Effects of Acipimox on Mitochondrial Function in Obesity

• ClinicalTrials.gov Identifier: NCT01488409
• Recruitment Status: Completed
• First Posted: December 8, 2011
• Results First Posted: February 3, 2016
• Last Update Posted: March 1, 2016
• Sponsor: Massachusetts General Hospital
• Collaborator: American Diabetes Association
• Information provided by (Responsible Party): Steven K. Grinspoon, MD, Massachusetts General Hospital

Study Description

Brief Summary:

The purpose of the study is to examine whether a medication called acipimox can improve your body's mitochondria. Mitochondria are the "power house" of the cell and make energy for your body.

Obesity is associated with increased risk for developing diabetes. However, the investigators do not know how obesity leads to diabetes. Previous studies have shown levels of fat in the blood (free fatty acids or FFA) are higher in obesity, and elevated FFA can affect how our body uses glucose and responds to insulin. Recent studies have shown that changes in mitochondria may be involved in the development of diabetes and may be affected by FFA. The investigators propose to improve the function of mitochondria in obese people with pre-diabetes by treating with acipimox, a medication which decreases FFA. The investigators will use state of the art techniques to evaluate the mitochondria, including a new magnetic resonance imaging (MRI) technique to measure function of mitochondria in muscle.

Condition or disease	Intervention/treatment	Phase
Abdominal Obesity; Insulin Resistance; Hypertriglyceridemia	Drug: Acipimox; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effects of Short Term Acipimox Treatment on Skeletal Muscle Phosphocreatine Recovery in Obesity
• Study Start Date: May 2012
• Actual Primary Completion Date: January 2015
• Actual Study Completion Date: January 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Acipimox; Treatment with the study drug Acipimox	Drug: Acipimox; 250 mg by mouth (PO) three times daily
Placebo Comparator: Placebo; Treatment with Placebo control.	Drug: Placebo; 0 mg by mouth (PO) three times daily

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months [ Time Frame: Change from Baseline to 6-months Visit ]
   The rate of recovery of phosphocreatine concentration after depletion by exercise is considered a measurement of mitochondrial function. Change in phosphocreatine recovery from baseline to 6 months will therefore give a measurement of change in mitochondrial function. ViPCR is given -- a higher value indicates better mitochondrial function.

Secondary Outcome Measures :

1. Change From Baseline in Insulin Sensitivity at 6-months [ Time Frame: Change from Baseline to 6-months visit ]
   Change in insulin resistance assessed by hyperinsulinemic-euglycemic clamp study at Baseline and at 6-months. Change in insulin-stimulated glucose uptake (M) during 40 mU/m2/min insulin clamp is given.
2. Change From Baseline in Mitochondrial Density at 6 Months [ Time Frame: Change from Baseline to 6-months ]
   Muscle tissue obtained from biopsy will be used to assess mitochondrial number and morphology by microscopes at Baseline and at 6-months. The change in mitochondrial density from 6 months to baseline is given.
3. Change From Baseline in Intramyocellular Lipid Content at 6-months [ Time Frame: Change from Baseline to 6-months ]
   Change in tibialis intramyocellular lipid (IMCL) normalized to creatinine is given.
4. Change From Baseline in Lipid Profile at 6-months [ Time Frame: Change from Baseline to 6-months ]
   Change in direct low density lipoprotein (LDL) cholesterol is given

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Men and women age 18-55 years old
2. Body Mass Index (BMI) ≥ 30 kg/m2
3. Waist circumference ≥ 102 cm in men and ≥ 88 cm in women
4. Hypertriglyceridemia defined as triglycerides ≥ 150 mg/dl OR Insulin resistance defined as elevated fasting glucose (≥ 100 mg/dl but <125 mg/dl) or hyperinsulinemia defined as fasting serum insulin ≥ 10 uU/ml.

Exclusion Criteria:

1. Subjects on any hormonal treatment including estrogen, hormone replacement therapy, oral contraceptives, testosterone, glucocorticoids, anabolic steroids, GH, GH releasing hormone or Insulin like growth factor (IGF)-1 within 3months of enrollment.
2. Subjects who have a known history of diabetes, using any anti-diabetic drugs, or fasting blood glucose of ≥ 125 mg/dl.
3. Use of cholesterol lowering medication including niacin or fish oil.
4. Changes in anti-hypertensive regimen within 3months of screening.
5. Chronic illness including HIV, anemia (Hgb <12 g/dL), chronic kidney disease (Creatinine > 2 mg/dL), or liver disease (SGOT > 2.5 x upper limit normal).
6. Use of Aspirin, Clopidogrel (Plavix), Warfarin (Coumadin) or other anti-coagulants
7. History of or active peptic ulcer disease
8. History of any recent cardiovascular event including myocardial infarction (MI; heart attack), cerebral vascular accident (CVA; or stroke) or transient ischemic attack (TIA; or mini-stroke) within 3 months of screening visit, unstable angina pectoris, oxygen-dependent severe pulmonary disease
9. Subjects with contraindication for an MRI study including any significant metal in their body including surgical clippings, or pacemakers and known claustrophobia.
10. History of recent alcohol or substance abuse (< 1 year)
11. Positive pregnancy test or lactating females
12. Women of child-bearing potential not currently using non-hormonal birth control methods including barrier methods (intra-uterine device or IUD, condoms, diaphragms) or abstinence
13. Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit.

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Massachusetts General Hospital

American Diabetes Association

Investigators

• Principal Investigator: Steven Grinspoon, MD; Massachusetts General Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Makimura H, Stanley TL, Suresh C, De Sousa-Coelho AL, Frontera WR, Syu S, Braun LR, Looby SE, Feldpausch MN, Torriani M, Lee H, Patti ME, Grinspoon SK. Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial. J Clin Endocrinol Metab. 2016 Mar;101(3):1123-33. doi: 10.1210/jc.2015-3696. Epub 2015 Dec 21.

• Responsible Party: Steven K. Grinspoon, MD, Professor of Medicine, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01488409
• Other Study ID Numbers: 2011-P-000175
• First Posted: December 8, 2011
• Results First Posted: February 3, 2016
• Last Update Posted: March 1, 2016
• Last Verified: February 2016

Additional relevant MeSH terms:

Obesity; Insulin Resistance; Hypertriglyceridemia; Obesity, Abdominal; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Acipimox; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents