HypoMR: Hypoglycemia and the Mineralocorticoid Receptor

• Sponsor: Brigham and Women's Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01394627
• Collaborator: Robert Wood Johnson Foundation (Other), National Institutes of Health (NIH) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 21
• Location: 1
• Arms: 2
• Duration (Months): 67
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to look at whether blockade of the mineralocorticoid receptor will result in changes in the cardiovascular and inflammatory response to hypoglycemia.

Condition or Disease	Intervention/Treatment	Phase
Hypoglycemia	Drug: Eplerenone; Drug: Placebo	N/A

Detailed Description

The effect of ongoing hypoglycemia on cardiovascular autonomic function is unclear and the focus of this protocol. In our preliminary studies, the investigators demonstrated that baroreflex sensitivity is impaired during hypoglycemia in healthy individuals. Treatment with eplerenone (200mg total administered in two doses in the 15 hours prior to the hypoglycemic clamp) prevented this impairment.

The study is based on the overarching hypothesis that hypoglycemia leads to increases in aldosterone/mineralocorticoid receptor (MR) activity and increased cardiovascular injury.

This study will address the following Specific Aims:

To test the hypothesis that MR blockade will reduce the adverse effects of hypoglycemia on inflammation and on autonomic control of cardiovascular function.

The investigators will determine the effects of hypoglycemia (50 mg/dl for 2.0 hours) on the blood inflammatory factor interleukin-6 levels, and on cardiovascular autonomic function (baroreflex sensitivity) in each subject under two conditions - pretreatment with MR blockade (eplerenone) and pretreatment with placebo.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Hypoglycemia and the Mineralocorticoid Receptor
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eplerenone hypoglycemia (50 mg/dl) with pretreatment with two doses of eplerenone (100 mg of eplerenone per dose)	Drug: Eplerenone; 100mg x 2
Placebo Comparator: placebo hypoglycemia of 50 mg/dl plus placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Cardiovascular Autonomic Function [Baseline and 2 hours after hypoglycemia]

   Modified oxford procedures was performed in duplicate immediately prior to start of the hypoglycemic clamp and during the last 30 min of the clamp (i.e. during the last 30 min of exposure to 2 hours of hypoglycemia).. We calculated the baroreflex sensitivity (the relationship between RR interval and change in systolic blood pressure defined as the change in the inter-beat cardiac interval in milliseconds per unit change in blood pressure in mmHg) at each time point and then the change in baroreflex sensitivity (BRS during hypoglycemia minus BRS at baseline)

Secondary Outcome Measures

1. Change From Baseline in Inflammation [Baseline and 2 hours after hypoglycemia]

   Change in interleukin-6

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy volunteers

• Males and females age 18 to 40 years

Exclusion Criteria:

• Pregnancy

• Lactation

• Menopause

• Any medical condition other than treated hypothyroidism.

• Alcoholism

• Active tobacco use

• In all subjects, any individuals on oral, injected, inhaled or topical corticosteroids within the last year or oral contraceptives within the past 3 months will be excluded.

• Use of medications other than physiological thyroxine replacement

• Serum potassium >5.0 mmol/L

• Estimated glomerular filtration rate < 60 mL/min

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
• Robert Wood Johnson Foundation
• National Institutes of Health (NIH)
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Gail K Adler, MD, Brigham and Women's Hospital
• Principal Investigator: Gail K Adler, MD, PhD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gail Kurr Adler, Associate Professor, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01394627
• Other Study ID Numbers: 2010P002054; K24HL103845; R01HL109634; T32HL007609
• First Posted: Jul 14, 2011
• Last Update Posted: Nov 17, 2017
• Last Verified: Oct 1, 2017

• Additional relevant MeSH terms: Hypoglycemia; Eplerenone

Study Results

Participant Flow

Arm/Group Title	Placebo (Period 1) /Washout (Period 2)/Eplerenone (Period 3)	Eplerenone (Period 1) /Washout (Period 2)/Placebo (Period 3)
Arm/Group Description	hypoglycemia of 50 mg/dl with 1 day of placebo pretreatment then after 1-3 month washout hypoglycemia of 50 mg/dl with 1 day of eplerenone (100 mg x 2) pretreatment	hypoglycemia of 50 mg/dl with 1 day of eplerenone (100 mg x 2) pretreatment then after 1-3 month washout hypoglycemia of 50 mg/dl with 1 day of placebo pretreatment
Period Title: First Intervention (1 Day)
STARTED	8	13
COMPLETED	8	12
NOT COMPLETED	0	1
Period Title: First Intervention (1 Day)
STARTED	8	12
COMPLETED	7	12
NOT COMPLETED	1	0
Period Title: First Intervention (1 Day)
STARTED	7	12
COMPLETED	7	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description
Overall Participants	21
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	21 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.5 (5.6)
Sex: Female, Male (Count of Participants)
Female	5 23.8%
Male	16 76.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.8%
Not Hispanic or Latino	19 90.5%
Unknown or Not Reported	1 4.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 19%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 19%
White	12 57.1%
More than one race	1 4.8%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Cardiovascular Autonomic Function
Description	Modified oxford procedures was performed in duplicate immediately prior to start of the hypoglycemic clamp and during the last 30 min of the clamp (i.e. during the last 30 min of exposure to 2 hours of hypoglycemia).. We calculated the baroreflex sensitivity (the relationship between RR interval and change in systolic blood pressure defined as the change in the inter-beat cardiac interval in milliseconds per unit change in blood pressure in mmHg) at each time point and then the change in baroreflex sensitivity (BRS during hypoglycemia minus BRS at baseline)
Time Frame	Baseline and 2 hours after hypoglycemia

Outcome Measure Data

Analysis Population Description

We included the 13 subjects who completed each arm, had usable baroreflex sensitivity data for both treatments (placebo and eplerenone), and achieved a blood sugar during hypoglycemia of less than or equal to 3.0 mmol/L for each clamp.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	hypoglycemia (50 mg/dl) with pretreatment with two doses of eplerenone (100 mg of eplerenone per dose) Eplerenone: 100mg x 2	hypoglycemia of 50 mg/dl plus placebo Placebo
Measure Participants	13	13
Mean (Standard Deviation) [ms/mmHg]	-16.00 (18.39)	-16.59 (16.77)

2. Secondary Outcome

Title	Change From Baseline in Inflammation
Description	Change in interleukin-6
Time Frame	Baseline and 2 hours after hypoglycemia

Outcome Measure Data

Analysis Population Description

We included the 17 subjects who completed each arm and had interleukin-6 data for both arms (placebo and eplerenone). We calculated the change in IL-6 as IL-6 during hypoglycemia minus IL-6 at baseline.

Arm/Group Title	Eplerenone	Placebo
Arm/Group Description	hypoglycemia (50 mg/dl) with pretreatment with two doses of eplerenone (100 mg of eplerenone per dose) Eplerenone: 100mg x 2	hypoglycemia of 50 mg/dl plus placebo Placebo
Measure Participants	17	17
Mean (Standard Deviation) [pg/ml]	2.03 (1.27)	2.61 (2.63)

Adverse Events

Arm/Group Title	Eplerenone		Placebo
Arm/Group Description	hypoglycemia (50 mg/dl) with pretreatment with two doses of eplerenone (100 mg of eplerenone per dose) Eplerenone: 100mg x 2		hypoglycemia of 50 mg/dl plus placebo Placebo
All Cause Mortality
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Serious Adverse Events
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Eplerenone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (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.