Angiotensin-(1-7) and Energy Expenditure in Human Obesity

• ClinicalTrials.gov Identifier: NCT03777215
• Recruitment Status: Recruiting
• First Posted: December 17, 2018
• Last Update Posted: December 14, 2021
• Sponsor: Amy Arnold
• Information provided by (Responsible Party): Amy Arnold, Milton S. Hershey Medical Center

Tracking Information

• First Submitted Date: December 12, 2018
• First Posted Date: December 17, 2018
• Last Update Posted Date: December 14, 2021
• Actual Study Start Date: September 26, 2019
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 18, 2019)

• Resting energy expenditure [ Time Frame: 120 minutes ]
  Change in resting energy expenditure measured by indirect calorimetry at baseline and at end of angiotensin-(1-7) versus saline infusion.
• Uncoupling protein 1 [ Time Frame: 120 minutes ]
  White adipose tissue biopsies will be taken at end of angiotensin-(1-7) versus saline infusion to assess gene expression of the heat producing (thermogenic) marker uncoupling protein 1.

Original Primary Outcome Measures (submitted: December 14, 2018)

Energy expenditure [ Time Frame: 120 minutes ]

Change in energy expenditure measured by indirect calorimetry at baseline and at end of angiotensin-(1-7) versus saline infusion.

Current Secondary Outcome Measures (submitted: April 18, 2019)

• Blood pressure [ Time Frame: 120 minutes ]
  Change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion
• Heart rate [ Time Frame: 120 minutes ]
  Change in heart rate following angiotensin-(1-7) versus saline infusion

Original Secondary Outcome Measures (submitted: December 14, 2018)

• Uncoupling Protein 1 [ Time Frame: 120 minutes ]
  White adipose tissue biopsies will be taken at end of angiotensin-(1-7) versus saline infusion to assess gene expression of the heat producing (thermogenic) marker uncoupling protein 1.
• Abdominal heat production [ Time Frame: 1 minute at baseline and end of infusion ]
  Change in abdominal heat production will be measured by infrared heat photographs taken at baseline and at end of angiotensin-(1-7) versus saline infusion.
• Blood pressure [ Time Frame: 120 minutes ]
  Change in arm and finger cuff blood pressure following angiotensin-(1-7) versus saline infusion
• Angiotensin II [ Time Frame: 120 minutes ]
  Change in circulating levels of angiotensin II measured at baseline and following angiotensin-(1-7) versus saline infusion.
• Insulin [ Time Frame: 120 minutes ]
  Change in circulating levels of insulin at baseline and following angiotensin-(1-7) versus saline infusion.
• Angiotensin-(1-7) [ Time Frame: 120 minutes ]
  Change in circulating levels of angiotensin-(1-7) measured at baseline and following angiotensin-(1-7) versus saline infusion.
• Plasma Renin Activity [ Time Frame: 120 minutes ]
  Change in plasma renin activity measured at baseline and following angiotensin-(1-7) versus saline infusion.
• Aldosterone [ Time Frame: 120 minutes ]
  Change in circulating levels of aldosterone measured at baseline and following angiotensin-(1-7) versus saline infusion.
• Glucose [ Time Frame: 120 minutes ]
  Change in circulating levels of glucose measured at baseline and following angiotensin-(1-7) versus saline infusion.
• Free Fatty Acids [ Time Frame: 120 minutes ]
  Change in circulating levels of free fatty acids measured at baseline and following angiotensin-(1-7) versus saline infusion.

Current Other Pre-specified Outcome Measures (submitted: April 18, 2019)

• Skin temperature [ Time Frame: 120 minutes ]
  Change in skin temperature following angiotensin-(1-7) versus saline infusion
• Skin blood flow [ Time Frame: 120 minutes ]
  Change in skin blood flow following angiotensin-(1-7) versus saline infusion
• Abdominal heat production [ Time Frame: 120 minutes ]
  Change in abdominal heat production as measured by thermal imaging following angiotensin-(1-7) versus saline infusion
• Catecholamines [ Time Frame: 120 minutes ]
  Change in plasma catecholamines following angiotensin-(1-7) versus saline infusion
• Insulin [ Time Frame: 120 minutes ]
  Change in plasma insulin levels following angiotensin-(1-7) versus saline infusion
• Glucose [ Time Frame: 120 minutes ]
  Change in plasma glucose levels following angiotensin-(1-7) versus saline infusion
• Fatty acids [ Time Frame: 120 minutes ]
  Change in plasma free fatty acid levels following angiotensin-(1-7) versus saline infusion
• Angiotensin II [ Time Frame: 120 minutes ]
  Change in plasma angiotensin II levels following angiotensin-(1-7) versus saline infusion
• Angiotensin-(1-7) [ Time Frame: 120 minutes ]
  Change in plasma angiotensin-(1-7) levels following angiotensin-(1-7) versus saline infusion
• Renin [ Time Frame: 120 minutes ]
  Change in plasma renin activity following angiotensin-(1-7) versus saline infusion
• Aldosterone [ Time Frame: 120 minutes ]
  Change in plasma aldosterone levels following angiotensin-(1-7) versus saline infusion

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Angiotensin-(1-7) and Energy Expenditure in Human Obesity
• Official Title: Angiotensin-(1-7) and Energy Expenditure in Human Obesity
• Brief Summary: The objective of this study is to better define the role of the hormone angiotensin-(1-7) in energy balance. We will test the overall hypothesis that angiotensin-(1-7) increases resting energy expenditure and promotes markers of heat production (thermogenesis) in white adipose tissue in human obesity.
• Detailed Description: Angiotensin-(1-7) is a beneficial hormone of the renin-angiotensin system known to produce positive cardiovascular and metabolic effects in animal models. In this study, the investigators will determine if angiotensin-(1-7) can increase resting energy expenditure and promote white adipose tissue heat production (thermogenesis) in obese human subjects. The investigators will perform a randomized, double-blind, two-arm parallel group study to determine effects of acute intravenous angiotensin-(1-7) versus saline infusion on resting energy expenditure measured by indirect calorimetry in obese human participants. In addition, blood pressure and heart rate will be measured and blood samples obtained to measure for changes in circulating renin-angiotensin system and metabolic hormones. Abdominal subcutaneous white adipose biopsies will also be obtained from obese human participants during acute angiotensin-(1-7) versus saline infusions to examine for changes in gene expression for markers of thermogenesis. The findings from these studies will advance understanding of hormonal mechanisms involved in the etiology of obesity, and provide new insight into the potential for targeting angiotensin-(1-7) to improve energy balance in human obesity.
• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Other
• Condition: Obesity

Intervention

• Drug: Angiotensin-(1-7)
  This is a biologically active beneficial hormone of the renin-angiotensin system.
  Other Name: Angiotensin I/II (1-7) Acetate
• Drug: Saline
  Saline will be used as the placebo comparator.
  Other Names:

  • 0.9% sodium chloride
  • normal saline

Study Arms

• Experimental: Angiotensin-(1-7)
  Subjects will receive intravenous infusion of three ascending doses of angiotensin-(1-7). The doses are: 2, 4, and 8 ng/kg/min. Each dose will be maintained for 10 minutes, with the highest dose maintained for an additional 90 minutes. The total infusion period is 120 minutes.
  Intervention: Drug: Angiotensin-(1-7)
• Placebo Comparator: Placebo
  Subjects will receive intravenous infusion of saline that is matched in volume to the angiotensin-(1-7). The total infusion period is 120 minutes.
  Intervention: Drug: Saline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 14, 2018): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2023
• Estimated Primary Completion Date: September 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Men and women of all races
• Capable of giving informed consent
• Age 18-60 years
• Body mass index (BMI) between 30-40 kg/m2
• Satisfactory history and physical exam

Exclusion Criteria:

• Age ≤ 17 or ≥ 61 years
• Pregnant, nursing, or postmenopausal women
• Decisional impairment
• Prisoners
• Alcohol or drug abuse
• Current smokers
• Highly trained athletes
• Claustrophobia
• Subjects with >5% weight change in the past 3 months
• Evidence of type I or type II diabetes (fasting glucose > 126 mg/dL or use of anti-diabetic medications)
• History of serious cardiovascular disease other than hypertension (e.g. myocardial infarction within 6 months, symptomatic coronary artery disease, presence of angina pectoris, significant arrhythmia, congestive heart failure, deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis, hypertrophic cardiomyopathy) or cerebrovascular disease (e.g. cerebral hemorrhage, stroke, transient Ischemic attack).
• History or presence of immunological or hematological disorders
• Impaired hepatic function (aspartate aminotransferase or alanine aminotransferase levels >2 times upper limit of normal range)
• Impaired renal function (serum creatinine >2.0 mg/dl)
• Anemia
• Treatment with anticoagulants (e.g. warfarin)
• Treatment with chronic systemic glucocorticoid therapy (>7 consecutive days in 1 month)
• Treatment with medications influencing energy expenditure (e.g. psychostimulants)
• Treatment with any investigational drug in the 1-month preceding the study
• Inability to give, or withdraw, informed consent

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Aimee C Cauffman, BSN; 717-531-1617; acauffman@pennstatehealth.psu.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03777215
• Other Study ID Numbers: 00009895
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual participant data will not be made available to other researchers.

• Responsible Party: Amy Arnold, Milton S. Hershey Medical Center
• Study Sponsor: Amy Arnold
• Collaborators: Not Provided

Investigators

• Principal Investigator: Amy C Arnold, PhD; Pennsylvania State University College of Medicine

• PRS Account: Milton S. Hershey Medical Center
• Verification Date: December 2021