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| ID | Type | Description | Link |
|---|---|---|---|
| CX001678 | Other Grant/Funding Number | VA CSR&D |
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Study drug no longer available
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Accumulating evidence suggests that the natriuretic peptide (NP) hormonal system has important effects on metabolism. However, more information is needed to better understand the effects of NPs on metabolism in humans. Therefore, the investigators propose a study to determine the effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in fat tissue suggestive of fat "beiging" in humans. Interventions that safely increase energy expenditure and promote fat "beiging" represent potential strategies for treating metabolic dysfunction due to obesity.
Objective: The natriuretic peptide (NP) hormonal system is well-known for its important role in blood pressure regulation. However, accumulating evidence suggests that the NPs have significant effects on metabolism as well. For instance, administration of B-type natriuretic peptide (BNP) to wild-type mice leads to increased energy expenditure, changes in gene expression in fat tissue suggestive of fat "beiging" (which may be associated with cardiovascular and metabolic benefits), and reduced fat accumulation. Although recent studies in rodents suggest that NPs have important metabolic effects, there are few prospective data on the metabolic effects of NPs in humans.
Therefore, the investigators propose a physiologic, proof-of-concept study to determine the acute effects of b-type natriuretic peptide (BNP) on energy and fat metabolism in humans. The investigators' primary hypothesis is that the administration of BNP will increase energy expenditure in humans. The investigators' secondary hypothesis is that BNP administration will promote changes in gene expression in adipose tissue suggestive of a "beige" fat phenotype in humans.
Research Plan: The investigators propose the following research plan to address the investigators' specific aims:
Primary Aim: To investigate the acute effects of administration of BNP on energy expenditure in humans. The investigators propose a randomized, placebo-controlled, cross-over study in 50 adults (25 lean and 25 obese) without significant medical problems. Subjects will be randomized to intravenous infusion of recombinant human BNP(1-32) or normal saline (control), with assessment of energy expenditure and other physiologic measures. After a 7-day washout period, subjects will then undergo the other intervention.
Secondary Aim: To determine the acute effects of BNP on gene expression in white adipose tissue in humans. The investigators will assess markers suggestive of fat beiging in subcutaneous white adipose tissue biopsies after BNP infusion vs. control. This secondary aim will allow us to explore potential mechanisms underlying the hypothesized changes in energy expenditure.
Methods: In this cross-over study, each subject will receive BNP infusion at one visit and control at the other visit, in random order. The sequence of the treatments will be randomized. There will be a washout period (at least 14 days) between visits. Subjects will be stratified by BMI category (lean or obese). To address the Primary Aim, energy expenditure will be assessed via indirect calorimetry (metabolic cart). To address the Secondary Aim, subcutaneous fat biopsies will be performed, and tissue will be analyzed for gene expression of markers suggestive of fat beiging.
Clinical Relevance: This study will generate novel human data regarding the effects of the NPs on energy metabolism and adipose tissue. Interventions that safely increase energy expenditure and promote a beige fat phenotype represent potential strategies for treating obesity-associated metabolic dysfunction. The overarching scientific goals of this line of investigation are (1) to elucidate the role of the natriuretic peptide system in cardiometabolic health in humans, and (2) to investigate the potential for NP directed therapies in obesity-associated cardiometabolic dysfunction.
Update about Study Drug Supply Issues: The study started in 7/2018, and the last time participants were able to receive study drug was in May 2019, due to discontinuation of study drug by the drug manufacturer (nesiritide, Natrecor, Scios, LLC) after May 2019. Another potential source of drug supply was being sought out by the study team, and study recruitment was placed on hold during the search for new potential sources of study drug. A new viable source of study drug has not been identified, and funding is being closed. Thus, this study is being terminated. Results will be posted for the 5 participants who were able to complete the study procedures prior to the discontinuation of study drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| BNP, then placebo | Experimental | At Study Visit 1, subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of placebo (control, normal saline) for 240 minutes. |
|
| Placebo, then BNP | Experimental | At Study Visit 1, subjects will receive an IV infusion of placebo (control, normal saline) for 240 minutes. After a washout period of at least 2 weeks, subjects then present for Study Visit 2, where they will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32), nesiritide) for 240 minutes. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| recombinant human BNP(1-32) | Drug | Subjects will receive an IV infusion of recombinant human BNP(1-32) for 240 minutes at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Resting Energy Expenditure (EE) | At each visit (Study Visits 1 and 2), resting energy expenditure (EE) will be determined by indirect calorimetry, using a metabolic cart. Energy expenditure will be measured at baseline (just prior to the infusion) and during the 240-minute intravenous infusion at Study Visits 1 and 2. The primary endpoint will be change in resting energy expenditure, calculated as final resting energy expenditure (at end of 240-minute infusion) adjusted for baseline value. | At baseline and at end of 240-minute IV infusion (at each study visit). (At Study Visit 1 and 2, EE will be assessed at baseline and at end of 240-minute intravenous infusion. Visits will be separated by at least 14 days.) |
| Measure | Description | Time Frame |
|---|---|---|
| Adipose Tissue Gene Expression of Uncoupling Protein 1 (UCP1) | Subcutaneous adipose tissue biopsies will be obtained after the conclusion of the 240-minute IV infusion at Study Visits 1 and 2. These tissues will be analyzed for adipose tissue gene expression. The adipose tissue gene expression after the BNP infusion will be compared to expression after the placebo infusion. Units are relative UCP1 gene expression (quantified using quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR)), normalized to a housekeeping gene). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Talat A Ikizler, MD | Tennessee Valley Healthcare System Nashville Campus, Nashville, TN | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Tennessee Valley Healthcare System Nashville Campus, Nashville, TN | Nashville | Tennessee | 37212-2637 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38686535 | Derived | Bachmann KN, Ceddia RP, Gupta DK, Collins S, Wang TJ. Human adipose tissue expression of uncoupling protein 1 in response to intravenous administration of B-type natriuretic peptide hormone: Results from a randomized controlled crossover study. Diabetes Obes Metab. 2024 Aug;26(8):3458-3461. doi: 10.1111/dom.15628. Epub 2024 Apr 30. No abstract available. |
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Individual enrolled subjects will not receive any of their unique study data. IPD (in a de-identified, anonymized format) underlying publications from this research will be shared publicly.
Relevant IPA underlying a publication will be available within 6 months after publication date
Data requests will be evaluated for appropriateness and relevance.
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Enrolled subjects underwent a screening visit to determine eligibility for the study. The screening visit included a medical history, physical examination, and a blood draw for CMP, CBC, HbA1c, TSH, and free T4. A pregnancy test was completed on female subjects of child-bearing potential. Eligible subjects who still wished to participate in the study were then enrolled for the main study visits.
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| ID | Title | Description |
|---|---|---|
| FG000 | BNP Followed by Placebo (Control) | At study visit 1, subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes (at a rate of 10 ng/kg/minute, preceded by IV bolus of 100 ng/kg). After a washout of a minimum of 2 weeks, subjects will present for Study Visit 2, where they will receive an IV infusion of placebo control (normal saline) for 240 minutes. |
| FG001 | Placebo (Control) Followed by BNP | At study visit 1, subjects will receive an IV infusion of placebo (normal saline). After a washout of a minimum of 2 weeks, subjects will present for Study Visit 2, where they will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes (at a rate of 10 ng/kg/ minute, preceded by IV bolus of 100 ng/kg). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study Visit 1 |
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| Washout Period (2+ Weeks) |
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| Study Visit 2 |
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| ID | Title | Description |
|---|---|---|
| BG000 | BNP Followed by Placebo | At study visit 1, subjects will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes (at a rate of 10 ng/kg/minute, preceded by IV bolus of 100 ng/kg). After a washout of a minimum of 2 weeks, subjects will present for Study Visit 2, where they will receive an IV infusion of placebo control (normal saline) for 240 minutes. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Resting Energy Expenditure (EE) | At each visit (Study Visits 1 and 2), resting energy expenditure (EE) will be determined by indirect calorimetry, using a metabolic cart. Energy expenditure will be measured at baseline (just prior to the infusion) and during the 240-minute intravenous infusion at Study Visits 1 and 2. The primary endpoint will be change in resting energy expenditure, calculated as final resting energy expenditure (at end of 240-minute infusion) adjusted for baseline value. | All participants who received both interventions and completed all study visits are included in the analysis. | Posted | Median | Inter-Quartile Range | kcal/day | At baseline and at end of 240-minute IV infusion (at each study visit). (At Study Visit 1 and 2, EE will be assessed at baseline and at end of 240-minute intravenous infusion. Visits will be separated by at least 14 days.) |
|
Approximately 1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | BNP Followed by Normal Saline (Control) | Subjects will initially receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes. After a wash out of a minimum of 2 weeks subject will receive an IV infusion of normal saline for 240 minutes. recombinant human BNP (1-32): Subjects will receive an IV infusion of recombinant human BNP1-32 (6 mcg BNP/ml saline) for 240 minutes. normal saline (placebo): Subjects will receive an IV infusion of normal saline for 240 minutes. The volume of saline delivered will be equivalent to the volume of saline that the subject receives during the BNP infusion visit. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Local skin reaction | Skin and subcutaneous tissue disorders | Systematic Assessment | Bruising at biopsy site. |
Sample size is limited due to discontinuation of study drug (recombinant human BNP(1-32), nesiritide, Natrecor) by the drug manufacturer (Scios, LLC) after 5/2019. Results are posted for the 5 participants who were able to complete the study procedures prior to the discontinuation of study drug.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Alp Ikizler, Catherine McLaughlin Hakim Chair in Vascular Biology, Professor of Medicine | Vanderbilt University Medical Center | 615-343-7592 | alp.ikizler@vumc.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 21, 2023 | Nov 10, 2023 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 27, 2018 | Nov 10, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D009765 | Obesity |
| ID | Term |
|---|---|
| D050177 | Overweight |
| D044343 | Overnutrition |
| D009748 | Nutrition Disorders |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D020097 | Natriuretic Peptide, Brain |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D045265 | Natriuretic Peptides |
| D036361 | Peptide Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
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In this cross-over study, each subject will receive BNP infusion at one visit and placebo (control) at the other visit, in random order. The sequence of the treatments will be randomized. There will be a washout period (at least 14 days) between visits.
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The participant and study investigators will be blinded as to which infusion the participant is receiving at which visit. Also, the individuals analyzing the energy expenditure and fat gene expression will be blinded.
|
| placebo (control, normal saline) | Drug | Subjects will receive an IV infusion of placebo (normal saline) at a rate of 10 ng/kg/minute for 240 minutes, preceded by an IV bolus of 100 ng/kg. |
|
| A subcutaneous biopsy will be collected after the end of 240-minute IV infusion, at both Study Visits 1 and 2 (Visits will be separated by at least 14 days.) |
| Vanderbilt University Medical Center |
| Nashville |
| Tennessee |
| 37232 |
| United States |
| NOT COMPLETED |
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| NOT COMPLETED |
|
| BG001 | Placebo Followed by BNP | At study visit 1, subjects will receive an IV infusion of placebo (normal saline). After a washout of a minimum of 2 weeks, subjects will present for Study Visit 2, where they will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes (at a rate of 10 ng/kg/minute, preceded by IV bolus of 100 ng/kg). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
Participants who received BNP infusion at either Study Visit 1 or Study Visit 2.
| OG001 | Placebo (Control) | Participants who received placebo (normal saline) infusion at either Study Visit 1 or Study Visit 2. |
|
|
|
| Secondary | Adipose Tissue Gene Expression of Uncoupling Protein 1 (UCP1) | Subcutaneous adipose tissue biopsies will be obtained after the conclusion of the 240-minute IV infusion at Study Visits 1 and 2. These tissues will be analyzed for adipose tissue gene expression. The adipose tissue gene expression after the BNP infusion will be compared to expression after the placebo infusion. Units are relative UCP1 gene expression (quantified using quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR)), normalized to a housekeeping gene). | All participants (N= 4) who had paired adipose tissue samples available (who had adipose tissue sample collected after both the BNP infusion and after the placebo infusion). There was 1 subject who did not have adipose tissue collected at one of the study visits, and thus is not included in the statistical analysis. | Posted | Mean | Standard Error | fold change | A subcutaneous biopsy will be collected after the end of 240-minute IV infusion, at both Study Visits 1 and 2 (Visits will be separated by at least 14 days.) |
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|
|
| 3 |
| 5 |
| 0 |
| 5 |
| 3 |
| 5 |
| EG001 | Normal Saline (Control) Followed by BNP | Subjects will initially receive an IV infusion of normal saline for 240 minutes. After a wash out of a minimum of 2 weeks subject will receive an IV infusion of recombinant human b-type natriuretic peptide (BNP (1-32)) for 240 minutes. The volume of saline delivered will be equivalent to the volume of saline that the subject receives during the BNP infusion visit. normal saline (placebo): Subjects will receive an IV infusion of normal saline for 240 minutes. The volume of saline delivered will be equivalent to the volume of saline that the subject receives during the BNP infusion visit. recombinant human BNP (1-32): Subjects will receive an IV infusion of recombinant human BNP1-32 (6 mcg BNP/ml saline) for 240 minutes. | 2 | 5 | 0 | 5 | 2 | 5 |
|
| Vasovagal response | Cardiac disorders | Systematic Assessment | Vasovagal response during biopsy. |
|
| Finger Fracture prior to intervention (unrelated to study) | Musculoskeletal and connective tissue disorders | Systematic Assessment | Finger fracture occurred at home after screening visit and prior to receiving any intervention. Unrelated to study. |
|
| Headache | Vascular disorders | Systematic Assessment | Headache during study infusion. |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment | Nausea during study infusion. |
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| D001835 |
| Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D009419 | Nerve Tissue Proteins |
| D011506 | Proteins |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |