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Hypoglycemia and Autonomic Nervous System Function-B (HypoANS-B)

Primary Purpose

Hypoglycemia, Healthy

Status
Active
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Spironolactone
Placebo
Hypoglycemic Hyperinsulinemic Clamp
Euglycemic Hyperinsulinemic Clamp
Sponsored by
Brigham and Women's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Hypoglycemia

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Beth Israel Deaconess Medical Center
  • Brigham and Women's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

Hypoglycemia and Spironolactone

Hypoglycemia and Placebo

Euglycemia and Placebo

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Baroreflex Sensitivity assessed on Day 3
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
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.

Full Information

First Posted
January 30, 2018
Last Updated
July 18, 2022
Sponsor
Brigham and Women's Hospital
Collaborators
Beth Israel Deaconess Medical Center, National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT03429946
Brief Title
Hypoglycemia and Autonomic Nervous System Function-B
Acronym
HypoANS-B
Official Title
Hypoglycemia and Autonomic Nervous System Function
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 17, 2013 (Actual)
Primary Completion Date
January 4, 2024 (Anticipated)
Study Completion Date
January 4, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Brigham and Women's Hospital
Collaborators
Beth Israel Deaconess Medical Center, National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. 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.
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..

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypoglycemia, Healthy

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
Participants complete all 3 arms of the study in random order.
Masking
ParticipantInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hypoglycemia and Spironolactone
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Hypoglycemia and Placebo
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Euglycemia and Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Spironolactone
Intervention Description
Participants will receive spironolactone 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Participants will receive placebo 12 hours and 3 hours before the initiation of the hyperinsulinemic clamp treatment.
Intervention Type
Other
Intervention Name(s)
Hypoglycemic Hyperinsulinemic Clamp
Other Intervention Name(s)
Hypoglycemic Hyperinsulinemic Clamp Procedure
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Euglycemic Hyperinsulinemic Clamp
Other Intervention Name(s)
Euglycemic Hyperinsulinemic Clamp Procedure
Intervention Description
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.
Primary Outcome Measure Information:
Title
Baroreflex Sensitivity assessed on Day 3
Description
Comparison of Day 3 baroreflex sensitivity (milliseconds/mm Hg) assessed during Hypoglycemic hyperinsulinemic clamp + Placebo treatment as compared to Hypoglycemic hyperinsulinemic clamp + Spironolactone treatment.
Time Frame
Baroreflex sensitivity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)
Secondary Outcome Measure Information:
Title
Muscle sympathetic nerve activity assessed on Day 3
Description
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.
Time Frame
Muscle sympathetic nerve activity is assessed on the 3rd day of each treatment (i.e. about 16 hours after completion of the hyperinsulinemic clamp)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gail Adler, MD/PhD
Organizational Affiliation
Brigham and Women's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Roy Freeman, MD
Organizational Affiliation
Beth Israel Deaconess Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The data collected will comply with the NIH requirements for timely release and data sharing. Data will be shared in the form of publications and presentations in scientific forums. As the NIH has noted, the investigators reserve the right to keep the data restricted in order to perform the initial analyses for this grant proposal and will continue to use the data for further, but not prolonged, exclusive use. Of note, the sharing of this data will be limited by at least the following issues, some unique to this proposal and some not unique. Some of the data obtained in this study is defined to be sensitive in nature, which may restrict its ability to be shared. Data may only be shared with the approval of our IRB and is limited by HIPPA and any other regulations that may be promulgated during the course of this proposal.
IPD Sharing Time Frame
Data will be shared after completion of study and initial publications which we anticipate to be within 18 months of the final participant completing the study protocol.
IPD Sharing Access Criteria
Access to data must be approved by the IRB at our institution.

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Hypoglycemia and Autonomic Nervous System Function-B

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