Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients

• ClinicalTrials.gov Identifier: NCT01834404
• Recruitment Status: Completed
• First Posted: April 17, 2013
• Results First Posted: February 23, 2015
• Last Update Posted: February 23, 2015
• Sponsor: Mayo Clinic
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Michael Camilleri, Mayo Clinic

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.

Condition or disease	Intervention/treatment	Phase
Obesity	Drug: Phentermine-Topiramate ER; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Peripheral Pharmacodynamics of Phentermine-Topiramate in Obese Patients
• Study Start Date: April 2013
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: March 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: Phentermine-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.; Other Name: Qsymia
Placebo Comparator: 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.	Drug: Placebo; Placebo pills matched the study drug in appearance for the 2 dose levels.

Outcome Measures

Primary Outcome Measures :

1. Gastric Emptying of Solids Half-Time (T 1/2) [ Time Frame: 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.
2. Fasting Gastric Volume [ Time Frame: 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.
3. Postprandial Gastric Volume [ Time Frame: 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.
4. Volume to Fullness [ Time Frame: 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.
5. Maximum Tolerated Volume [ Time Frame: 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.
6. Buffet Meal Intake [ Time Frame: 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 Outcome Measures :

1. Solid Gastric Emptying: Proportion of Meal Emptied at 2 Hours [ Time Frame: 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.
2. Solid Gastric Emptying: Proportion Remaining at 4 Hours [ Time Frame: 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.
3. Change in Postprandial Gastric Volume [ Time Frame: 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.
4. Fasting Ghrelin [ Time Frame: Day 14, before liquid meal ]
   Plasma gastrointestinal hormone total ghrelin was measured by radioimmunoassay.
5. Peak Postprandial Level of Cholecystokinin (CCK) [ Time Frame: 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.
6. Peak Postprandial Level of Total Glucagon-Like Peptide-1 (GLP-1) [ Time Frame: Day 14, approximately 45 minutes after liquid meal ]
   Plasma gastrointestinal hormone GLP-1 was measured by radioimmunoassay.
7. Peak Postprandial Level of Total Peptide Tyrosine-Tyrosine (PYY) [ Time Frame: Day 14, approximately 45 minutes after liquid meal ]
   Plasma gastrointestinal hormone PYY was measured by radioimmunoassay.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

United States, Minnesota

Mayo Clinic in Rochester

Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Mayo Clinic

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

Investigators

• Principal Investigator: Michael Camilleri, MD; Mayo Clinic

More Information

Publications of Results:

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.

• Responsible Party: Michael Camilleri, Primary Investigator, Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01834404
• Other Study ID Numbers: 13-000948; R01DK067071 ( U.S. NIH Grant/Contract ); UL1TR000135 ( U.S. NIH Grant/Contract )
• First Posted: April 17, 2013
• Results First Posted: February 23, 2015
• Last Update Posted: February 23, 2015
• Last Verified: February 2015

Keywords provided by Michael Camilleri, Mayo Clinic:

Obesity; BMI; Incretin; Satiety; Phentermine; Topiramate

Additional relevant MeSH terms:

Obesity; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Topiramate; Phentermine; Anticonvulsants; Hypoglycemic Agents; Physiological Effects of Drugs; Central Nervous System Stimulants; Appetite Depressants; Anti-Obesity Agents; Sympathomimetics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action