Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000428763p
Ethics application status
Submitted, not yet approved
Date submitted
11/03/2022
Date registered
16/03/2022
Date last updated
16/03/2022
Date data sharing statement initially provided
16/03/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Chemoreflex inactivation, arterial stiffness and exercising muscle blood flow in human hypertension
Scientific title
Circulatory effects of peripheral chemoreflex inhibition at rest and exercise in hypertension
Secondary ID [1] 306616 0
None
Universal Trial Number (UTN)
U1111-1273-6661
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 325534 0
Condition category
Condition code
Respiratory 322904 322904 0 0
Normal development and function of the respiratory system
Cardiovascular 322905 322905 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a non-therapeutic mechanistic physiological study.

All the following measurements and tests described will be conducted by a trained human physiologist staff member.

At an initial visit to the laboratory (~1hr), written informed consent will be obtained from participants. Anthropometric (height, weight, hip-to-waist ratio), demographic, clinical history information will be obtained, and health questionnaires and 7-day physical activity recall data will be collected.

Following, participants will attend 2 experimental visits (~2.5hr each), including set-up time.
The first experimental visit will be scheduled ~2-7 days after the initial familiarisation visit and the second experimental visit will be scheduled ~2 weeks after the first experimental visit.

In the experimental visit 1 participants will be asked to perform a lung function test. The participants will be asked to empty their lungs by gently breathing out as much air as they can. Then they will breathe in a quick (but deep breath), hold your breath for 10 seconds, and then breathe out as instructed. This test will be undertaken to test how well their lungs are working.

Following this, participants will be asked to lie in a semi-recumbent position on a medical examination couch and to remain in that position throughout the session. Participants will then be instrumented for continuous monitoring of blood pressure (BP), heart rate (HR), ventilation and arterial stiffness recordings. More specifically, brachial BP will be measured with a clinically validated automated sphygmomanometer (Omron), using a cuff wrapped around the upper arm. In addition, beat-to-beat BP will be measured using finger photoplethysmography, using a small lightweight cuff wrapped around the finger. Heart rate will be measured using a standard electrocardiogram involving the placement of sticky patch electrodes on the collarbones and chest (standard 3 lead ECG). For breathing monitoring, participants will wear a mouthpiece and a nose clip. Arterial stiffness will be recorded using two different ways: 1) using the BP+ device (Uscom) which involves a blood pressure cuff placed around the upper arm; 2) using the Complior device (Artech Medical) which involves lightweight probes that are positioned at three specific locations (neck, wrist, and top of the thigh/groin) and held lightly in place with a probe holder.

After a resting period of 15 min (last 5 min used for analysis), peripheral chemoreflex testing will be undertaken. Peripheral chemoreflex testing will involve two tests. Each test lasts 5 min and is separated by a 15-minute recovery period. Each participant will receive both tests in a randomised order. The two tests are: 1) isocapnic hypoxia (to evaluate peripheral chemoreflex stimulation, using a gas concentration of 10% O2 and 90% N2); and 2) isocapnic hyperoxia (to evaluate a decrease in the peripheral chemoreflex activity, using a gas concentration of 50% O2 and 50% N2). After each trial participants will be asked to rate the difficulty of their breathing.

On the second visit, participants will be asked to lie in a semi-recumbent position on a medical examination couch and to remain in that position throughout the session again. A thin, flexible tube will be inserted into the hand of the participant by a clinically qualified investigator. Participants will be instrumented again for BP, heart rate, and ventilation. Brachial artery blood flow will be measured using duplex Doppler ultrasound. This ultrasound examination is similar to the scan done for pregnant women, but a large artery is examined. This is a simple and safe procedure and involves a probe being put on the patients’ skin over the region of interest with the help of a ‘water jelly’. Sympathetic nerve activity will also be measured using the microneurography technique. This involves the insertion of a small, sterile wire (unipolar tungsten microelectrodes, tip measuring 1-5 um) near the fibular head on the outside of the leg, to obtain a multiunit recording of postganglionic muscle sympathetic nerve activity from the peroneal nerve.

After a resting baseline of 15 min (last 5 min used for analysis), two trials will then be performed to test the peripheral chemoreflex deactivation. Trials will be undertaken with either intravenous 0.9% saline (control) or intravenous low-dose dopamine (2 mcg·Kg-1·min-1) to deactivate the peripheral chemoreflex. Following the drug infusion participants will be asked to breathe an isocapnic hypoxia mixture (the same gas concentration as the one from the first visit - 10% O2 and 90% N2) for 5 minutes to evaluate peripheral chemoreflex activity. After that, a 10-minute recovery will be undertaken. Following the recovery, a rhythmic handgrip exercise (1-second contraction, 1-second relaxation) will be performed at 50% of the participant’s maximal voluntary contraction for 3 minutes. After the breathing trial participants will be asked to rate the difficulty of their breathing and after the exercise participants will be asked to rate their perceived exertion.
Intervention code [1] 323076 0
Early detection / Screening
Comparator / control treatment
Healthy control participants with a normal blood pressure
Control group
Active

Outcomes
Primary outcome [1] 330698 0
Arterial stiffness as assessed by pulse wave velocity
Timepoint [1] 330698 0
Normotensive and hypertensive participants will be assessed at three timepoints during the first experimental session: at rest, during isocapnic hypoxia and during isocapnic hyperoxia.
Secondary outcome [1] 407239 0
Muscle sympathetic nerve activity as assessed by microneurography.
Timepoint [1] 407239 0
Normotensive and hypertensive participants will be assessed at thee timepoints during the second experimental session: at rest, during isocapnic hypoxia and during exercise.

Eligibility
Key inclusion criteria
- Participants with essential hypertension (At least Stage 2 hypertension; untreated office SBP > 140 mmHg or DBP > 90 mmHg)
- Normotensive controls (office SBP < 120 mmHg and DBP < 80 mmHg)
- Men and women
- Aged over 18 years
- Body mass index < 35 kg/m2
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Significant arrhythmias (e.g., atrial fibrillation, previous VT / significant ventricular ectopy)
- Significant valvular heart disease
- Previous coronary artery bypass surgery
- Primary angioplasty for acute ST elevation
- Myocardial infarction
- Severe left ventricular dysfunction
- Recent (< 3 months) ischemic stroke
- Current smoker
- Body mass index < 18 kg·m2
- Current pregnancy
- Users of recreational drugs
- Abusers of alcohol
- Inability to fully or appropriately provide consent (e.g., language issue, reading capability)
- Underlying medical conditions, which in the opinion of the Investigator place the participant at unacceptably high risk for participating in the study

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Other
Other design features
Both groups (hypertensive and normotensive participants) will receive both gases (isocapnic hypoxia and isocapnic hyperoxia) inhalation protocols in random order during the study.
Both groups will also receive both drug infusion (saline and dopamine) protocols in random order during the study.
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Anthropometric (e.g., BMI) and demographic (e.g., age) information gathered at primary screening will be quantified using basic statistics (mean, SD, Median, IQR) and graphical presentations (boxplots, histograms, scatter plots). Likewise, levels of primary and secondary outcomes will be similarly reported. Responses (last 1 min of each trial) will be compared in normotensive and hypertensive individuals. Normal distribution will be evaluated using Shapiro-Wilk tests. Comparisons of normally distributed physiological variables for a given trial will be made using a t-test, and non-normally distributed data evaluated using a Mann–Whitney U test. In the event of potential confounding differences in baseline characteristics (e.g., physical activity), analysis of covariance (ANCOVA) will be employed. Associations between carotid body activity and the severity of hypertension and sympathetic activity will be made using Pearson’s product or Spearman’s rank correlation coefficient, as appropriate. Statistical analysis will be performed using SPSS (IBM Corp.,). Significance will be set at p < 0.05. Normally distributed data will be presented as mean (SD) while non-normally distributed data will be presented as median [interquartile range].

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
4/04/2022
Actual
Date of last participant enrolment
Anticipated
31/08/2023
Actual
Date of last data collection
Anticipated
21/09/2023
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment outside Australia
Country [1] 24649 0
New Zealand
State/province [1] 24649 0
Auckland

Funding & Sponsors
Funding source category [1] 310949 0
Government body
Name [1] 310949 0
Health Research Council of New Zealand (HRC)
Country [1] 310949 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 312251 0
None
Name [1] 312251 0
Address [1] 312251 0
Country [1] 312251 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 310508 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 310508 0
Ethics committee country [1] 310508 0
New Zealand
Date submitted for ethics approval [1] 310508 0
25/02/2022
Approval date [1] 310508 0
Ethics approval number [1] 310508 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117898 0
A/Prof James P Fisher
Address 117898 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 117898 0
New Zealand
Phone 117898 0
+64225446014
Fax 117898 0
Email 117898 0
[email protected]
Contact person for public queries
Name 117899 0
James P Fisher
Address 117899 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 117899 0
New Zealand
Phone 117899 0
+64225446014
Fax 117899 0
Email 117899 0
[email protected]
Contact person for scientific queries
Name 117900 0
James P Fisher
Address 117900 0
Faculty of Medical and Health Sciences
Department of Physiology
University of Auckland
85 Park Road
Grafton
Auckland 1023
Country 117900 0
New Zealand
Phone 117900 0
+64225446014
Fax 117900 0
Email 117900 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.