Effect of Caloric Restriction on Fat Oxidation in Obese Men and Women (Magellan II)

Study Overview
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Brief Summary
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The purpose of this study is to better understand the different ways our bodies burn fat which may be important for obesity, diabetes, and cardiovascular disease.

Detailed Description
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In this study the investigators will examine the hypothesis that overweight/obese individuals that are unable to meet target weight loss goals on a low calorie diet (LCD) are intrinsically less metabolically flexible than their weight-losing counterparts. The investigators expect that this 'inflexibility' will be characterized by impaired fat oxidation (as determined by indirect calorimetry) in response to caloric restriction. If this were the case, these subjects may represent a population of 'super-responders' likely to demonstrate a robust response to approaches to increase fat oxidation. The investigators will also measure lipid concentrations in skeletal muscle and liver by hydrogen 1 magnetic resonance (1H-MRS) to determine both the stability of these measurements as well as the magnitude of changes that can be seen during LCD.

Official Title
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Effect of Caloric Restriction on Metabolic Biomarkers and Fat Oxidation in Obese Men and Women (Magellan II)

Conditions
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Obesity, Overweight, Metabolic Diseases

Intervention / Treatment
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* Behavioral: Low Calorie Diet (LCD)
* Drug: Phentermine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between the ages of 18 and 55 years, inclusive Body Mass Index (BMI) 27-30 kg/m2, inclusive, with hypertension, controlled (<140 / <90) either by diet or medication. BMI 30-40 kg/m2, inclusive. An informed consent document signed and dated by the subject or a legally acceptable representative. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (hypertension controlled (<140 / <90) either by diet or medication is acceptable), hepatic, psychiatric, neurologic, allergic, (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing), muscle disease, diabetes, or severe uncontrolled hypertension. Known hypersensitivity to phentermine, lidocaine, bupivicaine or any medication component of the study procedure. Presence of cardiac pacemaker, implanted cardiac defibrillator, or brain aneurysm clips. Any significant bleeding diathesis which could preclude recovery from the biopsy procedure. ASA, ibuprofen, and any other oral anti platelet agent will be discontinued at least 7 days prior to procedure. Abnormal CK as per site laboratory ranges. Subjects with either a medical history of or physical evidence of keloid scar formation upon physical examination. 12-lead electrocardiogram (ECG) demonstrating a clinically significant abnormality. Pregnant or nursing females or females less than 6 months postpartum from the scheduled date of collection. Participation in non-routine rigorous exercise (e.g., road races, heavy lifting, etc.) within one week prior to the muscle biopsy procedures. Presence of any condition in the investigator's opinion that may negatively affect subject safety or protocol adherence. Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses > 2years) unwilling to use an approved method of contraception (condom, diaphragm, implantable uterine device (IUD) that does not release hormones). Prior participation in the Magellan I study at the Translational Research Institute for Metabolism and Diabetes.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Overwight/Obese with no drug<br>After screening, overweight/obese subjects (BMI >27 - ≤40.0) subjects will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved. | Behavioral: Low Calorie Diet (LCD)<br>* A Diet History Questionnaire was completed and subjects had dietary counseling and were provided shakes. The low calorie diet began, to continued for a period of 8 weeks.<br>|
| Active Comparator: Overweight/obese with Phentermine<br>After screening, overweight/obese (BMI >27.0 - ≤40.0) subjects will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved. Individuals not on track to achieve their target weight by four weeks will receive the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects will be given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision. | Behavioral: Low Calorie Diet (LCD)<br>* A Diet History Questionnaire was completed and subjects had dietary counseling and were provided shakes. The low calorie diet began, to continued for a period of 8 weeks.<br>Drug: Phentermine<br>* Individuals not on track to achieve their target weight by four weeks received the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects were given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision. Protection Against Risk: Prior to administering any phentermine, a history and physical including EKG will be conducted (at the screening visit) and will be used to determine whether the participant is clear to receive the medication. Participants will see the study doctor or nurse practitioner at every study visit after the drug is initiated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Amount of Fat Oxidation at 14 Days | Measured with respiratory quotient obtained with indirect calorimetry Expected Results Overweight and obese subjects will show a wide variation in fat oxidation in response to the low calorie diet Approximately one-third of study participants will not meet target weight loss by four weeks Following an overnight fast (prior to and during LCD) individuals that fail to meet the target weight loss will be characterized by decreased whole body fat oxidation and increased carbohydrate oxidation (measured by indirect calorimetry) | Days 0, 14 | 
| Fat Oxidation Rates at 1 Week Intervals | Measured with respiratory quotient using indirect calorimetry Expected Results Overweight and obese subjects will show a wide variation in fat oxidation in response to the low calorie diet Approximately one-third of study participants will not meet target weight loss by four weeks Following an overnight fast (prior to and during LCD) individuals that fail to meet the target weight loss will be charaterized by decreased whole body fat oxidation and increased carbohydrate oxidation (measured by indirect calorimetry) | Days 0, 7, 14, 28, 49, 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Soleus IMCL Content | Measured with magnetic resonance spectroscopy (MRS) Expected results 1H-MRS can measure skeletal muscle (intramyocellular lipid) IMCL content with low test-retest variability 1H-MRS can sensitively monitor reductions (or lack thereof) in skeletal muscle IMCL during caloric restriction Reductions in IMCL will be higher in subjects with lower fasting respiratory quotients (RQ) at baseline/during LCD | Days -7, -1, 14, 56 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fatty acid oxidation, Proton magnetic resonance spectroscopy