Mineralocorticoid Receptor and Obesity Induced Cardiovascular Complications

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01406015
• Collaborator: (none)
• Enrollment: 38
• Location: 1
• Arms: 2
• Duration (Months): 58
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if spironolactone, a drug that blocks the action of aldosterone, can make the blood vessels work better in people with obesity. The investigators also want to find out whether spironolactone causes changes in levels of insulin and markers of inflammation.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Insulin Resistance	Drug: Spironolactone; Drug: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Mineralocorticoid Receptor and Obesity Induced Cardiovascular Complications
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Spironolactone	Drug: Spironolactone; 50 mg once daily for 6 weeks.
Placebo Comparator: Placebo	Drug: Placebo; Placebo-matching spironolactone once daily for 6 weeks.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Post-ischemic Dilatation [Baseline and Week 6]

   Ultrasonography of the brachial artery was performed to evaluate endothelial function by flow mediated dilatation (FMD) studies. A blood pressure cuff was placed on the participant's upper arm and was compressed for 5 minutes. After release of compression, brachial artery diameter and blood flow velocity were measured. FMD was expressed as the percentage change in brachial artery diameter. A positive change from Baseline indicates improvement.

Secondary Outcome Measures

1. Change From Baseline in Para-aminohippurate (PAH) Clearance [Baseline and Week 6 (Prior to PAH infusion and at 50 and 60 minutes post PAH infusion)]

   Renal plasma blood flow was determined by clearance of para-aminohippurate (PAH). A loading dose of PAH (8 mg/kg) was given intravenously followed by a 1 hour constant infusion of PAH at a rate of 12 mg/minute (min). Plasma samples were obtained at Baseline and at 50 and 60 minutes. PAH clearance was calculated from the plasma levels and infusion rates and reported in millimeters (mL)/minute (min). A positive change from Baseline indicates improvement.

2. Change From Baseline in Markers of Inflammation [Baseline and Week 6]

   Blood was to be collected and tested for Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemotactic Protein-1 (MCP-1), markers of inflammation; However, due to lack of funding, blood samples were not analyzed and data for levels of inflammation markers were not collected.

3. Change From Baseline in Insulin Sensitivity Index (ISI) [Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)]

   Insulin sensitivity was measured using the 75 gram (G) glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 milliliters (mL) of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. Insulin sensitivity index was calculated by Matsuda and Defronzo's formula using the values obtained. A positive change from Baseline (increase in insulin sensitivity) indicates improvement.

4. Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) [Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)]

   Insulin resistance was measured using the 75 G glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 mL of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. HOMA-IR was calculated using the Insulin and glucose levels obtained. A negative change (decrease in insulin resistance) indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 18-70 years

2. Good health as evidenced by history and physical exam

3. Body Mass Index (BMI): >30 kg/m2 and <45 kg/m2

Exclusion criteria:

1. Medical illnesses other than treated hypothyroidism

2. Blood Pressure (BP) >135/85 or systolic BP <90 mm Hg

3. Hepatic disease (transaminase > 3 times normal)

4. Renal impairment (Creatinine clearance <60 ml/min)

5. Baseline serum Potassium (K) >5.0 mmol/L

6. History of drug or alcohol abuse

7. Allergies to spironolactone

8. Participation in any other concurrent clinical trial

9. Women using oral contraceptives within the last 3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Brigham and Women's Hospital

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Rajesh K. Garg, Associate Physician, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01406015
• Other Study ID Numbers: 2009P-000311
• First Posted: Jul 29, 2011
• Last Update Posted: Apr 28, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Rajesh K. Garg, Associate Physician, Brigham and Women's Hospital: Obesity; Insulin resistance; Mineralocorticoid receptor
• Additional relevant MeSH terms: Obesity; Insulin Resistance; Spironolactone

Study Results

Participant Flow

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Period Title: Overall Study
STARTED	19	19
COMPLETED	16	16
NOT COMPLETED	3	3

Baseline Characteristics

Arm/Group Title	Spironolactone	Placebo	Total
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.	Total of all reporting groups
Overall Participants	16	16	32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47 (11.6)	40 (12.3)	43.4 (12.3)
Sex: Female, Male (Count of Participants)
Female	10 62.5%	12 75%	22 68.8%
Male	6 37.5%	4 25%	10 31.3%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	38 (6.6)	36 (4.6)	36.8 (5.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Post-ischemic Dilatation
Description	Ultrasonography of the brachial artery was performed to evaluate endothelial function by flow mediated dilatation (FMD) studies. A blood pressure cuff was placed on the participant's upper arm and was compressed for 5 minutes. After release of compression, brachial artery diameter and blood flow velocity were measured. FMD was expressed as the percentage change in brachial artery diameter. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

All randomized participants who completed the study.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Measure Participants	16	16
Baseline	9.6 (7.8)	10.2 (6.9)
Change from Baseline at Week 6	-1.2 (6.1)	-2.0 (4.7)

2. Secondary Outcome

Title	Change From Baseline in Para-aminohippurate (PAH) Clearance
Description	Renal plasma blood flow was determined by clearance of para-aminohippurate (PAH). A loading dose of PAH (8 mg/kg) was given intravenously followed by a 1 hour constant infusion of PAH at a rate of 12 mg/minute (min). Plasma samples were obtained at Baseline and at 50 and 60 minutes. PAH clearance was calculated from the plasma levels and infusion rates and reported in millimeters (mL)/minute (min). A positive change from Baseline indicates improvement.
Time Frame	Baseline and Week 6 (Prior to PAH infusion and at 50 and 60 minutes post PAH infusion)

Outcome Measure Data

Analysis Population Description

All randomized participants who completed the study.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Measure Participants	16	16
Baseline	488 (80)	521 (116)
Change from Baseline at Week 6	-2.3 (28.7)	-5.2 (25.3)

3. Secondary Outcome

Title	Change From Baseline in Markers of Inflammation
Description	Blood was to be collected and tested for Tumor Necrosis Factor Alpha (TNF-α) and Monocyte Chemotactic Protein-1 (MCP-1), markers of inflammation; However, due to lack of funding, blood samples were not analyzed and data for levels of inflammation markers were not collected.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Analysis was not performed.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Measure Participants	0	0

4. Secondary Outcome

Title	Change From Baseline in Insulin Sensitivity Index (ISI)
Description	Insulin sensitivity was measured using the 75 gram (G) glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 milliliters (mL) of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. Insulin sensitivity index was calculated by Matsuda and Defronzo's formula using the values obtained. A positive change from Baseline (increase in insulin sensitivity) indicates improvement.
Time Frame	Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)

Outcome Measure Data

Analysis Population Description

All randomized participants who completed the study.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Measure Participants	16	16
Baseline	3.7 (1.4)	4.6 (3.7)
Change from Baseline at Week 6	-0.1 (0.8)	-1.1 (2.7)

5. Secondary Outcome

Title	Change From Baseline in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
Description	Insulin resistance was measured using the 75 G glucose tolerance test. Participants ingested 75 grams of glucose in 300-400 mL of water over 5 minutes. Blood samples were taken before ingesting glucose and then every 30 minutes for 120 minutes. HOMA-IR was calculated using the Insulin and glucose levels obtained. A negative change (decrease in insulin resistance) indicates improvement.
Time Frame	Baseline and Week 6 (Prior to ingesting glucose and every 30 minutes for 120 minutes)

Outcome Measure Data

Analysis Population Description

All randomized participants who completed the study.

Arm/Group Title	Spironolactone	Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.	Placebo-matching spironolactone once daily for 6 weeks.
Measure Participants	16	16
Baseline	2.7 (1.2)	3.4 (3.2)
Change from Baseline at Week 6	0.1 (1.1)	0.1 (4.4)

Adverse Events

Time Frame	6 Weeks
Arm/Group Title	Spironolactone		Placebo
Arm/Group Description	Spironolactone 50 mg once daily for 6 weeks.		Placebo-matching spironolactone once daily for 6 weeks.
All Cause Mortality
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Serious Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Spironolactone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.