RDVCGH: Racial Differences in Vagal Control of Glucose Homeostasis

• Sponsor: Vanderbilt University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02365285
• Collaborator: Doris Duke Charitable Foundation (Other)
• Enrollment: 23
• Location: 1
• Arms: 2
• Actual Duration (Months): 31.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The investigators will test the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity and reduce oxidation in AAW compared to whites.

Condition or Disease	Intervention/Treatment	Phase
Obesity	Drug: Galantamine; Drug: Placebo Oral Capsule; Drug: Intralipid; Drug: Heparin	Phase 1/Phase 2

Detailed Description

Obesity has a greater detrimental impact on the health of African American women (AAW) than on any other racial or gender group. Nearly 80% of AAW are overweight or obese. Reduced insulin sensitivity is more prevalent among AAW as compared to white women and men of both races. This condition puts AAW at increased risk for the development of type 2 diabetes mellitus. The exact mechanism underlying these pathophysiological differences remains unknown. The investigators have found that obese AAW have decreased parasympathetic nerve (PNS) activity compared to whites and recent studies in animal models showed that the PNS confers protection against oxidative stress. In our AA cohort, PNS activity was directly correlated with insulin sensitivity in obese AAW even after controlling for differences in age, blood pressure and visceral adiposity. Equally important, the investigators also showed that the decrease in insulin sensitivity was associated with increased oxidative stress as measured by plasma levels of F2-isoprostanes. Taken together these findings lead us to hypothesize that the decreased PNS activity in obese AAW compared to white women has deleterious effects on oxidative stress and insulin sensitivity.The investigators will test the hypothesis that acute central acetylcholinesterase inhibition will restore PNS activity and reduce oxidation in AAW compared to whites.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Racial Differences in Vagal Control of Glucose Homeostasis
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Oct 5, 2017
• Actual Study Completion Date: Oct 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Galantamine 16 mg then placebo Galantamine 16 mg po one time dose then placebo on 2nd visit	Drug: Galantamine; 16 mg po prior to the infusion of intralipid; Other Names: Razadyne ; Drug: Placebo Oral Capsule; Placebo oral capsule prior to the infusion of intralipid/heparin; Drug: Intralipid; Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine; Other Names: I.V. Fat Emulsion ; Drug: Heparin; heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Placebo Comparator: Placebo then Galantamine 16 mg Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit	Drug: Galantamine; 16 mg po prior to the infusion of intralipid; Other Names: Razadyne ; Drug: Placebo Oral Capsule; Placebo oral capsule prior to the infusion of intralipid/heparin; Drug: Intralipid; Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine; Other Names: I.V. Fat Emulsion ; Drug: Heparin; heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine

Outcome Measures

Primary Outcome Measures

1. Change in Oxidative Stress: Baseline to 2 Hours [Baseline to 2 hours]

   Measure F-2 isoprostanes as a marker of oxidation

2. Change in Oxidative Stress: Baseline to 4 Hours [Baseline to 4 hours]

   Measure F-2 isoprostanes as a marker of oxidation

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Female

• African American or white (race will be self-defined, but only subjects who report both parents of the same race will be included)

• 18-60 years old

• BMI 30-45 Kg/m2

• Not pregnant or breastfeeding

Exclusion Criteria:

• Pregnant or breastfeeding

• Diabetes diagnosis (defined by the American Diabetes Association (ADA) criteria)38

• Cardiovascular disease such as myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy.

• Arrhythmia (first-, second-, and third-degree atrioventricular (AV) block)

• Significant weight change >5% in the past 3 months

• Impaired hepatic function (AST and/or Alanine transaminase (ALT) > one and one half times (1.5X) upper limit of normal range)

• Impaired renal function (eGFR <60ml/min)

• Users of strong inhibitors of Cytochrome P450 3A4 (CYP3A4) or cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6)

• Users of other acetylcholinesterase inhibitors such as pyridostigmine or bethanechol

• History of alcohol or drug abuse

• Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study

• Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University Medical Center
• Doris Duke Charitable Foundation

Investigators

• Principal Investigator: Cyndya Shibao, MD, Vanderbilt University Medical Center, Clinical Pharmacology

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 5, 2017

More Information

Publications

None provided.

• Responsible Party: Cyndya Shibao, Medical Doctor, Assistant Professor of Medicine, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT02365285
• Other Study ID Numbers: 141552
• First Posted: Feb 18, 2015
• Last Update Posted: Mar 19, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• 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.: No
• Additional relevant MeSH terms: Heparin; Galantamine; Soybean oil, phospholipid emulsion

Study Results

Participant Flow

Pre-assignment Detail	52 participants were screen failures and did not receive an intervention.

Arm/Group Title	Galantamine 16 mg Then Placebo (African-American)	Galantamine 16 mg Then Placebo (White)	Placebo Then Galantamine 16 mg (African-American)	Placebo Then Galantamine 16 mg (White)
Arm/Group Description	Galantamine 16 mg po one time dose then placebo on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Galantamine 16 mg po one time dose then placebo on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Period Title: Overall Study
STARTED	7	6	7	3
COMPLETED	7	5	6	1
NOT COMPLETED	0	1	1	2

Baseline Characteristics

Arm/Group Title	Galantamine 16 mg Then Placebo (African-American)	Galantamine 16 mg Then Placebo (White)	Placebo Then Galantamine 16 mg (African-American)	Placebo Then Galantamine 16 mg (White)	Total
Arm/Group Description	Galantamine 16 mg po one time dose then placebo on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Galantamine 16 mg po one time dose then placebo on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose then Galantamine 16 mg on 2nd visit Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Total of all reporting groups
Overall Participants	7	6	7	3	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	6 100%	7 100%	3 100%	23 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 100%	6 100%	7 100%	3 100%	23 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	7 100%	0 0%	7 100%	0 0%	14 60.9%
White	0 0%	6 100%	0 0%	3 100%	9 39.1%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	6 100%	7 100%	3 100%	23 100%

Outcome Measures

1. Primary Outcome

Title	Change in Oxidative Stress: Baseline to 2 Hours
Description	Measure F-2 isoprostanes as a marker of oxidation
Time Frame	Baseline to 2 hours

Outcome Measure Data

Analysis Population Description

2 white participants dropped out due to nausea. 1 African-American was withdrawn, MD decision.

Arm/Group Title	Galantamine 16 mg (African-American)	Galantamine 16 mg (White)	Placebo (African-American)	Placebo (White)
Arm/Group Description	Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Measure Participants	13	7	13	7
Mean (Standard Deviation) [pg /ml]	-0.003 (0.012)	-0.006 (0.018)	0.01 (0.018)	-0.006 (0.01)

2. Primary Outcome

Title	Change in Oxidative Stress: Baseline to 4 Hours
Description	Measure F-2 isoprostanes as a marker of oxidation
Time Frame	Baseline to 4 hours

Outcome Measure Data

Analysis Population Description

1 white participant did not have 4 hour F-2 isoprostanes drawn after receiving placebo. 2 white participants dropped out due to nausea. 1 African-American was withdrawn, MD decision.

Arm/Group Title	Galantamine 16 mg (African-American)	Galantamine 16 mg(White)	Placebo (African-American)	Placebo(White)
Arm/Group Description	Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine	Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
Measure Participants	13	7	13	6
Mean (Standard Deviation) [pg/ml]	0 (0.016)	-0.008 (0.014)	0.003 (0.005)	-0.008 (0.014)

Adverse Events

Time Frame	Baseline through 2nd study day, usually about 1 month.
Arm/Group Title	Galantamine 16 mg (African-American)		Galantamine 16 mg (White)		Placebo (African-American)		Placebo (White)
Arm/Group Description	Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine		Galantamine 16 mg po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine		Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine		Placebo capsule po one time dose Intralipid: Intralipid 20% will be infused at 0.8 mL/m2/min for 4h after oral placebo or Galantamine Heparin: heparin bolus of 1000 U will be followed by 200 U/h infusion for 4h after oral placebo or Galantamine
All Cause Mortality
	Galantamine 16 mg (African-American)		Galantamine 16 mg (White)		Placebo (African-American)		Placebo (White)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/9 (0%)		0/14 (0%)		0/9 (0%)
Serious Adverse Events
	Galantamine 16 mg (African-American)		Galantamine 16 mg (White)		Placebo (African-American)		Placebo (White)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/9 (0%)		0/14 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Galantamine 16 mg (African-American)		Galantamine 16 mg (White)		Placebo (African-American)		Placebo (White)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		6/9 (66.7%)		2/14 (14.3%)		2/9 (22.2%)
Gastrointestinal disorders
Nausea and Vomiting	3/14 (21.4%)	3	5/9 (55.6%)	5	2/14 (14.3%)	2	1/9 (11.1%)	1
Abdominal Pain	1/14 (7.1%)	1	0/9 (0%)	0	0/14 (0%)	0	0/9 (0%)	0
General disorders
Lightheadness	0/14 (0%)	0	0/9 (0%)	0	1/14 (7.1%)	1	1/9 (11.1%)	1
Headache	0/14 (0%)	0	1/9 (11.1%)	1	0/14 (0%)	0	0/9 (0%)	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.