Metabolic Diseases, Obesity, Overweight
Conditions
Keywords
fatty acid oxidation, Proton magnetic resonance spectroscopy
Brief summary
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
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.
Interventions
BEHAVIORALLow Calorie Diet (LCD)
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.
DRUGPhentermine
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.
Sponsors
Takeda
AdventHealth Translational Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Amount of Fat Oxidation at 14 Days | Days 0, 14 | 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) |
| Fat Oxidation Rates at 1 Week Intervals | Days 0, 7, 14, 28, 49, 56 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Soleus IMCL Content | Days -7, -1, 14, 56 | 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 |
Countries
United States
Participant flow
Pre-assignment details
Overweight/obese participant were recruited to the study to participate in a 28 day low calorie diet (LCD). After 28 days, participants were evaluated for whether they met their expected weight loss targets. If participants met their targets they continued the LCD for a further 28 days and are defined as Overweight/Obese With no Drug. If participants did not reach their weight loss target they continued with LCD with an addition of phentermine and are defined as Overweight/Obese With Phentermine
Participants by arm
| Arm | Count |
|---|---|
| Ovweight/Obese With no Drug After screening, overweight (obese subjects (BMI \>27 - ≤40.0) subjects (n=35) will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved.
Low Calorie Diet (LCD): A Diet History Questionnaire will be completed, and the subjects will have dietary counseling and be provided shakes. The low calorie diet will begin, to continue for a period of 8 weeks. | 19 |
| Overweigh/Obese With Phentermine After screening, 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. 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.
Low Calorie Diet (LCD): See prior information.
Phentermine: See prior information.
Protection Against Risk: See prior information.
. | 20 |
| Total | 39 |
Baseline characteristics
| Characteristic | Overweigh/Obese With Phentermine | Ovweight/Obese With no Drug | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 19 Participants | 39 Participants |
| Age, Continuous | 43.6 years | 37.3 years | 42.3 years |
| Region of Enrollment United States | 20 participants | 19 participants | 39 participants |
| Sex: Female, Male Female | 17 Participants | 17 Participants | 34 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 19 | 0 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 |
Outcome results
Primary
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)
Time frame: Days 0, 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overweight/Obese With no Drug | Change From Baseline Amount of Fat Oxidation at 14 Days | 0.91 Fold change of RQ ratio | Standard Deviation 0.05 |
| Overweight/ Obese With Phentermine | Change From Baseline Amount of Fat Oxidation at 14 Days | 0.94 Fold change of RQ ratio | Standard Deviation 0.07 |
Primary
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)
Time frame: Days 0, 7, 14, 28, 49, 56
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 14 | 0.791 Ratio | Standard Deviation 0.036 |
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 0 | 0.867 Ratio | Standard Deviation 0.052 |
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 7 | 0.795 Ratio | Standard Deviation 0.041 |
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 28 | 0.808 Ratio | Standard Deviation 0.034 |
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 49 | 0.800 Ratio | Standard Deviation 0.048 |
| Overweight/Obese With no Drug | Fat Oxidation Rates at 1 Week Intervals | Day 56 | 0.798 Ratio | Standard Deviation 0.048 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 49 | 0.784 Ratio | Standard Deviation 0.044 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 28 | 0.811 Ratio | Standard Deviation 0.069 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 0 | 0.857 Ratio | Standard Deviation 0.059 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 56 | 0.785 Ratio | Standard Deviation 0.048 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 7 | 0.787 Ratio | Standard Deviation 0.039 |
| Overweight/ Obese With Phentermine | Fat Oxidation Rates at 1 Week Intervals | Day 14 | 0.801 Ratio | Standard Deviation 0.041 |
Secondary
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
Time frame: Days -7, -1, 14, 56
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overweight/Obese With no Drug | Soleus IMCL Content | Day -7 | 0.025 ratio of peak height of IMCL to water | Standard Deviation 0.01 |
| Overweight/Obese With no Drug | Soleus IMCL Content | Day 0 | 0.028 ratio of peak height of IMCL to water | Standard Deviation 0.014 |
| Overweight/Obese With no Drug | Soleus IMCL Content | Day 14 | 0.030 ratio of peak height of IMCL to water | Standard Deviation 0.011 |
| Overweight/Obese With no Drug | Soleus IMCL Content | Day 56 | 0.027 ratio of peak height of IMCL to water | Standard Deviation 0.014 |
| Overweight/ Obese With Phentermine | Soleus IMCL Content | Day 56 | 0.034 ratio of peak height of IMCL to water | Standard Deviation 0.013 |
| Overweight/ Obese With Phentermine | Soleus IMCL Content | Day -7 | 0.032 ratio of peak height of IMCL to water | Standard Deviation 0.015 |
| Overweight/ Obese With Phentermine | Soleus IMCL Content | Day 14 | 0.034 ratio of peak height of IMCL to water | Standard Deviation 0.011 |
| Overweight/ Obese With Phentermine | Soleus IMCL Content | Day 0 | 0.034 ratio of peak height of IMCL to water | Standard Deviation 0.019 |