LIVARM: Leptin Infusion and Endothelial Vasomotor Response

• Sponsor: Stefan Soderberg (Other)
• Overall Status: Completed
• CT.gov ID: NCT04374500
• Collaborator: University of Edinburgh (Other)
• Enrollment: 103
• Locations: 2
• Arms: 3
• Actual Duration (Months): 11.6
• Patients Per Site: 51.5
• Patients Per Site Per Month: 4.4

Study Details

Study Description

Brief Summary

Adipose tissue is an active endocrine organ producing several hormones with circulatory and metabolic effects. In 1994, the hormone leptin was discovered. The lack of this hormone explained extreme obesity in rare patients and parenteral substitution restored body weight and metabolic disturbances. It was however soon discovered that most humans had too high levels which were related to development of cardiovascular diseases and diabetes. It was hypothesised that leptin induced vessel dysfunction which could explain this association.

In this study, we wanted to examine the association between leptin and vessel function by using the venous occlusion plethysmography method. We used three protocols to evaluate this association.

First protocol. In ten healthy males, leptin was infused locally in the forearm and blood flow was measured.

Second protocol. In ten healthy males, leptin or normal saline was infused locally in the forearm and blood flow was measured. Concomitantly, four vasodilatators were infused locally in the forearm in a randomised order and the response (blood flow and fibrinolysis) was measured.

Third protocol. In eighty-three patients with known coronary artery disease, three vasodilators were infused locally in the forearm in a random order and response (blood flow and fibrinolysis) was measured. The response was related to endogenous leptin levels.

The two first protocols were performed in Umeå, Sweden whereas the third was performed in Edinburgh, UK, all in 2006.

Condition or Disease	Intervention/Treatment	Phase
Endothelial Dysfunction; Obesity; Vasodilation; Venous Occlusion Plethysmography	Drug: Leptin infusion plus vasodilators in healthy men; Drug: Leptin infusion in healthy men; Drug: Vasodilators in CAD patients	Early Phase 1

Detailed Description

Introduction High BMI and particularly fat mass index are associated with increased risk of coronary artery disease and other cardiovascular conditions, but the underlying mechanisms are not well understood. Endothelial dysfunction precedes atherosclerosis and represents an important link between obesity and cardiovascular events.

The adipose tissue produces cytokines and hormones (adipokines), which, in excess, may promote cardiovascular disease by proinflammatory, prothrombotic, dyslipidemic and atherosclerotic effects.

Leptin is an adipokine with pleiotropic effects and circulating leptin levels are positively associated with the amount of body fat. High plasma leptin levels (hyperleptinemia) associate with the development of atherosclerosis, hypertension and coronary artery disease (CAD). Leptin activates specific leptin receptors expressed, among other tissues, in vascular cells, suggesting that leptin may participate in the development of endothelial dysfunction and atherosclerosis.

However, the net effect of leptin on vasomotor function remains unclear, as both vasodilation and vasoconstriction have been reported. Leptin induces release of nitric oxide (NO) in vitro and elicits endothelium-dependent vasodilation in mice by inducing endothelial expression of NO synthase. In addition, studies in humans have shown that leptin infusion exerts vasodilatation. In contrast, others have shown leptin-induced vasoconstriction in vitro and impaired vasodilatation in dogs. Different mechanisms have been proposed causing increased peripheral vascular resistance, such as vascular inflammation, increased sympathetic nervous system (SNS) activity, increased endothelin-1 (ET-1) production, and decreased nitric oxide (NO) bioavailability.

Hyperleptinemia has been associated to states of altered fibrinolysis, which is common in diabetes, cardiovascular disease and obesity. However, whether leptin directly influences the endogenous fibrinolytic function remains unclear.

The aim of these studies was to evaluate the role of leptin on endothelial function in humans. For this purpose, the vasomotor and the fibrinolytic functions were assessed in healthy men during a state of pharmacologically induced hyperleptinemia. In a parallel study, the endothelial function was assessed in patients with established CAD and related to plasma leptin levels.

Material and Methods

Subjects Seventeen healthy non-smoking male volunteers not taking any regular medication were recruited in Umeå, Sweden (three males participated both protocol 1 and in protocol 2). Eighty-three patients with established CAD were recruited from the cardiology outpatient clinic at the Royal Infirmary, Edinburgh, Scotland, and the characteristics of this cohort have been reported previously. These patients had stable angina and had a prior angiographic documentation of ≥50% luminal stenosis of at least one major epicardial coronary vessel. Written informed consent was obtained from each subject and the studies were carried out in accordance with the Declaration of Helsinki.

Venous occlusion plethysmography Subjects abstained from alcohol for 24 hours and from food, tobacco and caffeine-containing drinks for at least 4 hours before each study visit. All studies were carried out in a quiet temperature-controlled room maintained at 22-25 degrees Celsius (ºC). A 17-G venous cannula was inserted into the antecubital vein of each arm and the brachial artery of the non-dominant arm was cannulated with a 27-G needle (Cooper's Needle Works Ltd, UK). Bilateral forearm blood flow was measured by venous occlusion plethysmography using mercury-in-silastic strain gauges. Blood pressure and heart rate were measured using a semi-automated non-invasive sphygmomanometer. To avoid acute vasomotor effects, all medications were withheld on the morning of each study.

Study design

Protocol 1 In ten healthy male volunteers, recombinant human leptin (Sigma-Aldrich, Saint-Louis, Missouri, USA) was infused intra-arterially at ascending doses of 80, 800 and 8,000 ng/min (6 minutes each). Heart rate, blood pressure, forearm blood flow, leptin, tissue plasminogen activator (tPA) antigen and plasminogen activator inhibitor type 1(PAI-1) antigen concentrations were determined at the end of each dose.

Protocol 2 In a double-blind randomized crossover study, ten healthy male volunteers received intra-arterial infusions of either leptin (800 ng/min) or saline on two separate occasions with at least 2 weeks between visits. Forearm blood flow was measured in the infused and non-infused arms at baseline and at regular intervals during the one-hour leptin/saline infusion. Thereafter four vasodilators were infused concomitantly with intra-arterial leptin/saline infusions; bradykinin (endothelium-dependent vasodilator that releases tPA) at 100, 300 and 1,000 pmol/min (Clinalfa Ltd, Switzerland), acetylcholine (endothelium-dependent vasodilator that does not release tPA) at 5, 10 and 20 µg/min (Clinalfa Ltd, Switzerland), sodium nitroprusside (endothelium-independent vasodilator) at 2, 4 and 8 µg/min (David Bull laboratories, UK) and verapamil (endothelium-independent vasodilator) at 10, 30, 100 µg/min (Abbott UK Ltd) for 6 minutes at each concentration. Vasodilators were infused in a randomized order with a 15-minute saline washout period between each drug. Verapamil was always administered at the end because of its long-lasting vasomotor effects.

Venous blood was obtained from the infused and non-infused arms at baseline, before and during infusion of bradykinin, at 60 minutes and at the end of the study protocol.

Protocol 3 In patients with CAD (n=83), bilateral forearm blood flow was measured before and during intra-arterial infusions of substance P (endothelium-dependent vasodilator that releases tPA) at 2, 4 and 8 pmol/min (Clinalfa Ltd, Switzerland), acetylcholine at 5, 10 and 20 µg/min (as above) and sodium nitroprusside at 2, 4 and 8 µg/min (as above) for 6 minutes at each concentration. Bradykinin was not administered because many subjects were being treated with angiotensin-converting enzyme inhibition and this markedly potentiates its vasodilator and fibrinolytic effects. The vasodilators were administered in a randomized order with a 15-minute saline washout period between each drug. Venous blood samples were obtained before and during intra-arterial infusion of substance P to measure fibrinolytic markers.

Venous Sampling and Assays Fasting venous blood samples were drawn into tubes containing acidified buffered citrate or trisodium citrate. Samples were collected immediately onto ice and centrifuged at 2,000 g for 30 min. Platelet-free plasma and serum were stored at -80°C before assay. Brain natriuretic peptide (BNP), cholesterol and glucose concentrations were determined according to clinical routine, and high sensitivity C-reactive protein (hsCRP) with a highly sensitive assay using particle-enhanced immunonephelometry (Behring BN II nephelometer). Plasma leptin concentrations were measured using a double-antibody radioimmunoassay (Millipore, Billerica, Massachusetts, USA). Intra- and inter-assay coefficients of variation were less than 5% at both low (2-4 ng/mL) and high (10-15 ng/mL) leptin concentrations. Plasma tPA and PAI-1 antigen concentrations were determined using enzyme-linked immunosorbent assays (Coaliza®, Chromogenix Ltd) and plasma tPA activity using a photometric method (Coatest tPA, Chromogenix Ltd). The coefficients of variation for fibrinolytic assays were 5.9% and 12% for tPA antigen and activity respectively, and 6.2% for PAI-1 antigen. Estimated net release of tPA (antigen and activity) was calculated as previously described after each dose of bradykinin or substance P, as the product of the infused forearm plasma flow and the difference in plasma levels between the infused and non-infused forearms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 103 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: In protocol 1, each participant was examined once. Leptin was given intraarterially in the forearm in increasing doses and blood flow was measured. No masking, no randomisation. In protocol 2, each participant was examined twice and they got either leptin or saline intraarterially in the forearm at least 2 weeks apart, and the order was randomised. Concomitantly, they got four vasodilatators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) intraarterially in a randomised order. In protocol 3, each participant was examined once and the three vasodilatators (substance P, acetylcholine, and sodium nitroprusside) were given intraarterially in the forearm in a randomised order.In protocol 1, each participant was examined once. Leptin was given intraarterially in the forearm in increasing doses and blood flow was measured. No masking, no randomisation. In protocol 2, each participant was examined twice and they got either leptin or saline intraarterially in the forearm at least 2 weeks apart, and the order was randomised. Concomitantly, they got four vasodilatators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) intraarterially in a randomised order. In protocol 3, each participant was examined once and the three vasodilatators (substance P, acetylcholine, and sodium nitroprusside) were given intraarterially in the forearm in a randomised order.
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: The Effect of the Adipocyte-derived Hormone Leptin on Endothelial Function in Healthy Men and in Persons With Known Cardiovascular Disease
• Actual Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Oct 27, 2006
• Actual Study Completion Date: Dec 20, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Leptin infusion This applies to protocol 1 when 10 healthy men got leptin infused locally in the forearm and blood flow was measured. The other forearm was used as the control.	Drug: Leptin infusion in healthy men; This applies only to protocol 1 when only leptin was given; Other Names: Leptin infusion only and blood flow measured
Experimental: Leptin infusion plus vasodilator infusion This applies to protocol 2 when 10 healthy men got either a background infusion of leptin or saline locally in the forearm when measuring vasoresponse to four vasodilatators. Each participant had two examinations with either leptin or saline and the order was randomised. The other forearm was used as the control.	Drug: Leptin infusion plus vasodilators in healthy men; This applies only to protocol 2 with two arms (leptin or saline) where four vasodilatators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) were infused concomitantly; Other Names: Four vasodilators (bradykinin, acetylcholine, sodium nitroprusside and verapamil) on top of leptin or saline infusion
Experimental: Vasodilator infusion in CAD patients This applies to protocol 3 when 83 men and women with known CAD (coronary artery disease) got three vasodilators locally infused in the forearm while measuring vasoresponse. The other forearm was used as the control.	Drug: Vasodilators in CAD patients; This applies only to protocol 3; Other Names: Three vasodilators (acetylcholine, sodium nitroprusside, substance P) only, related to endogenous leptin levels

Outcome Measures

Primary Outcome Measures

1. Blood-flow [18 minutes in protocol 1, 3 hours in protocol 2, non-applicable (NA) in protocol 3]

   The primary outcome in all protocols were local blood-flow in the forearm. This was measured by venous occlusion plethysmography using mercury-in-silastic strain gauges and the unit is mL/100mL of tissue/min. In protocol 1, the blood flow response to increasing levels of leptin was evaluated, In protocol 2, the blood flow response to vasodilators on top of leptin or saline infusion was evaluated, and in protocol 3, the blood flow response was measured to vasodilators and related to endogenous leptin levels (no leptin given)

Secondary Outcome Measures

1. Release of Fibrinolytic Variables (Tissue Plasminogen Activator [tPA] and Plasminogen Activator Inhibitor-1 [PAI-1]) [18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3]

   In all protocols, fibrinolytic variables were measured. In protocol 2 and 3, in the infused forearm after vasodilatation with bradykinin or substance P, respectively. The fibrinolytic variable measured in all protocols was tPA activity (IU/mL) and is reported here after the leptin infusion, when applicable.

2. Blod Pressure and Pulse [18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3]

   In all protocols, blood pressure (mmHg) was measured concomitantly using a semi-automated non-invasive sphygmomanometer. Systolic blood pressure is reported here after leptin infusion, when applicable.

3. Leptin [18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3]

   Plasma leptin concentration (ng/mL) was measured in all protocols, and in protocol 1 and 2, specifically in both infused and in non-infused arms. Data given are leptin concentrations in the infused arm at the end of the infusion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion criteria protocol 1 and 2;

• Healthy male

• No regular medication

• Non-smoking

• Abstain from alcohol for 24 hours and from food, tobacco and caffeine-containing drinks for at least 4 hours before each study visit

Inclusion criteria protocol 3;

• Established coronary artery disease

• Stable angina pectoris

• Documented ≥ 50% stenosis of at least one major epicardial coronary vessel

Exclusion criteria protocol 3;

• Coronary revascularisation within three months

• Diabetes mellitus

• Cardiac failure (ejection fraction <35% or New York Heart Association (NYHA) ≥2)

• Renal impairment (creatinine ≥200 µmol/L)

• Systolic blood pressure <100 or >190 mmHg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Umeå University Hopsital	Umeå		Sweden	90185
2	British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh	Edinburgh		United Kingdom

Sponsors and Collaborators

• Stefan Soderberg
• University of Edinburgh

Investigators

• Principal Investigator: Stefan Söderberg, MD, PhD, Umeå University, Umeå Sweden

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Stefan Soderberg, Professor, Umeå University
• ClinicalTrials.gov Identifier: NCT04374500
• Other Study ID Numbers: 05-150M
• First Posted: May 5, 2020
• Last Update Posted: Jul 17, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Verapamil; Nitroprusside; Acetylcholine; Vasodilator Agents; Bradykinin; Substance P

Study Results

Participant Flow

Recruitment Details	Seventeen healthy non-smoking male volunteers not taking any regular medication were recruited in Umeå, Sweden. Ten participated in protocol 1 and ten in protocol 2 (3 in both). Eighty-three men and women with established coronary artery disease were recruited from the cardiology outpatient clinic at the Royal Infirmary, Edinburgh, Scotland.

Arm/Group Title	Leptin Infusion in Healthy Men	Leptin or Saline Infusion Plus Vasodilators in Healthy Men	Vasodilators in CAD Patients
Arm/Group Description	This applies to protocol 1 when 10 healthy men got infusion of leptin locally and forearm blood flow was measured with the other arm as the control.	This applies to protocol 2 when 10 healthy men got either a background infusion of leptin or saline when measuring vasoresponse to four vasodilatators. Each participant had two examinations with either leptin or saline and the order was randomised.	This applies to protocol 3 when blood flow was measured in the forearm after infusion of 3 vasodilators, and the response was related to endogenous leptin levels
Period Title: Overall Study
STARTED	10	10	83
COMPLETED	10	10	83
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Healthy Males (n=17) and CAD Patients (n=83)
Arm/Group Description	Table 1. Baseline characteristics 17 healthy males Age (years) Weight (kg) Height (cm) BMI (kg/m2) Waist circumference (cm) Hip circumference (cm) Waist-to-Hip (ratio) Heart rate (beats/min) Systolic blood pressure (SBT) (mmHg) Diastolic blood pressure (DBT) (mmHg) Table 2. Baseline characteristics 83 men and women with CAD Age (years) Sex (male/female) BMI (kg/m2) Heart rate (beats/min) SBT (mmHg) DBT (mmHg) Cigarette smoking (n) Co-morbidity (n) Previous myocardial infarction Hypertension Family history of coronary heart disease Hypercholesterolaemia Medication (n) Aspirin Lipid lowering therapy Angiotensin converting enzyme inhibitor (ACEi) Angiotensin receptor blocker (ARB)Creatinine (µmol/L) Glucose (mmol/L) Total cholesterol (mmol/L) ProBNP (pg/nL) C-reactive protein (mg/L)
Overall Participants	100
Age (Years) [Mean (Standard Deviation) ]
Healthy males	26.4 (1.4)
Coronary artery disease (CAD) patients	60 (6)
Sex: Female, Male (Count of Participants)
Female	17 17%
Male	83 83%
Region of Enrollment (participants) [Number]
Sweden	17 17%
United Kingdom	83 83%

Outcome Measures

1. Primary Outcome

Title	Blood-flow
Description	The primary outcome in all protocols were local blood-flow in the forearm. This was measured by venous occlusion plethysmography using mercury-in-silastic strain gauges and the unit is mL/100mL of tissue/min. In protocol 1, the blood flow response to increasing levels of leptin was evaluated, In protocol 2, the blood flow response to vasodilators on top of leptin or saline infusion was evaluated, and in protocol 3, the blood flow response was measured to vasodilators and related to endogenous leptin levels (no leptin given)
Time Frame	18 minutes in protocol 1, 3 hours in protocol 2, non-applicable (NA) in protocol 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leptin Infusion	Leptin Plus Vasodilators	Vasodilators in CAD Patients
Arm/Group Description	In protocol 1, blood flow in the infused forearm did not change with leptin infusion	In protocol 2, blood flow in the infused forearm did not change with leptin infusion whereas blod flow changed as expected with vasodilators, but blunted with concomitant leptin infusion versus saline infusion	Blood flow was measured locally in the forearm after infusion of vasodilators. No leptin was given.
Measure Participants	10	10	83
Mean (Standard Error) [ml/100 mg tissue/min]	1.75 (0.14)	1.75 (0.14)	NA (NA)

2. Secondary Outcome

Title	Release of Fibrinolytic Variables (Tissue Plasminogen Activator [tPA] and Plasminogen Activator Inhibitor-1 [PAI-1])
Description	In all protocols, fibrinolytic variables were measured. In protocol 2 and 3, in the infused forearm after vasodilatation with bradykinin or substance P, respectively. The fibrinolytic variable measured in all protocols was tPA activity (IU/mL) and is reported here after the leptin infusion, when applicable.
Time Frame	18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leptin Infusion	Leptin Plus Vasodilators	Vasodilators in CAD Patients
Arm/Group Description	In protocol 1, blood flow in the infused forearm did not change with leptin infusion	In protocol 2, blood flow in the infused forearm did not change with leptin infusion whereas blod flow changed as expected with vasodilators, but blunted with concomitant leptin infusion versus saline infusion	Blood flow was measured locally in the forearm after infusion of vasodilators. No leptin was given.
Measure Participants	10	10	83
Mean (Standard Error) [IU/mL]	0.70 (0.14)	0.80 (0.38)	NA (NA)

3. Secondary Outcome

Title	Blod Pressure and Pulse
Description	In all protocols, blood pressure (mmHg) was measured concomitantly using a semi-automated non-invasive sphygmomanometer. Systolic blood pressure is reported here after leptin infusion, when applicable.
Time Frame	18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Leptin Infusion in Healthy Men	Leptin or Saline Infusion Plus Vasodilators in Healthy Men	Vasodilators in CAD Patients
Arm/Group Description	This applies to protocol 1 when 10 healthy men got infusion of leptin locally and forearm blood flow was measured with the other arm as the control.	This applies to protocol 2 when 10 healthy men got either a background infusion of leptin or saline when measuring vasoresponse to four vasodilatators. Each participant had two examinations with either leptin or saline and the order was randomised.	This applies to protocol 3 when blood flow was measured in the forearm after infusion of 3 vasodilators, and the response was related to endogenous leptin levels
Measure Participants	10	10	83
Mean (Standard Error) [mmHg]	140 (3.7)	134 (3.3)	NA (NA)

4. Secondary Outcome

Title	Leptin
Description	Plasma leptin concentration (ng/mL) was measured in all protocols, and in protocol 1 and 2, specifically in both infused and in non-infused arms. Data given are leptin concentrations in the infused arm at the end of the infusion.
Time Frame	18 minutes in protocol 1, 3 hours in protocol 2, NA in protocol 3

Outcome Measure Data

Analysis Population Description

In arm 3, the participants were not given any leptin, endogenous leptin was measured

Arm/Group Title	Leptin Infusion	Leptin Plus Vasodilators	Vasodilators in CAD Patients
Arm/Group Description	In protocol 1, blood flow in the infused forearm did not change with leptin infusion	In protocol 2, blood flow in the infused forearm did not change with leptin infusion whereas blod flow changed as expected with vasodilators, but blunted with concomitant leptin infusion versus saline infusion	Blood flow was measured locally in the forearm after infusion of vasodilators. No leptin was given.
Measure Participants	10	10	83
Mean (Standard Error) [ng/mL]	186.2 (10.2)	13.1 (3.4)	NA (NA)

Adverse Events

Time Frame	During the actual infusion plus 24 hours.
Adverse Event Reporting Description	We measured blood pressure and pulse during and after the infusion and each participant was interrogated about subjective side effects like nausea, flush etc.
Arm/Group Title	Leptin Infusion		Leptin Infusion Plus Vasodilator Infusion		Vasodilator Infusion in CAD Patients
Arm/Group Description	In protocol 1, each participant got leptin locally in the studied forearm whereas the other forearm acted as control. No adverse effects were reported.		In protocol 2, each participant got ether saline or leptin locally in the studied forearm whereas the other arm acted as control. Local vasodilators were given in the studied forearm on top of leptin/saline infusion. The experiment was repeated and each participant participated twice. No adverse effects were reported.		In protocol 3, only vasodilators were given in the studied forearm, and no leptin was given. No adverse effects were reported.
All Cause Mortality
	Leptin Infusion		Leptin Infusion Plus Vasodilator Infusion		Vasodilator Infusion in CAD Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/83 (0%)
Serious Adverse Events
	Leptin Infusion		Leptin Infusion Plus Vasodilator Infusion		Vasodilator Infusion in CAD Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	Leptin Infusion		Leptin Infusion Plus Vasodilator Infusion		Vasodilator Infusion in CAD Patients
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/83 (0%)

Limitations/Caveats

Sympathetic activity should have been measured simultaneously, but was not done.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.