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

• ClinicalTrials.gov Identifier: NCT03429946
• Recruitment Status: Active, not recruiting
• First Posted: February 12, 2018
• Last Update Posted: March 30, 2021
• Sponsor: Brigham and Women's Hospital
• Collaborators: Beth Israel Deaconess Medical Center; National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Gail Kurr Adler, Brigham and Women's Hospital

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 (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: 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: July 17, 2013
• Estimated Primary Completion Date: January 4, 2022
• Estimated Study Completion Date: January 4, 2022

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 Name: 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 Name: 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 Name: Euglycemic Hyperinsulinemic Clamp Procedure

Outcome Measures

Primary Outcome Measures :

1. Baroreflex Sensitivity assessed on Day 3 [ Time Frame: 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 :

1. Muscle sympathetic nerve activity assessed on Day 3 [ 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) ]
   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

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

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

More Information

• Responsible Party: Gail Kurr Adler, Principal Investigator, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT03429946
• Other Study ID Numbers: 2004P001233-B; R01HL109634 ( U.S. NIH Grant/Contract ); K24HL103845 ( U.S. NIH Grant/Contract ); UL1TR001102 ( U.S. NIH Grant/Contract )
• First Posted: February 12, 2018
• Last Update Posted: March 30, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• 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.
• Access Criteria: Access to data must be approved by the IRB at our institution.

• 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

Additional relevant MeSH terms:

Hypoglycemia; Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemic Agents; Spironolactone; Mineralocorticoid Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Diuretics, Potassium Sparing; Diuretics; Natriuretic Agents