Obesity
Conditions
Keywords
Obesity, BMI, Incretin, Satiety, Phentermine, Topiramate
Brief summary
Our overall goal is to determine the effect of Phentermine and Topiramate ER on gastric emptying, gastric accommodation, satiety, and satiation in obese participants.
Detailed description
Investigators propose a randomized controlled trial of combination phentermine topiramate ER versus placebo given orally for 10-15 days. At visit 1 subjects had a brief interview, body measurements, and completed 4 questionnaires to rule out any gastrointestinal or significant psychological distress. At visit 2 subjects did a satiation/nutrient drink test. They drank a nutrient drink until they reached the maximum volume that could be tolerated, symptoms were recorded and blood samples taken at 4 times. They were randomized to one of the arms, and received a 5 day supply of study medication or placebo. The dosing of the study drug was phentermine 3.75 mg / topiramate 23 mg days 1-5. At visit 3 subjects returned to pick up a nine day supply of study medication or placebo. The dosing of the study drug was increased to phentermine 7.5 mg / topiramate 46 mg days 6-14. At visit 4 subjects underwent imaging to measure the volume of their stomach with an external camera that revolved around abdomen while they were lying on a table. Stomach volume was checked during fasting, starting 10 min after an intravenous injection of a radioactive material. The subjects ingested more of the liquid nutrient drink and 2 more images were obtained over 30 minutes. On the same day, subjects participated in an all you can eat meal, starting 4 hours after the ingestion of the liquid nutrient drink. At visit 5 subjects repeated the satiation/nutrient drink test. They drank a nutrient drink until they reached the maximum volume that could be tolerated, symptoms were recorded and blood samples taken at 4 times. At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals.
Interventions
DRUGPhentermine-Topiramate ER
The dosing of the study drug was phentermine 3.75 mg / topiramate 23 mg days 1-5. The dosing of the study drug was increased to phentermine 7.5 mg / topiramate 46 mg days 6-14.
DRUGPlacebo
Placebo pills matched the study drug in appearance for the 2 dose levels.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Obese subjects with BMI\> 30 Kg/m\^2. Otherwise healthy individuals who are not currently on treatment for cardiac, pulmonary, gastrointestinal, hepatic, renal, hematological, neurological, endocrine (other than hyperglycemia not requiring medical therapy) and unstable psychiatric disease. * Women of childbearing potential will have negative pregnancy test before initiation of medication.
Exclusion criteria
* Weight \>300 lbs, which is the limit of safety for the SPECT scanner * Concomitant use of appetite suppressants (i.e., caffeine based or diethylpropion) or orlistat (Xenical®) * Uncontrolled hypertension (Blood pressure greater than 160/90 mmHg) * Concentration of fasting glucose greater than 240 mg/dl * Concentration of triglycerides greater than 400 mg/dl * Type 1 Diabetes * Use of anti-diabetic drugs other than metformin, * History of nephrolithiasis, * Recurrent major depression, presence or history of suicidal behavior or ideation with intent to act, and current substantial depressive symptoms (Patient Health Questionnaire-9, 21 total score ≥10). * Concomitant use of Monoamine Oxidase Inhibitors (MAOI) (i.e., phenelzine, selegiline), serotonergic agents, and other centrally acting appetite suppressants * Significant psychiatric dysfunction based upon screening with the Hospital Anxiety and Depression Scale \[HADS\] self-administered alcoholism screening test (SAAST, substance abuse) and the questionnaire on eating and weight patterns (binge eating disorders and bulimia). If such a dysfunction is identified by a Hospital Anxiety and Depression Scale (HADS) score ≥11 in any of the subscales 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. * End stage renal disease or liver cirrhosis * Intake of medication that could interfere with the interpretation of the study or cause drug interaction (i.e., ketoconazole, erythromycin). Specifically, birth control pill, estrogen replacement therapy, and thyroxine replacement are permissible.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Gastric Emptying of Solids Half-Time (T 1/2) | Day 15, approximately 2 hours after radiolabeled meal was ingested | Gastric emptying of solids half-time is defined as the time for half of the ingested solids to leave the stomach. At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals. |
| Fasting Gastric Volume | Day 13, approximately 10 minutes after Technetium (99mTC) injection | Fasting whole gastric volume was measured by Technetium (99mTc)-SPECT Imaging. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. 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. |
| Postprandial Gastric Volume | Day 13, approximately 30 minutes after liquid meal | Postprandial gastric volume was measured by 99mTc-SPECT Imaging. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. After the liquid meal 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. |
| Volume to Fullness | Day 14, approximately 30 minutes after liquid meal | At visit 5, subjects did a satiation/nutrient drink test. Participants recorded their sensations every 5 minutes using a numerical scale from 0-5, 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). This measure was the volume consumed when the fullness sensation reached level 3. |
| Maximum Tolerated Volume | Day 14, approximately 30 minutes after liquid meal | At visit 5, subjects did a satiation/nutrient drink test. Participants recorded their sensations every 5 minutes using a numerical scale from 0-5, 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). This measure is the volume consumed when the fullness sensation reached level 5. |
| Buffet Meal Intake | Day 13, approximately 4.5 hours after liquid meal | At visit 4 subjects underwent imaging to measure the volume of their stomach, fasting and after ingesting a liquid nutrient drink. Four hours after the liquid meal, subjects were invited to eat, over a 30-minute period, a standard all you can eat meal vegetable lasagna, vanilla pudding, and skim milk. The total Kcal of the food consumed was analyzed by using validated software. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours | Day 15, approximately 2 hours after radiolabeled meal was ingested | At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals. This outcome measure is the proportion of the radiolabeled meal emptied at 2 hours. |
| Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY) | Day 14, approximately 45 minutes after liquid meal | Plasma gastrointestinal hormone PYY was measured by radioimmunoassay. |
| Solid Gastric Emptying: Proportion Remaining at 4 Hours | Day 15, approximately 4 hours after radiolabeled meal was ingested | At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals. This outcome measure is the proportion of the radiolabeled meal remaining at 4 hours. |
| Change in Postprandial Gastric Volume | Day 13, approximately approximately 30 min after liquid meal | 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. |
| Fasting Ghrelin | Day 14, before liquid meal | Plasma gastrointestinal hormone total ghrelin was measured by radioimmunoassay. |
| Peak Postprandial Level of Cholecystokinin (CCK) | Day 14, approximately 45 minutes after liquid meal | Plasma gastrointestinal hormone CCK was measured by radioimmunoassay based on an antibody with very low cross-reactivity to gastrin 17 and its sulfated counterpart, and to sensitivity to a concentration of 0.3 pmol/L. |
| Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1) | Day 14, approximately 45 minutes after liquid meal | Plasma gastrointestinal hormone GLP-1 was measured by radioimmunoassay. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from patients attending the Mayo Clinic in Rochester, Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Phentermine-Topiramate ER Qualifying participants were assigned to the Phentermine-Topiramate ER for a minimum of 5 days. The dosing of the study drug was phentermine 3.75 mg / topiramate 23 mg days 1-5. The dosing of the study drug was increased to phentermine 7.5 mg / topiramate 46 mg days 6-14. | 12 |
| Placebo Qualifying participants were assigned to placebo for a minimum of 5 days. Placebo pills matched the study drug in appearance for the 2 dose levels. | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Phentermine-Topiramate ER | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 31.8 years STANDARD_DEVIATION 1.8 | 38.2 years STANDARD_DEVIATION 2.4 | 34.8 years STANDARD_DEVIATION 7.4 |
| Baseline Maximum Tolerated Volume | 1368 ml STANDARD_DEVIATION 111 | 1227 ml STANDARD_DEVIATION 111 | 1297.8 ml STANDARD_DEVIATION 383.2 |
| Baseline Volume to Fullness | 712 ml STANDARD_DEVIATION 86 | 710 ml STANDARD_DEVIATION 95 | 711.3 ml STANDARD_DEVIATION 306.3 |
| Body Mass Index (BMI) | 35.8 kg/m^2 STANDARD_DEVIATION 0.9 | 33.9 kg/m^2 STANDARD_DEVIATION 1.9 | 34.9 kg/m^2 STANDARD_DEVIATION 5.1 |
| Fasting Plasma Glucose | 94.2 mg/dL STANDARD_DEVIATION 2.7 | 96.5 mg/dL STANDARD_DEVIATION 3.6 | 95.3 mg/dL STANDARD_DEVIATION 10.6 |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 10 Participants | 20 Participants |
| Waist Circumference | 108.5 cm STANDARD_DEVIATION 2.2 | 111.2 cm STANDARD_DEVIATION 2.2 | 109.8 cm STANDARD_DEVIATION 7.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 12 | 0 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 |
Outcome results
Primary
Buffet Meal Intake
At visit 4 subjects underwent imaging to measure the volume of their stomach, fasting and after ingesting a liquid nutrient drink. Four hours after the liquid meal, subjects were invited to eat, over a 30-minute period, a standard all you can eat meal vegetable lasagna, vanilla pudding, and skim milk. The total Kcal of the food consumed was analyzed by using validated software.
Time frame: Day 13, approximately 4.5 hours after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Buffet Meal Intake | 728 Kcal | Standard Error 79 |
| Placebo | Buffet Meal Intake | 988 Kcal | Standard Error 79 |
p-value: 0.032ANCOVA
Primary
Fasting Gastric Volume
Fasting whole gastric volume was measured by Technetium (99mTc)-SPECT Imaging. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. 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: Day 13, approximately 10 minutes after Technetium (99mTC) injection
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Fasting Gastric Volume | 227 mL | Standard Error 25 |
| Placebo | Fasting Gastric Volume | 261 mL | Standard Error 25 |
p-value: 0.36ANCOVA
Primary
Gastric Emptying of Solids Half-Time (T 1/2)
Gastric emptying of solids half-time is defined as the time for half of the ingested solids to leave the stomach. At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals.
Time frame: Day 15, approximately 2 hours after radiolabeled meal was ingested
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Gastric Emptying of Solids Half-Time (T 1/2) | 109 minutes | Standard Error 7 |
| Placebo | Gastric Emptying of Solids Half-Time (T 1/2) | 88 minutes | Standard Error 7 |
p-value: 0.057ANCOVA
Primary
Maximum Tolerated Volume
At visit 5, subjects did a satiation/nutrient drink test. Participants recorded their sensations every 5 minutes using a numerical scale from 0-5, 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). This measure is the volume consumed when the fullness sensation reached level 5.
Time frame: Day 14, approximately 30 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Maximum Tolerated Volume | 966 mL | Standard Error 79 |
| Placebo | Maximum Tolerated Volume | 1108 mL | Standard Error 79 |
p-value: 0.22ANCOVA
Primary
Postprandial Gastric Volume
Postprandial gastric volume was measured by 99mTc-SPECT Imaging. Subjects reported to the clinic after an overnight fast. 99mTC was given by an intravenous injection in the forearm. After the liquid meal 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: Day 13, approximately 30 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Postprandial Gastric Volume | 680 mL | Standard Error 37 |
| Placebo | Postprandial Gastric Volume | 681 mL | Standard Error 37 |
p-value: 0.99ANCOVA
Primary
Volume to Fullness
At visit 5, subjects did a satiation/nutrient drink test. Participants recorded their sensations every 5 minutes using a numerical scale from 0-5, 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). This measure was the volume consumed when the fullness sensation reached level 3.
Time frame: Day 14, approximately 30 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Volume to Fullness | 570 mL | Standard Error 63.2 |
| Placebo | Volume to Fullness | 630 mL | Standard Error 61.1 |
p-value: 0.45ANCOVA
Secondary
Change in Postprandial Gastric Volume
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: Day 13, approximately approximately 30 min after liquid meal
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Change in Postprandial Gastric Volume | 453 mL | Standard Error 24 |
| Placebo | Change in Postprandial Gastric Volume | 420 mL | Standard Error 24 |
p-value: 0.35ANCOVA
Secondary
Fasting Ghrelin
Plasma gastrointestinal hormone total ghrelin was measured by radioimmunoassay.
Time frame: Day 14, before liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Fasting Ghrelin | 78.1 pg/mL | Standard Error 5.6 |
| Placebo | Fasting Ghrelin | 82.6 pg/mL | Standard Error 10.8 |
p-value: 0.72ANCOVA
Secondary
Peak Postprandial Level of Cholecystokinin (CCK)
Plasma gastrointestinal hormone CCK was measured by radioimmunoassay based on an antibody with very low cross-reactivity to gastrin 17 and its sulfated counterpart, and to sensitivity to a concentration of 0.3 pmol/L.
Time frame: Day 14, approximately 45 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Peak Postprandial Level of Cholecystokinin (CCK) | 8.1 pg/mL | Standard Error 0.9 |
| Placebo | Peak Postprandial Level of Cholecystokinin (CCK) | 8.3 pg/mL | Standard Error 1 |
p-value: 0.9ANCOVA
Secondary
Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1)
Plasma gastrointestinal hormone GLP-1 was measured by radioimmunoassay.
Time frame: Day 14, approximately 45 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1) | 13.0 pg/mL | Standard Error 1.8 |
| Placebo | Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1) | 11.9 pg/mL | Standard Error 1.6 |
p-value: 0.54Wilcoxon (Mann-Whitney)
Secondary
Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY)
Plasma gastrointestinal hormone PYY was measured by radioimmunoassay.
Time frame: Day 14, approximately 45 minutes after liquid meal
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY) | 195.3 pg/mL | Standard Error 21.2 |
| Placebo | Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY) | 166 pg/mL | Standard Error 15.7 |
p-value: 0.26Wilcoxon (Mann-Whitney)
Secondary
Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours
At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals. This outcome measure is the proportion of the radiolabeled meal emptied at 2 hours.
Time frame: Day 15, approximately 2 hours after radiolabeled meal was ingested
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours | 0.56 proportion of meal emptied | Standard Error 0.03 |
| Placebo | Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours | 0.66 proportion of meal emptied | Standard Error 0.03 |
p-value: 0.052ANCOVA
Secondary
Solid Gastric Emptying: Proportion Remaining at 4 Hours
At visit 6 subjects took part in a gastric emptying by scintigraphy test. Subjects were given a scrambled egg breakfast with toast and a glass of milk. The eggs and milk contained a small amount of radioactive substance. At the completion of the meal, subjects stood in front of a special camera and pictures were taken at specific intervals. This outcome measure is the proportion of the radiolabeled meal remaining at 4 hours.
Time frame: Day 15, approximately 4 hours after radiolabeled meal was ingested
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phentermine-Topiramate ER | Solid Gastric Emptying: Proportion Remaining at 4 Hours | 0.09 proportion of meal remaining | Standard Error 0.02 |
| Placebo | Solid Gastric Emptying: Proportion Remaining at 4 Hours | 0.16 proportion of meal remaining | Standard Error 0.02 |
Comparison: This p-value was based on a rank transformation.p-value: 0.03ANCOVA