Effects of Acipimox on Mitochondrial Function in Obesity

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01488409
• Collaborator: American Diabetes Association (Other)
• Enrollment: 39
• Location: 1
• Arms: 2
• Duration (Months): 32
• Patients Per Site Per Month: 1.2

Study Details

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
• 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 1, 2012
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 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 [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 [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 [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 [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 [Change from Baseline to 6-months]

   Change in direct low density lipoprotein (LDL) cholesterol is given

Eligibility Criteria

Criteria

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

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• 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: Dec 8, 2011
• Last Update Posted: Mar 1, 2016
• Last Verified: Feb 1, 2016

• Additional relevant MeSH terms: Obesity; Insulin Resistance; Hypertriglyceridemia; Obesity, Abdominal; Acipimox

Study Results

Participant Flow

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Period Title: Overall Study
STARTED	20	19
COMPLETED	16	15
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Acipimox	Placebo	Total
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily	Total of all reporting groups
Overall Participants	20	19	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47 (5)	45 (7)	46 (6)
Sex: Female, Male (Count of Participants)
Female	7 35%	6 31.6%	13 33.3%
Male	13 65%	13 68.4%	26 66.7%
Race/Ethnicity, Customized (participants) [Number]
White	8 40%	10 52.6%	18 46.2%
Black	12 60%	8 42.1%	20 51.3%
Other	0 0%	1 5.3%	1 2.6%
Region of Enrollment (participants) [Number]
United States	20 100%	19 100%	39 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Phosphocreatine Recovery (ViPCr) at 6-months
Description	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.
Time Frame	Change from Baseline to 6-months Visit

Outcome Measure Data

Analysis Population Description

all available data used

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Measure Participants	16	12
Mean (Standard Deviation) [mM/s]	1.7 (9.6)	1.6 (10.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acipimox, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.97
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Change From Baseline in Insulin Sensitivity at 6-months
Description	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.
Time Frame	Change from Baseline to 6-months visit

Outcome Measure Data

Analysis Population Description

all available data used

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Measure Participants	15	14
Mean (Standard Deviation) [mg/kg/min]	0.1 (1.9)	0.2 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acipimox, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.85
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Change From Baseline in Mitochondrial Density at 6 Months
Description	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.
Time Frame	Change from Baseline to 6-months

Outcome Measure Data

Analysis Population Description

all available data used

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Measure Participants	8	9
Mean (Standard Deviation) [percentage of total muscle fiber area]	0.4 (1.3)	0 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acipimox, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.52
	Comments
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

Title	Change From Baseline in Intramyocellular Lipid Content at 6-months
Description	Change in tibialis intramyocellular lipid (IMCL) normalized to creatinine is given.
Time Frame	Change from Baseline to 6-months

Outcome Measure Data

Analysis Population Description

all available data used

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Measure Participants	14	15
Mean (Standard Deviation) [ratio of IMCL peak to Creatinine peak]	-0.2 (3.0)	0.0 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acipimox, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	t-test, 2 sided
	Comments

5. Secondary Outcome

Title	Change From Baseline in Lipid Profile at 6-months
Description	Change in direct low density lipoprotein (LDL) cholesterol is given
Time Frame	Change from Baseline to 6-months

Outcome Measure Data

Analysis Population Description

all available data used

Arm/Group Title	Acipimox	Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily	Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
Measure Participants	16	15
Mean (Standard Deviation) [mg/dL]	-19 (26)	6 (22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Acipimox, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	6 months
Arm/Group Title	Acipimox		Placebo
Arm/Group Description	Treatment with the study drug Acipimox Acipimox: 250 mg by mouth (PO) three times daily		Treatment with Placebo control. Placebo: 0 mg by mouth (PO) three times daily
All Cause Mortality
	Acipimox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acipimox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Acipimox		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/20 (80%)		16/19 (84.2%)
Gastrointestinal disorders
nausea	4/20 (20%)		3/19 (15.8%)
abdominal bloating	3/20 (15%)		2/19 (10.5%)
gastroesophageal reflux	7/20 (35%)		5/19 (26.3%)
abdominal pain	2/20 (10%)		2/19 (10.5%)
diarrhea	7/20 (35%)		2/19 (10.5%)
vomiting	0/20 (0%)		1/19 (5.3%)
constipation	0/20 (0%)		1/19 (5.3%)
General disorders
Dizziness	1/20 (5%)		1/19 (5.3%)
dry mouth	1/20 (5%)		0/19 (0%)
loss of appetite	0/20 (0%)		1/19 (5.3%)
Musculoskeletal and connective tissue disorders
joint pain and swelling	1/20 (5%)		0/19 (0%)
Skin and subcutaneous tissue disorders
Flushing	8/20 (40%)		4/19 (21.1%)
rash	1/20 (5%)		0/19 (0%)
Surgical and medical procedures
pain following biopsy	0/20 (0%)		1/19 (5.3%)
bleeding following biopsy	1/20 (5%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.