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BNP Pharmacodynamics and Effects on Metabolism in Lean and Obese Subjects

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ClinicalTrials.gov Identifier: NCT01977859
Recruitment Status : Completed
First Posted : November 7, 2013
Last Update Posted : February 14, 2018
Sponsor:
Collaborator:
Sanford-Burnham Medical Research Institute
Information provided by (Responsible Party):
Translational Research Institute for Metabolism and Diabetes, Florida

Study Description
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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.

Condition or disease Intervention/treatment Phase
Obesity Cardiovascular Disease Hypertension Diabetes Drug: Nesiritide Drug: Saline Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: BNP Pharmacodynamics and Effects on Metabolism in Lean and Obese Subjects
Study Start Date : November 2013
Actual Primary Completion Date : February 15, 2016
Actual Study Completion Date : February 28, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Nesiritide

Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: Saline
Saline infusion
 Drug: Saline
Active Comparator: Nesiritide 1.0
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).
 Drug: Nesiritide
Active Comparator: Nesiritide 2.0
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).
 Drug: Nesiritide
Active Comparator: Nesiritide 4.0
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).
 Drug: Nesiritide
Active Comparator: Nesiritide 8.0
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).
 Drug: Nesiritide


Outcome Measures
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Primary Outcome Measures :
  1. Difference in level of B-type Natriuretic Peptide (BNP) [ Time Frame: 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 :
  1. Differences in the expression of NPRC [ Time Frame: 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

  2. Determine whether short term infusion of rhBNP increases metabolic rate and/or fat oxidation [ Time Frame: 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.

  3. 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 [ Time Frame: 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).

  4. Difference in responses of lean and obese subjects [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01977859


Locations
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United States, Florida
Translational Research Institute for Metabolism and Diabetes
Orlando, Florida, United States, 32804
Sponsors and Collaborators
Translational Research Institute for Metabolism and Diabetes, Florida
Sanford-Burnham Medical Research Institute
Investigators
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Principal Investigator: Richard E. Pratley, MD AdventHealth
More Information
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Additional Information:

Publications:

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Responsible Party: Translational Research Institute for Metabolism and Diabetes, Florida
ClinicalTrials.gov Identifier: NCT01977859    
Other Study ID Numbers: TRIMDFH 472930
First Posted: November 7, 2013    Key Record Dates
Last Update Posted: February 14, 2018
Last Verified: February 2018
Keywords provided by Translational Research Institute for Metabolism and Diabetes, Florida:
B-type Natriuretic Peptide
Metabolism
Insulin infusion
Additional relevant MeSH terms:
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Cardiovascular Diseases
Natriuretic Peptide, Brain
Natriuretic Agents
Physiological Effects of Drugs