HypertensionPhase 1/2NCT01462591
L-citrulline Supplementation & Cold Exposure
A Phase 1/2 study testing L-citrulline in people with Hypertension, run by Florida State University at 1 site in United States.
Trial summary
Cardiovascular disease (CVD) is considered the primary cause of death in the developed world. Large scale epidemiological studies indicate that prevalence of hypertension along with adverse cardiovascular events peak during the winter months. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Hypertension
- What is being tested?
- L-citrulline
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- May 2011to May 2012
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Men
- Blood pressure lower than 140/90mmHg
- Age 18 to 35 years
- BMI 20-39 kg/m2
Who cannot join
- Blood Pressure >160/100 mmHg
- Asthma
- Glaucoma
- Herpes simplex
- Uncontrolled diabetes
- Neurological disease
Show all 18Show fewer
- Cardiovascular disease
- Inflammatory disease
- Kidney disease
- Hormone replacement therapy (HRT)
- Amino acid/vitamin supplementation\
- Corticosteroids or non-steroidal anti-inflammatory drugs
- Any drug known to affect BP or heart rate
- Glycemic control drugs
- Lipids reducing drugs
- Participants should not consume > 12 alcoholic drink/week
- Smokers
- Regular Exercisers (>1.5 hour/week).
Trial locations and contacts
1 site in 1 country.
United States1 site
FSU College of Human Sciences
Tallahassee, Florida, 32306
About this study
Official title: The Effects L-citrulline Supplementation on Arterial Stiffness, Wave Reflection, and Cardiac Autonomic Responses to Cold Exposure With Isometric Exercise
Cardiovascular disease (CVD) is considered the primary cause of death in the developed world. Large scale epidemiological studies indicate that prevalence of hypertension along with adverse cardiovascular events peak during the winter months. Moreover, during the winter months outdoor activities and physical stressors such as exercise have been associated with higher cardiovascular mortality when compared to other periods of the year. Although low environmental temperatures have been implicated as the triggering factor for cardiovascular complications, the mechanisms on how cold exposure increase cardiovascular morbidity and mortality remain to be elucidated. However, new research suggests that cold exposure may induce increases in cardiac sympathetic activity, endothelial damage and increased arterial stiffness of central arteries. Cardiovascular drugs including antihypertensive pharmacological agents seem to be inefficient to provide appropriate therapeutic effects during cold exposure. Therefore, it is imperative to propose alternative non-pharmacological therapies intended to prevent the detrimental effects of low environmental temperatures on cardiovascular function. Recently, oral supplementation of the amino acid L-citrulline has been proposed as an effective therapeutic adjuvant for the treatment of hypertension. L-citrulline is known to enhance the bioavailability of L-arginine levels and increase endothelial nitric oxide (NO) production, one of the main modulators of vascular tone and blood pressure (BP). L-citrulline supplementation has been shown to increase endothelial function, reduce BP, and ameliorate endothelial oxidative damage without any adverse effects. Our group has demonstrated that L-citrulline supplementation attenuates the BP response to cold exposure (the cold pressor test, CPT). These studies suggest that L-citrulline supplementation may be a feasible therapeutic aid in order to prevent cardiovascular complications associated with cold exposure. However the potential cardioprotective effects of L-citrulline supplementation during cold exposure with exercise have yet to be evaluated. It is hypothesized that L-citrulline supplementation would reduce arterial stiffness and blood pressure (BP) responses to physiological stress (cold exposure). This study may lead to the development of an adjunct therapy for the prevention and management of cardiovascular adverse events that are particularly increased during the winter months.
Read the detailed description
The specific aims of the study are:
AIM 1: To determine the acute effects of cold exposure and isometric exercise, on cardiovascular hemodynamics and autonomic regulation. The working hypothesis is that the combination of cold exposure with isometric hand grip (IHG) exercise would evoke a greater acute increase in arterial stiffness, wave reflection, arterial BP and sympathetic activity than cold exposure or IHG alone. In order to test this hypothesis, the investigators will use an environmental chamber at a temperature of 4oC to perform non-invasive measurements of arterial stiffness (carotid-femoral, femoral-ankle, and brachial-ankle pulse wave velocity [PWV]), pulse wave analysis (aortic BP and augmentation index [AIx]) using applanation tonometry of the radial artery. In addition, the investigators will use continuous beat-by-beat digital BP, power spectral analysis of heart rate variability and blood pressure variability, and spontaneous BRS to evaluate autonomic function during cold exposure.
AIM 2: To examine the effects of L-citrulline supplementation on cardiovascular hemodynamics, autonomic regulation and endothelial function. The investigators will test the working hypothesis that L-citrulline supplementation for 14 days will attenuate the cardiovascular responses to physiological stress. The investigators will perform the same procedures previously specified in AIM I.
AIM 3: To determine the acute and chronic L-citrulline supplementation on endothelial function by measuring flow-mediated vasodilation, vasoactive substances, and Endothelial Progenitor Cells (EPCs). This aim will examine the working hypothesis L-citrulline will result in greater circulating levels of vasodilatory substances including nitric oxide, prostacyclin, and EPCs whereas vasoconstrictor substances endothelin-I (ET-1) will decrease. This aim will be tested by measuring serum levels of these substances before and immediately after the session at baseline and 7 days after the intervention.
Description of the study Forty individuals (20 men and 20 women) 18-35 years of age with normal resting BP (< 140/90 mmHg) will be enrolled in this study. Subjects should not be smokers, L-citrulline users or regular exercisers (defined as more than 120 min per week) in the last 6 months. The exclusion criteria will be any contraindication to exercise and medical conditions. Subjects with diverse ethnic backgrounds will be recruited from the Tallahassee metropolitan area by advertisement and direct communication.
Study design:
After completion of initial screening, cardiovascular function of eligible subjects will be evaluated at a room temperature of 4oor 23oC in random order. After baseline measurements, subjects will be randomly assigned to Placebo (Malt dextrin) or L-citrulline group for 14 days. Cardiovascular function will be evaluated at the end of the study.
- Conditions
- Hypertension
- Being tested
- L-citrulline
- Keywords
- wave reflection, augmentation Index, heart rate variability, wasted left ventricular energy
- Medical subject headings
- Hypertension
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
L-citrullineDietary supplement
2 weeks of L-citrulline supplementation (100mg/kg of body weight).
| Study group | Role | What they receive |
|---|---|---|
| L-citrulline | Experimental | L-citrulline (100mg/kg of body weight per day for 2 weeks) Receives: Dietary Supplement: L-citrulline |
| Maltodextrin | Placebo comparator | 6g/day of placebo (maltodextrin) Receives: Dietary Supplement: L-citrulline |
What is being measured
The primary outcome is the main question the study is designed to answer.
Blood Pressure
By measuring brachial and central (aortic and carotid) BP at rest and during physiological stress (cold exposure and handgrip test)
Measured: 6 weeks
Secondary outcomes (1)
Autonomic control of heart rate
By measuring heart rate variability at rest and during physiological stress.
Measured: 6 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2011 (estimated)
- Study startMay 2011
- Primary completionDec 2011
- Study completionMay 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HypertensionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Florida State University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Arturo Figueroa, Florida State University
- Investigators
- Marcos A Sanchez-Gonzalez, M.D., Principal investigator, The Florida State University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01462591
- Sponsor's protocol ID
- HSC2011.6686
- Status last verified
- Aug 2014
- First submitted
- 27 Oct 2011
- Last updated
- 5 Aug 2014
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects L-citrulline Supplementation on Arterial Stiffness, Wave Reflection, and Cardiac Autonomic Responses to Cold Exposure With Isometric Exercise
- ClinicalTrials.gov ID
- NCT01462591
- Acronym / sponsor ID
- HSC2011.6686
- Conditions
- Hypertension
- Keywords
- wave reflection, augmentation Index, heart rate variability, wasted left ventricular energy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Florida State UniversityUniversity, hospital or other
- Study start
- May 2011
- Primary completion
- Dec 2011 (actual)
- Study completion
- May 2012 (actual)
- First posted
- 31 Oct 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cardiovascular disease (CVD) is considered the primary cause of death in the developed world. Large scale epidemiological studies indicate that prevalence of hypertension along with adverse cardiovascular events peak during the winter months. Moreover, during the winter months outdoor activities and physical stressors such as exercise have been associated with higher cardiovascular mortality when compared to other periods of the year. Although low environmental temperatures have been implicated as the triggering factor for cardiovascular complications, the mechanisms on how cold exposure increase cardiovascular morbidity and mortality remain to be elucidated. However, new research suggests that cold exposure may induce increases in cardiac sympathetic activity, endothelial damage and increased arterial stiffness of central arteries. Cardiovascular drugs including antihypertensive pharmacological agents seem to be inefficient to provide appropriate therapeutic effects during cold exposure. Therefore, it is imperative to propose alternative non-pharmacological therapies intended to prevent the detrimental effects of low environmental temperatures on cardiovascular function. Recently, oral supplementation of the amino acid L-citrulline has been proposed as an effective therapeutic adjuvant for the treatment of hypertension. L-citrulline is known to enhance the bioavailability of L-arginine levels and increase endothelial nitric oxide (NO) production, one of the main modulators of vascular tone and blood pressure (BP). L-citrulline supplementation has been shown to increase endothelial function, reduce BP, and ameliorate endothelial oxidative damage without any adverse effects. Our group has demonstrated that L-citrulline supplementation attenuates the BP response to cold exposure (the cold pressor test, CPT). These studies suggest that L-citrulline supplementation may be a feasible therapeutic aid in order to prevent cardiovascular complications associated with cold exposure. However the potential cardioprotective effects of L-citrulline supplementation during cold exposure with exercise have yet to be evaluated. It is hypothesized that L-citrulline supplementation would reduce arterial stiffness and blood pressure (BP) responses to physiological stress (cold exposure). This study may lead to the development of an adjunct therapy for the prevention and management of cardiovascular adverse events that are particularly increased during the winter months.
Detailed description
The specific aims of the study are:
AIM 1: To determine the acute effects of cold exposure and isometric exercise, on cardiovascular hemodynamics and autonomic regulation. The working hypothesis is that the combination of cold exposure with isometric hand grip (IHG) exercise would evoke a greater acute increase in arterial stiffness, wave reflection, arterial BP and sympathetic activity than cold exposure or IHG alone. In order to test this hypothesis, the investigators will use an environmental chamber at a temperature of 4oC to perform non-invasive measurements of arterial stiffness (carotid-femoral, femoral-ankle, and brachial-ankle pulse wave velocity [PWV]), pulse wave analysis (aortic BP and augmentation index [AIx]) using applanation tonometry of the radial artery. In addition, the investigators will use continuous beat-by-beat digital BP, power spectral analysis of heart rate variability and blood pressure variability, and spontaneous BRS to evaluate autonomic function during cold exposure.
AIM 2: To examine the effects of L-citrulline supplementation on cardiovascular hemodynamics, autonomic regulation and endothelial function. The investigators will test the working hypothesis that L-citrulline supplementation for 14 days will attenuate the cardiovascular responses to physiological stress. The investigators will perform the same procedures previously specified in AIM I.
AIM 3: To determine the acute and chronic L-citrulline supplementation on endothelial function by measuring flow-mediated vasodilation, vasoactive substances, and Endothelial Progenitor Cells (EPCs). This aim will examine the working hypothesis L-citrulline will result in greater circulating levels of vasodilatory substances including nitric oxide, prostacyclin, and EPCs whereas vasoconstrictor substances endothelin-I (ET-1) will decrease. This aim will be tested by measuring serum levels of these substances before and immediately after the session at baseline and 7 days after the intervention.
Description of the study Forty individuals (20 men and 20 women) 18-35 years of age with normal resting BP (< 140/90 mmHg) will be enrolled in this study. Subjects should not be smokers, L-citrulline users or regular exercisers (defined as more than 120 min per week) in the last 6 months. The exclusion criteria will be any contraindication to exercise and medical conditions. Subjects with diverse ethnic backgrounds will be recruited from the Tallahassee metropolitan area by advertisement and direct communication.
Study design:
After completion of initial screening, cardiovascular function of eligible subjects will be evaluated at a room temperature of 4oor 23oC in random order. After baseline measurements, subjects will be randomly assigned to Placebo (Malt dextrin) or L-citrulline group for 14 days. Cardiovascular function will be evaluated at the end of the study.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| L-citrulline | Experimental | Dietary Supplement: L-citrullineL-citrulline (100mg/kg of body weight per day for 2 weeks) |
| Maltodextrin | Placebo comparator | Dietary Supplement: L-citrulline6g/day of placebo (maltodextrin) |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Men
- Blood pressure lower than 140/90mmHg
- Age 18 to 35 years
- BMI 20-39 kg/m2
Key exclusion criteria (18 listed)
- Blood Pressure >160/100 mmHg
- Asthma
- Glaucoma
- Herpes simplex
- Uncontrolled diabetes
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| L-citrulline2 weeks of L-citrulline supplementation (100mg/kg of body weight). | Dietary supplement | L-citrulline, Maltodextrin |
Primary outcome
Blood Pressure
Time frame: 6 weeks
By measuring brachial and central (aortic and carotid) BP at rest and during physiological stress (cold exposure and handgrip test)
1 secondary outcome
Autonomic control of heart rate
Time frame: 6 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2014.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marcos A Sanchez-Gonzalez, M.D. principal investigator
The Florida State University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing L-citrulline in people with Hypertension, run by Florida State University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Blood Pressure (time frame: 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2014.