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Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients

Primary Purpose

Obesity

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Phentermine-Topiramate ER

Placebo

About this trial

This is an interventional treatment trial for Obesity focused on measuring Obesity, BMI, Incretin, Satiety, Phentermine, Topiramate

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Phentermine-Topiramate ER

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

Solid Gastric Emptying: Proportion Remaining at 4 Hours

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.

Fasting Ghrelin

Plasma gastrointestinal hormone total ghrelin was measured by radioimmunoassay.

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.

Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1)

Plasma gastrointestinal hormone GLP-1 was measured by radioimmunoassay.

Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY)

Plasma gastrointestinal hormone PYY was measured by radioimmunoassay.

Full Information

NCT ID

NCT01834404

First Posted

March 27, 2013

Last Updated

February 10, 2015

Sponsor

Mayo Clinic

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

1. Study Identification

Unique Protocol Identification Number

NCT01834404

Brief Title

Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients

Official Title

Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients

Study Type

Interventional

2. Study Status

Record Verification Date

February 2015

Overall Recruitment Status

Completed

Study Start Date

April 2013 (undefined)

Primary Completion Date

March 2014 (Actual)

Study Completion Date

March 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obesity

Keywords

Obesity, BMI, Incretin, Satiety, Phentermine, Topiramate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

24 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Phentermine-Topiramate ER

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

Phentermine-Topiramate ER

Other Intervention Name(s)

Qsymia

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo pills matched the study drug in appearance for the 2 dose levels.

Primary Outcome Measure Information:

Title

Gastric Emptying of Solids Half-Time (T 1/2)

Description

Time Frame

Day 15, approximately 2 hours after radiolabeled meal was ingested

Title

Fasting Gastric Volume

Description

Time Frame

Day 13, approximately 10 minutes after Technetium (99mTC) injection

Title

Postprandial Gastric Volume

Description

Time Frame

Day 13, approximately 30 minutes after liquid meal

Title

Volume to Fullness

Description

Time Frame

Day 14, approximately 30 minutes after liquid meal

Title

Maximum Tolerated Volume

Description

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

Title

Buffet Meal Intake

Description

Time Frame

Day 13, approximately 4.5 hours after liquid meal

Secondary Outcome Measure Information:

Title

Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours

Description

Time Frame

Day 15, approximately 2 hours after radiolabeled meal was ingested

Title

Solid Gastric Emptying: Proportion Remaining at 4 Hours

Description

Time Frame

Day 15, approximately 4 hours after radiolabeled meal was ingested

Title

Change in Postprandial Gastric Volume

Description

Time Frame

Day 13, approximately approximately 30 min after liquid meal

Title

Fasting Ghrelin

Description

Plasma gastrointestinal hormone total ghrelin was measured by radioimmunoassay.

Time Frame

Day 14, before liquid meal

Title

Peak Postprandial Level of Cholecystokinin (CCK)

Description

Time Frame

Day 14, approximately 45 minutes after liquid meal

Title

Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1)

Description

Plasma gastrointestinal hormone GLP-1 was measured by radioimmunoassay.

Time Frame

Day 14, approximately 45 minutes after liquid meal

Title

Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY)

Description

Plasma gastrointestinal hormone PYY was measured by radioimmunoassay.

Time Frame

Day 14, approximately 45 minutes after liquid meal

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Camilleri, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Rochester

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

25486131

Citation

Acosta A, Camilleri M, Shin A, Vazquez-Roque MI, Iturrino J, Burton D, O'Neill J, Eckert D, Zinsmeister AR. Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy. Gastroenterology. 2015 Mar;148(3):537-546.e4. doi: 10.1053/j.gastro.2014.11.020. Epub 2014 Dec 6.

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Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients

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