HypoANS-B: Hypoglycemia and Autonomic Nervous System Function-B

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03429946

Collaborator

Beth Israel Deaconess Medical Center (Other), National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Enrollment

Locations

Arms

125.6

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study tests the hypothesis that, compared to prior normal blood sugar, prior low blood sugar impairs cardiovascular autonomic function. The proposed studies will also test the hypothesis that the effects of prior low blood sugar on cardiovascular autonomic function are blocked by administration of a mineralocorticoid receptor antagonist.

Condition or Disease	Intervention/Treatment	Phase
Hypoglycemia Healthy	Drug: Spironolactone Drug: Placebo Other: Hypoglycemic Hyperinsulinemic Clamp Other: Euglycemic Hyperinsulinemic Clamp	Phase 4

Detailed Description

This study involves three interventions, which are performed in random order. Each intervention involves a 3-day inpatient visit. There is a space of 1-3 months between interventions. The three interventions are: 1) placebo with a hyperinsulinemic euglycemic clamp, 2) spironolactone with a hyperinsulinemic hypoglycemic clamp, or 3) placebo with a hyperinsulinemic hypoglycemic clamp. Each 3-day inpatient visit includes the following. On Day 1, autonomic testing is performed. Autonomic testing includes assessment of Baroreflex Sensitivity (BRS). BRS is assessed using the Modified Oxford procedure, which involves sequential administration of nitroprusside and phenylephrine while measuring heart rate and beat to beat blood pressure with a finapress and assessing Muscle Sympathetic Nerve Activity (MSNA). MSNA is measured using microelectrodes placed near the peroneal nerve. On Day 2, hyperinsulinemic clamps are performed with pre-treatment with either placebo or spironolactone. Modified Oxford Procedures are performed prior to and during each clamp on Day 2. On Day 3, the autonomic testing performed on Day 1 is repeated..

Study Design

Study Type:

Interventional

Actual Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Participants complete all 3 arms of the study in random order.Participants complete all 3 arms of the study in random order.

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Masking Description:

Investigator performing the clamp studies is only aware of the type of clamp - euglycemic versus hypoglycemic - but not aware of placebo versus spironolactone.

Primary Purpose:

Basic Science

Official Title:

Hypoglycemia and Autonomic Nervous System Function

Actual Study Start Date :

Jul 17, 2013

Anticipated Primary Completion Date :

Jan 4, 2024

Anticipated Study Completion Date :

Jan 4, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hypoglycemia and Spironolactone Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of 100 mg of spironolactone - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Drug: Spironolactone Participants will receive spironolactone 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment. Other: Hypoglycemic Hyperinsulinemic Clamp Participants undergo two 120-minute hypoglycemic (50 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity. Other Names: Hypoglycemic Hyperinsulinemic Clamp Procedure
Active Comparator: Hypoglycemia and Placebo Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Drug: Placebo Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment. Other: Hypoglycemic Hyperinsulinemic Clamp Participants undergo two 120-minute hypoglycemic (50 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity. Other Names: Hypoglycemic Hyperinsulinemic Clamp Procedure
Placebo Comparator: Euglycemia and Placebo Participants undergo two 120-minute euglycemic hyperinsulinemic clamp procedures (90 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.	Drug: Placebo Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment. Other: Euglycemic Hyperinsulinemic Clamp Participants undergo two 120-minute euglycemic (90 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit.Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity. Other Names: Euglycemic Hyperinsulinemic Clamp Procedure

Arm

Intervention/Treatment

Active Comparator: Hypoglycemia and Spironolactone

Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of 100 mg of spironolactone - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.

Drug: Spironolactone

Participants will receive spironolactone 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.

Other: Hypoglycemic Hyperinsulinemic Clamp

Participants undergo two 120-minute hypoglycemic (50 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.

Other Names:

Hypoglycemic Hyperinsulinemic Clamp Procedure

Active Comparator: Hypoglycemia and Placebo

Participants undergo two 120-minute hypoglycemic hyperinsulinemic clamp procedures (50 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.

Drug: Placebo

Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.

Other: Hypoglycemic Hyperinsulinemic Clamp

Other Names:

Hypoglycemic Hyperinsulinemic Clamp Procedure

Placebo Comparator: Euglycemia and Placebo

Participants undergo two 120-minute euglycemic hyperinsulinemic clamp procedures (90 mg/dL) - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit. Participants receive two doses of placebo - one dose 12 hours and one dose 3 hours before the first clamp starts. Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.

Drug: Placebo

Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.

Other: Euglycemic Hyperinsulinemic Clamp

Participants undergo two 120-minute euglycemic (90 mg/dL) hyperinsulinemic clamps - an AM clamp from about 9 am to 11 am and a PM clamp from 1 pm to 3 pm on Day 2 of a 3-Day study visit.Modified Oxford Procedure is performed in duplicate at six time points - on Day 1, before the AM hyperinsulinemic clamp, during the AM hyperinsulinemic clamp, before the PM hyperinsulinemic clamp, during the PM hyperinsulinemic clamp, and on Day 3. The Modified Oxford procedure is performed to calculate baroreflex sensitivity.

Other Names:

Euglycemic Hyperinsulinemic Clamp Procedure

Outcome Measures

Primary Outcome Measures

Baroreflex Sensitivity assessed on Day 3 [Baroreflex sensitivity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)]
Comparison of Day 3 baroreflex sensitivity (milliseconds/mm Hg) assessed during Hypoglycemic hyperinsulinemic clamp + Placebo treatment as compared to Hypoglycemic hyperinsulinemic clamp + Spironolactone treatment.

Secondary Outcome Measures

Muscle sympathetic nerve activity assessed on Day 3 [Muscle sympathetic nerve activity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)]
Comparison of Day 3 muscle sympathetic nerve activity (bursts/min) assessed during hypoglycemic hyperinsulinemic clamp + placebo treatment as compared to hypoglycemic hyperinsulinemic clamp + spironolactone treatment.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy volunteers
Males and females age 18 to 55 years

Exclusion Criteria:

Pregnancy
Lactation
Clinically evident coronary artery, cerebrovascular, or peripheral vascular disease, or presence of systemic illness that might affect autonomic function. Such illnesses include diabetes mellitus, congestive heart failure, hypertension, renal, pulmonary, hepatic disease, anemia, malignancies, untreated thyroid disease, and alcoholism.
Current major depressive illness
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 thyroxine
Known hypersensitivity to nitroglycerin, nitroprusside and/or phenylephrine.
Blood pressure > 140/90 mmHg
Creatinine > 1.5 mg/dL
Serum potassium >5.2 mmol/L
Estimated GFR < 50 mL/min
Use of Viagra, Cialis, and similar drugs within 72 hours of admission.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
2	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

Brigham and Women's Hospital
Beth Israel Deaconess Medical Center
National Heart, Lung, and Blood Institute (NHLBI)

Investigators

Principal Investigator: Gail Adler, MD/PhD, Brigham and Women's Hospital
Principal Investigator: Roy Freeman, MD, Beth Israel Deaconess Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Gail Kurr Adler, Principal Investigator, Brigham and Women's Hospital

ClinicalTrials.gov Identifier:

NCT03429946

Other Study ID Numbers:

2004P001233-B
R01HL109634
K24HL103845
UL1TR001102

First Posted:

Feb 12, 2018

Last Update Posted:

Jul 20, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Additional relevant MeSH terms:

Hypoglycemia

Hypoglycemic Agents

Spironolactone

Study Results

No Results Posted as of Jul 20, 2022