BNP Pharmacodynamics and Effects on Metabolism in Lean and Obese Subjects

Phase 1

Completed

• Conditions: Cardiovascular Disease; Hypertension; Diabetes; Obesity
• Interventions: Drug: Saline; Drug: Nesiritide

• Registration Number: NCT01977859
• Lead Sponsor: AdventHealth Translational Research Institute

Brief Summary

The purpose of this study is to collect data to help researchers better understand the various causes of obesity, which may lead to the development of new obesity treatment options.

Detailed Description

Obesity is major metabolic health concern and the potential beneficial effects of natriuretic peptides, specifically B-type natriuretic peptide (BNP) on adipocyte biology, energy expenditure and body weight could be of great significance. This study will provide insight into the mechanisms of dysregulation of the natriuretic peptides system in obesity and will contribute to delineate the roles and the clinical importance of BNP in the treatment of obesity.

Study Timeline

• Study First Submitted: 2013-10-31
• Study First Submitted QC: 2013-10-31
• Study Start: 2013-11
• Study First Posted: 2013-11-07
• Primary Completion: 2016-02-15
• Study Completion: 2017-02-28
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-13
• Last Update Posted: 2018-02-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 4

Inclusion Criteria

• Age 18-65 years, inclusive
• Men and women
• Able to provide written, informed consent
• Weight stable (± 3 kg) during the 3 months prior to enrollment
• BMI ≤ 25 kg/m2 for lean subjects or ≥ 30 kg/m2 for obese subjects

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Exclusion Criteria

• 1. Diagnosed with any of the following co-morbidities: a) coronary artery disease, angina or heart failure, b) diabetes, c) bleeding disorders, d) infections, e) hepatitis and/or cirrhosis, f) severe asthma or Chronic obstructive pulmonary disease (COPD), g) renal insufficiency, h) bariatric surgery, i) inflammatory bowel disease or malabsorption, j) cancer within the last 3 years (except non-melanoma skin cancer or treated cervical carcinoma in situ), k) psychiatric or eating disorders, l) untreated or inadequately controlled thyroid or other endocrine disorders, m) active rheumatoid arthritis or other inflammatory rheumatic disorder
• Pregnant or nursing women
• Presence of clinically significant abnormalities on electrocardiogram;
• Smoking
• Known hypersensitivity to nesiritide or any of its excipients
• Poor intravenous access
• Use of medications: a) nitrates, b) beta-blockers, c) digoxin, d) anti-diabetic agents, e) oral, injected or chronic topical steroids (inhaled steroids for mild asthma are acceptable), f) chronic use of aspirin or other non-steroidal anti-inflammatory drugs, including COX-2 inhibitors, g) other drugs known to affect immune or metabolic function and h) orlistat, phentermine or other weight loss or anorectic agents.
• Your blood pressure at your screening visit is less than or equal to 100/60 or greater than or equal to 160/100.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Saline	Saline	Saline infusion
Nesiritide 1.0	Nesiritide	Nesiritide infused for 90 minute, initially at 0.5 pmol/kg/min and doubled every 15 minutes to achieve a target infusion rate of 1.0 pmol/kg/min, followed by a steady state infusion at the target rate for an additional 150 minutes (4 hours total).
Nesiritide 2.0	Nesiritide	Nesiritide infused for 90 minute, initially at 0.5 pmol/kg/min and doubled every 15 minutes to achieve a target infusion rate of 2.0 pmol/kg/min, followed by a steady state infusion at the target rate for an additional 150 minutes (4 hours total).
Nesiritide 4.0	Nesiritide	Nesiritide infused for 90 minute, initially at 0.5 pmol/kg/min and doubled every 15 minutes to achieve a target infusion rate of 4.0 pmol/kg/min, followed by a steady state infusion at the target rate for an additional 150 minutes (4 hours total).
Nesiritide 8.0	Nesiritide	Nesiritide infused for 90 minute, initially at 0.5 pmol/kg/min and doubled every 15 minutes to achieve a target infusion rate of 8.0 pmol/kg/min, followed by a steady state infusion at the target rate for an additional 150 minutes (4 hours total).

Primary Outcome Measures

Name	Time	Method
Difference in level of B-type Natriuretic Peptide (BNP)	Days -2, 7, 14	Blood samples will be obtained at baseline, during the infusion and after the termination of the infusion for measurement of levels of recombinant human BNP (rhBNP) and N-terminal pro-brain natriuretic peptide (NTpro-BNP).

Secondary Outcome Measures

Name	Time	Method
Differences in the expression of NPRC	Day 7	Natriuretic peptides Type-A and Type-C (NPRA,NPRC) expression will be measured by RT-PCR in subcutaneous abdominal adipose tissue samples obtained by percutaneous biopsy prior to infusion of rhBNP and related to the Metabolic Clearance Rate (MCR) for BNP
determine whether short term infusion of rhBNP alters gene expression in subcutaneous adipose tissue and skeletal muscle in a pattern consistent with activation of thermogenic pathways	Day 7	Adipose tissue will be obtained from subcutaneous abdominal sites and skeletal muscle from the vastus lateralis by percutaneous biopsy prior to and after the infusion of rhBNP. The expression of Uncoupling Protein 1 (UCP1), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 α (PGC-1α), cytochrome c and PR domain containing 16 (PRDM16) (a significant factor in brown adipogenesis) will be measured by Reverse transcription polymerase chain reaction (RT-PCR).
Difference in responses of lean and obese subjects	Days -2, 7, 14	Blood pressure and heart rate will be monitored at 10 minute intervals with an automated blood pressure cuff to measure physiological response and to monitor hemodynamic status and safety. Fractional sodium excretion, cGMP and creatinine, and total urine output in response to the rhBNP infusion will be compared in lean and obese subjects. Blood samples will be obtained at baseline, during the infusion and after termination of the infusion for measurement of cyclic Guanosine 3´,5´-Cyclic Monophosphate (cGMP), Plasma Renin Activity (PRA), Aldosterone (ALD), Renin (REN), NE, glucose, insulin, Non-essential fatty acid (NEFA), glycerol, adiponectin, C-Reactive Protein (CRP), Tumor Necrosis Factor- α (TNF-α) and other cytokines/chemokines.
Determine whether short term infusion of rhBNP increases metabolic rate and/or fat oxidation	Day 7	Energy expenditure and substrate oxidation rates will be measured for 30 min at baseline, prior to the infusion of BNP, then continuously during the rhBNP infusion in a 3200 Liters Flex Room Calorimeter respiratory chambers.

Trial Locations

Locations (1)

Translational Research Institute for Metabolism and Diabetes; 🇺🇸 Orlando, Florida, United States