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The Effect of A2A Adrenoceptor Stimulation on the Diameter of Retinal Arterioles During Hypoxia in Vivo

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ClinicalTrials.gov Identifier: NCT03090087
Recruitment Status : Unknown
Verified March 2017 by University of Aarhus.
Recruitment status was:  Recruiting
First Posted : March 24, 2017
Last Update Posted : March 28, 2017
Sponsor:
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:

The purpose is to investigate how the adenosine affects the diameter regulation of retinal arterioles during changes in oxygen tension. A deeper understanding of the mechanisms involved in diameter regulation of retinal arterioles during changes in oxygen tension can be used to obtain a more detailed understanding of diseases where changes in the diameter regulation of retinal vessels are involved in the disease pathogenesis and possibly point to new therapeutic options for patients with retinal vascular disease, such as diabetic retinopathy and retinal vein thrombosis.

Preliminary, a routine ophthalmological evaluation, measurement of blood pressure, and electrocardiogram will be preformed to insure that only healthy test persons are included in the study.

The test persons will be randomly allocated to two groups, one group in which protocol 1 is followed by protocol 2, and the other group with the two protocols performed in the reverse order.

Protocol 1: Using the DVA, a video recording will capture the diameter of retinal vessels and the changes occurring during stimulation with flickering light. The recording lasts 4.5 minutes and is preformed before and after intravenous injection of adenosine.

Protocol 2: The procedures are similar to those of protocol 1 but are performed during breathing of a gas mixture with a reduced oxygen tension to 12,5 %, which results in a reduced oxygen saturation in the blood to 85-90 %.


Condition or disease Intervention/treatment Phase
Retinal Artery Occlusion Biological: Hypoxia Drug: Regadenoson Phase 2

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Detailed Description:

Background:

Occlusion of the retinal vessels leading to retinal ischaemia and hypoxia is an important element in the pathophysiology of the major vision threatening diseases in the Western World. The hypoxic areas release vasodilating factors that induce vasodilatation in adjacent retinal areas in order to increase blood flow and retinal oxygenation. An understanding of the mechanisms underlying this vasodilatation may help identifying new therapeutic principles for modulating retinal blood flow during changes in retinal blood flow secondary to hypoxia and other diseases.

The present study:

Two working hypotheses will be tested: 1) That systemic administration of an A2A adrenoceptor agonist affects retinal blood flow independently of its systemic effects. 2) That the vasodilating effect of A2A adrenoceptor stimulation and the vasodilating effects of systemic hypoxia and increased retinal metabolism induced by flicker stimulation are additive.

Methods:

The diameter of retinal vessels are measured using the Dynamic Vessel Analyser (DVA). This apparatus performs video recordings of the ocular fundus, and the single images in the video sequences are grabbed for computerised analysis. Special software enables calculation of the diameter of the vessel on the basis of the distance between the vessel borders. The fact that images are grabbed real time (25 times per second) allows the detection of immediate diameter changes when the retinal metabolism is increased by exposure to flickering light (metabolic autoregulation).

The A2A adrenoceptor agonist regadenoson is administered during continuous ECG monitoring as a single intravenous injection of 400 micrograms (5 ml) in an antecubital vein. No dose adjustments are necessary for body weight, age, renal og hepatic impairment. Due to a potential ischaemic effect of regadenoson, only persons with no history of arterial hypertension or cardiac disease and with normal blood pressure and ECG will be included.

The experiments will be performed during breathing of ambient air and after 10 minutes of breathing air containing 12.5% oxygen (corresponding to the saturation at an altitude of 4100 m), which induces a decline in the arterial oxygen saturation resulting in dilatation of retinal vessels.

Experimental design:

The project will be conducted as an open controlled interventional study performed on two days separated by at least one day. Initial a routine ophthalmological evaluation with a slit lamp examination, measurement of the intraocular pressure and ophthalmoscopy, supplemented with a measurement of central retinal thickness using optical coherence tomography scanning will be preformed as will measuring of ECG and blood pressure to make sure only healthy test persons are included.

The test persons will be randomly allocated to two groups, one group in which protocol 1 is followed by protocol 2, and the other group with the two protocols performed in the reverse order.

Protocol 1:

A) Using the DVA, the diameter of a larger retinal vascular arcade arteriole will be recorded for 90 seconds at baseline followed by a similar recording during stimulation with flickering light and a recording during rest, altogether lasting 4.5 minutes B) Intravenous injection of 0,4 mg regadenoson and repetition of the procedures in step A

Protocol 2:

The procedures are similar to those of protocol 1 but are performed during breathing of a hypoxic gas mixture.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Intervention Model Description:

The project will be conducted as an open controlled interventional study performed on two days separated by at least one day.

The test persons will be randomly allocated to two groups, one group in which protocol 1 is followed by protocol 2, and the other group with the two protocols performed in the reverse order.

Protocol 1: A) Using a Dynamic Vessel Analyzer, the diameter of a larger retinal vascular arcade arteriole will be recorded for 90 seconds at baseline followed by a similar recording during stimulation with flickering light and a recording during rest, altogether lasting 4.5 minutes. B) Intravenous injection of 0,4 mg regadenoson and repetition of the procedures in step A.

Protocol 2: The procedures are similar to those of protocol 1 but are performed during breathing of a hypoxic gas mixture.

Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of A2A Adrenoceptor Stimulation on the Diameter of Retinal Arterioles During Hypoxia in Vivo
Actual Study Start Date : March 22, 2017
Estimated Primary Completion Date : November 2017
Estimated Study Completion Date : November 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Regadenoson

Arm Intervention/treatment
Experimental: Healthy person
The purpose is to investigate the effect of A2A adrenoceptor stimulation using the drug regadenoson (Rapiscan) on the diameter of retinal arterioles during hypoxia in vivo.
Biological: Hypoxia
The purpose is to test the effect of A2A adrenoceptor stimulation on the diameter of retinal arterioles during hypoxia in vivo

Drug: Regadenoson
The purpose is to test the effect of A2A adrenoceptor stimulation on the diameter of retinal arterioles during hypoxia in vivo
Other Name: Rapiscan




Primary Outcome Measures :
  1. Diameter responses of retinal arterioles [ Time Frame: 11 minutes ]
    The main outcome variable of the DVA is the width measurement of the selected vessel(s), expressed in units of measurement (UM). In a normal Gullstrand eye, 1 UM is equivalent to 1 µm. For the stimulation with flicker light, the outcome is defined as the percent change from baseline.


Secondary Outcome Measures :
  1. Blood pressure [ Time Frame: The blood pressure is measured during the last 40 seconds in each phase using an oscillometric technique on the left arm. ]
    mmHg

  2. Systemic arterial saturation [ Time Frame: The systemic arterial saturation is registered at the beginning and half way through each examination phase and during the 2 min break where the drug Regadenoson is injected. ]
    Percentage

  3. Intraocular pressure [ Time Frame: The intraocular pressure is measured before and after the drug administration (time point 280 and 350 sec) and after the second DVA examination is terminated (time point 670 sec). ]
    mmHg



Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 35 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 20-35
  • Healthy, both current and prior
  • Normal echocardiogram
  • Signed and informed consent

Exclusion Criteria:

  • Former or current cardiovascular disease or high blood pressure
  • Lung diseases incl. asthma or chronic obstructive pulmonary disease (COPD)
  • Known eye disease or previously treated for an eye disease, particularly glaucoma and cataracts
  • People taking medication, except birth control pills
  • Persons who have or who have had epilepsy
  • Pregnant or breast-feeding women
  • Allergies to the constituent substance of the medication used in the study

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): NCT03090087


Contacts
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Contact: Anna Dons-Jensen, Student +45 78463250 annadonsjensen@gmail.com
Contact: Line Petersen, Ph.D. +45 78463250 linperse@rm.dk

Locations
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Denmark
Department of Ophthalmology, Aarhus University Hospital Recruiting
Aarhus, Denmark, 8000
Contact: Anna Dons-Jensen, Student    +45 78463250    annadonsjensen@gmail.com   
Contact: Line Petersen, Ph.D.    +45 78463250    linperse@rm.dk   
Sponsors and Collaborators
University of Aarhus
Investigators
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Study Chair: Toke Bek, Chair Main supervisor

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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT03090087     History of Changes
Other Study ID Numbers: Adenosine RVA
First Posted: March 24, 2017    Key Record Dates
Last Update Posted: March 28, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The project results will be published in recognized international journals. Both positive, negative and inconclusive results will be published.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Aarhus:
Diameter of retinal arteries
Adenosine
Hypoxia
Additional relevant MeSH terms:
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Retinal Artery Occlusion
Hypoxia
Signs and Symptoms, Respiratory
Signs and Symptoms
Retinal Diseases
Eye Diseases
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases
Regadenoson
Adenosine A2 Receptor Agonists
Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs