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NAUTICAL: Effect of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals

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ClinicalTrials.gov Identifier: NCT04055428
Recruitment Status : Recruiting
First Posted : August 13, 2019
Last Update Posted : June 1, 2021
Sponsor:
Information provided by (Responsible Party):
Pankaj Arora, MD, University of Alabama at Birmingham

Brief Summary:
Black individuals are more likely to have decreased insulin sensitivity which results in a high risk for the development of cardiometabolic disease. The reasons for this are incompletely understood. Natriuretic peptides (NPs) are hormones produced by the heart that play a role in regulating the metabolic health of an individual. Low circulating level of NPs is an important contributor to increased risk for diabetes. The NP levels are relatively lower among Black individuals thus affecting their metabolic health and putting them at a higher risk for diabetes. This study aims to test the hypothesis that by augmenting NP levels using sacubitril/valsartan, among Black Individuals one can improve their metabolic health (as measured by insulin sensitivity & energy expenditure) and help establish the role of NPs in the underlying mechanism behind increased risk for cardiometabolic disease in these population.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus Cardiovascular Diseases Insulin Sensitivity/Resistance Metabolic Disease Natriuretic Peptides Metabolism Energy Expenditure Drug: Sacubitril, Valsartan 97-103 mg Oral Tablet Drug: Valsartan 160 mg Other: Intravenous Glucose Tolerance Test Dietary Supplement: Standardized Meals Other: Exercise capacity VO2 maximum determination Phase 2

Detailed Description:

Black individuals are more likely to have a reduced insulin sensitivity which results in a greater risk for diabetes. However, the reasons for their decreased insulin sensitivity are not clearly understood. Natriuretic peptides (NPs) are hormones produced by the heart that is known to have a wide range of favorable metabolic effects. Studies indicate that lower NP levels are associated with a decreased insulin sensitivity and this may be causally related to the development of diabetes.

Evidence suggests that Black individuals have low levels of NPs. Increased clearance of NPs by neprilysin, an NP degrading enzyme, contributes to the low levels of NP among Black individuals. Since NPs play an important role in the regulation of insulin sensitivity and energy expenditure, one can infer that relatively low NP levels are an important biological contributor to the high prevalence rates of cardiometabolic disease in African Americans.

Sacubitril/valsartan is an FDA-approved inhibitor of neprilysin that augment NP levels. NP augmentation using sacubitril/valsartan has been shown to improve insulin sensitivity and lipid metabolism in a small clinical trial among obese White individuals. It can be postulated that NP augmentation in populations with relatively low NP levels will help in improving their metabolic health. Improvement in the metabolic health following NP augmentation will also help us to outline the relationship between the NP system and the risk of cardiometabolic disease among Black individuals.

We hypothesize that NP augmentation among Black individuals will show an improvement in their metabolic health as measured by insulin sensitivity and energy expenditure. We hypothesize that African American individuals will show an improvement in their insulin sensitivity and their resting & exercise energy expenditure after treatment with sacubitril/valsartan versus valsartan alone.

Our study will have the following aims. The first aim is to assess the change in the insulin sensitivity after NP augmentation therapy (using sacubitril/valsartan) as compared with NP neutral therapy (using valsartan) among Black individuals. We will measure the change in insulin sensitivity (assessed using IVGTT) after 12 weeks of intervention. We will also assess the change in NP levels (a marker of NP augmentation) & cyclic guanylate monophosphate (cGMP) levels after intervention and evaluate their relationship with the change in insulin sensitivity.

The second aim of our study is to examine the change in the energy expenditure after sacubitril/valsartan as compared to valsartan alone among Black individuals. The individuals enrolled in the first aim will also be examined for the change in resting as well as exercise energy expenditure. This will be assessed using standardized protocol performed using the metabolic cart and an exercise treadmill, at baseline and after 12 weeks of either sacubitril/valsartan or valsartan alone.

The secondary aim of our study is to assess the GLP-1 response to meals after treatment with sacubitril/valsartan in Black individuals. We will evaluate the change in postprandial GLP-1 response to meals at baseline and after 12 weeks of either sacubitril/valsartan or valsartan alone.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Official Title: The Effects of Natriuretic Peptide Augmentation on Cardiometabolic Health in Black Individuals (NAUTICAL)
Actual Study Start Date : August 15, 2020
Estimated Primary Completion Date : August 30, 2026
Estimated Study Completion Date : August 30, 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Valsartan

Arm Intervention/treatment
Experimental: Sacubitril/Valsartan
We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.
Drug: Sacubitril, Valsartan 97-103 mg Oral Tablet
The subject will be randomized, in a double-blind manner to sacubitril/valsartan 97/103 mg twice daily for a period of 12 weeks.
Other Name: Sacubitril/Valsartan arm

Other: Intravenous Glucose Tolerance Test
An assessment of the insulin sensitivity will be done using the IVGTT, at baseline and after 12 weeks of pharmacological interventions.

Dietary Supplement: Standardized Meals
Participants will consume the standardized study mixed meal for the assessment of postprandial GLP-1 response to the meal.

Other: Exercise capacity VO2 maximum determination
Each participant's maximal oxygen capacity will be determined using modified Bruce treadmill protocol.

Active Comparator: Valsartan
We will enroll 100 adult Black individuals. Each participant will take the assigned dose of medication twice daily for 12 weeks. We evaluate insulin sensitivity and energy expenditure at baseline and after 12 weeks of intervention.
Drug: Valsartan 160 mg
The subject will be randomized, in a double-blind manner to valsartan 160 mg twice daily for a period of 12 weeks.
Other Name: Valsartan arm

Other: Intravenous Glucose Tolerance Test
An assessment of the insulin sensitivity will be done using the IVGTT, at baseline and after 12 weeks of pharmacological interventions.

Dietary Supplement: Standardized Meals
Participants will consume the standardized study mixed meal for the assessment of postprandial GLP-1 response to the meal.

Other: Exercise capacity VO2 maximum determination
Each participant's maximal oxygen capacity will be determined using modified Bruce treadmill protocol.




Primary Outcome Measures :
  1. Change in insulin sensitivity after natriuretic peptide augmentation [ Time Frame: 12 weeks ]
    An assessment of the insulin sensitivity will be done at baseline and after 12 weeks of pharmacological intervention.

  2. Change in energy expenditure after natriuretic peptide augmentation [ Time Frame: 12 weeks ]
    An assessment of the resting energy expenditure will be done at baseline and after 12 weeks of pharmacological intervention.


Secondary Outcome Measures :
  1. Change in exercise energy expenditure after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    During standardized protocol after 12 weeks of intervention, the energy expenditure will be calculated using metabolic cart.

  2. Change in post-meal increase in GLP-1 levels [ Time Frame: 12 weeks ]
    Change in GLP-1 levels after a standardized meal after 12 weeks of pharmacological intervention

  3. Change in peak oxygen consumption after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    Change in the peak oxygen consumption (VO2 max) after 12 weeks of intervention.

  4. Change in fasting GLP-1 levels [ Time Frame: 12 weeks ]
    Change in fasting GLP-1 levels after 12 weeks of pharmacological intervention

  5. Change in natriuretic peptide levels [ Time Frame: 12 weeks ]
    Change in natriuretic peptide levels (ANP, MRproANP, BNP, NTproBNP) after 12 weeks of pharmacological intervention

  6. Change in measures of insulin sensitivity [ Time Frame: 12 weeks ]
    Change in measures of insulin sensitivity (AIRg, Sg, Kg, Disposition Index) after 12 weeks of pharmacological intervention

  7. Change in HBA1c levels [ Time Frame: 12 weeks ]
    Change in HBA1c levels after 12 weeks of pharmacological intervention

  8. Change in fasting blood glucose levels [ Time Frame: 12 weeks ]
    Change in fasting blood glucose levels after 12 weeks of pharmacological intervention

  9. Change in HOMA-IR [ Time Frame: 12 weeks ]
    Change in HOMA-IR after 12 weeks of pharmacological intervention

  10. Change in fasting insulin levels [ Time Frame: 12 weeks ]
    Change in fasting insulin levels after 12 weeks of pharmacological intervention

  11. Change in measures of body mass index [ Time Frame: 12 weeks ]
    Change in the measures of body mass index after 12 weeks of pharmacological intervention

  12. Change in measures of hip circumference [ Time Frame: 12 weeks ]
    Change in the measures of hip circumference after 12 weeks of pharmacological intervention

  13. Change in measures of waist circumference [ Time Frame: 12 weeks ]
    Change in the measures of waist circumference after 12 weeks of pharmacological intervention

  14. Change in measures of adipose tissue mass [ Time Frame: 12 weeks ]
    Change in the measures of adipose tissue mass after 12 weeks of pharmacological intervention

  15. Change in total cholesterol levels [ Time Frame: 12 weeks ]
    Change in the total cholesterol levels after 12 weeks of pharmacological intervention

  16. Change in LDL-C levels [ Time Frame: 12 weeks ]
    Change in LDL-C levels after 12 weeks of pharmacological intervention

  17. Change in HDL-C levels [ Time Frame: 12 weeks ]
    Change in HDL-C levels after 12 weeks of pharmacological intervention

  18. Change in triglyceride levels [ Time Frame: 12 weeks ]
    Change in triglyceride levels after 12 weeks of pharmacological intervention

  19. Correlation of change in MR-pro atrial natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in MR-pro atrial natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.

  20. Correlation of change in MR-pro atrial natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in MR-pro atrial natriuretic peptide levels with change in resting and exercise energy expenditure after 12 weeks of intervention will be examined.

  21. Correlation of change in B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.

  22. Correlation of change in B-type natriuretic peptide levels with change in resting energy expenditure after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in B-type natriuretic peptide levels with change in resting energy expenditure after 12 weeks of intervention will be examined.

  23. Correlation of change in NT-pro B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in NT-pro B-type natriuretic peptide levels with change in insulin sensitivity after 12 weeks of intervention will be examined.

  24. Correlation of change in NT-pro B-type natriuretic peptide levels with change in energy expenditure after 12 weeks of pharmacological intervention. [ Time Frame: 12 weeks ]
    The exposure-response relationship of change in NT-pro B-type natriuretic peptide levels with change in resting and exercise energy expenditure after 12 weeks of intervention will be examined.

  25. Impact of Natriuretic Peptide Genotype on Study Endpoints [ Time Frame: 12 weeks ]
    All study outcomes will be analyzed by natriuretic peptide genotypes


Other Outcome Measures:
  1. Change in Metabolomic Profile [ Time Frame: 12 weeks ]
    The change in the metabolomic profile examined using standardized platforms after 12 weeks of intervention.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adults: Age more than or equal to 18 years of age
  • Self-identified race/ethnicity as African-American or Black
  • Blood pressure: 120-160/80-100 mmHg (either untreated or after 4 weeks of washout in those treated with up to two classes of antihypertensives)
  • Baseline insulin resistance: HOMA-IR ≥2.5

Exclusion Criteria:

  • Women who are pregnant or breastfeeding or who can become pregnant and not practicing an acceptable method of birth control during the study (including abstinence)
  • Have any past or present history of cardiovascular diseases (stroke, myocardial infarction, heart failure, transient ischemic attack, angina, or cardiac arrhythmia)
  • BP more than 160/100 mmHg
  • BMI >45 kg/m2
  • History of diabetes or fasting plasma glucose >=126 mg/dL or HbA1C>=6.5%
  • History of angioedema
  • Current or past (<12 months) history of smoking
  • Estimated GFR < 60 ml/min/1.73 m2; albumin-creatinine ratio ≥30 mg/g
  • Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal
  • Significant psychiatric illness or seizure disorder
  • More than 2 Alcoholic drinks daily
  • Anemia (men, Hct < 38%, Hb<13 g/dL; women, Hct <36%, Hb <12 g/dL)
  • Inability to exercise on a treadmill

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): NCT04055428


Contacts
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Contact: Vibhu Parcha, MD 205-934-7936 vparcha@uabmc.edu
Contact: Leigh Powell, MSN, RN 205-975-9859 lcpowell@uabmc.edu

Locations
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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Vibhu Parcha, MD    205-934-7936    vparcha@uabmc.edu   
Principal Investigator: Pankaj Arora, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
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Principal Investigator: Pankaj Arora, MD, FAHA University of Alabama at Birmingham
Publications of Results:
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Responsible Party: Pankaj Arora, MD, Assisstant Professor, Division of Cardiovasular Disease, Department of Medicine, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT04055428    
Other Study ID Numbers: 300003702
First Posted: August 13, 2019    Key Record Dates
Last Update Posted: June 1, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pankaj Arora, MD, University of Alabama at Birmingham:
Natriuretic Peptides
Diabetes
Insulin Sensitivity
Energy Expenditure
Additional relevant MeSH terms:
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Cardiovascular Diseases
Insulin Resistance
Metabolic Diseases
Hypersensitivity
Immune System Diseases
Hyperinsulinism
Glucose Metabolism Disorders
Valsartan
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action