16 Weeks | 433 mL |
p-value: 0.95Wilcoxon (Mann-Whitney)
Secondary
Gastric Fasting Volume at 16 Weeks
Gastric fasting volume was measured by single photon emission computed tomography (SPECT) imaging of the stomach after intravenous injection of 99mTC-pertechnetate, which is taken up by the gastric mucosa.
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Gastric Fasting Volume at 16 Weeks | 231 mL |
| Placebo | Gastric Fasting Volume at 16 Weeks | 192 mL |
p-value: 0.13Wilcoxon (Mann-Whitney)
Secondary
Gastric Postprandial Volume at 16 Weeks
Gastric fasting volume was measured by single photon emission computed tomography (SPECT) imaging of the stomach after intravenous injection of 99mTC-pertechnetate, which is taken up by the gastric mucosa.
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Gastric Postprandial Volume at 16 Weeks | 705 mL |
| Placebo | Gastric Postprandial Volume at 16 Weeks | 668 mL |
p-value: 0.68Wilcoxon (Mann-Whitney)
Secondary
Satiation Maximum Tolerated Volume at 16 Weeks
After drinking Ensure, participants recorded their sensations every 5 minutes using a numerical scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal and level 5 corresponding to the maximal tolerated volume (maximum or unbearable fullness/satiation).
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Satiation Maximum Tolerated Volume at 16 Weeks | 750 mL |
| Placebo | Satiation Maximum Tolerated Volume at 16 Weeks | 1126 mL |
p-value: 0.054Wilcoxon (Mann-Whitney)
Secondary
Satiation Volume to Fullness at 16 Weeks
After drinking Ensure, participants recorded their sensations every 5 minutes using a numerical scale from 0 to 5, with level 0 being no symptoms, level 3 corresponding to fullness sensation after a typical meal and level 5 corresponding to the maximal tolerated volume (maximum or unbearable fullness/satiation).
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Satiation Volume to Fullness at 16 Weeks | 360 mL |
| Placebo | Satiation Volume to Fullness at 16 Weeks | 600 mL |
p-value: 0.069Wilcoxon (Mann-Whitney)
Secondary
Satiety by Buffet Meal, Total Calories Ingested at 16 Weeks
Satiety (a measure of appetite) was appraised by free feeding buffet meal consisting of standard foods of known nutrient composition. The total amount of food consumed was analyzed by the study dietitian.
Time frame: 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Satiety by Buffet Meal, Total Calories Ingested at 16 Weeks | 554.0 kcal |
| Placebo | Satiety by Buffet Meal, Total Calories Ingested at 16 Weeks | 680.5 kcal |
p-value: 0.27Wilcoxon (Mann-Whitney)
Secondary
Weight Change at 16 Weeks
Body weight in kg was measured at 16 weeks and compared to baseline.
Time frame: baseline, 16 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Weight Change at 16 Weeks | 5.30 kg |
| Placebo | Weight Change at 16 Weeks | 2.5 kg |
p-value: <0.001Wilcoxon (Mann-Whitney)
Secondary
Weight Change at 5 Weeks
Body weight in kg was measured at 5 weeks and compared to baseline.
Time frame: baseline, 5 weeks
Population: Intent to treat analysis; data were imputed for the 5 participants who dropped out.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Liraglutide | Weight Change at 5 Weeks | 3.70 kg |
| Placebo | Weight Change at 5 Weeks | 0.60 kg |
p-value: <0.001Wilcoxon (Mann-Whitney)