Cerebral and Cardiac Blood Flow During Exercise in Patients With COPD

COPD Clinical Trial

— REFLEX-COPD  

Official title:

Cardiac Output and Brain Perfusion and Architecture During Exercise in Patients With Chronic Obstructive Pulmonary Disease (COPD) and Healthy, Age Matched Volunteers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04138563
• Other study ID #: 18063
• Status: Recruiting
• Start date: January 3, 2019
• Est. completion date: September 30, 2020

Study information

• Verified date: October 2019
• Source: University of Nottingham
• Contact: Ayushman Gupta
• Phone: 01158231702
• Email: mszag4[@]exmail.nottingham.ac.uk
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Heart disease and conditions related to the blood vessels are responsible for a large proportion (over a quarter) of the deaths in people with chronic obstructive pulmonary disease (COPD). The changes can also affect the smaller smaller blood vessels within the body, in particular the brain and the kidneys. This might be related to how the heart pumps and if it is under any pressure. Investigations performed at the University in healthy older volunteers demonstrated how the blood flows in the brain and heart during exercise. Exercise gently puts the whole body under some pressure and therefore exposes any weaker areas.

In this study the investigators are hoping to find out what happens to the blood flow in the brain and in the heart in patients who have COPD when they exercise and in the resting state. This will be compared to people of a similar age with a similar smoking history but without COPD. This will be examined using state of the art magnetic resonance imaging (MRI) and will allow us to assess whether changes in structure and function are related to this altered blood flow.

Our hypothesis is that COPD will cause a larger change in blood flow during exercise compared to the healthy volunteers and that reduced cardiorespiratory fitness will be associated with increased age related structural within the brain.

Description:

The aim is to recruit 20 participants with COPD, who will be compared to 10 age and gender matched controls who also have a smoking history. The investigators aim for this number to complete the components of the study and therefore may have to over-recruit if some people drop out or are not eligible. The study elements are feasible, as the work extends a previous research study in healthy volunteers.

This research trial will consist of a medical screening visit and three investigation study visits spaced ideally one week apart. The investigation visits will begin within 6 (ideally within 4) weeks of the medical screening visit. The total duration of the study and screening visits should be 12 weeks maximum for each participant.

Screening visit:

If the participant expresses an interest in the clinical trial and wants to take part they will be invited (at a convenient time for them) to attend a medical screening visit located at the Nottingham City hospital. Here the investigator will discuss the research trial and answer any questions or concerns they might have regarding the research trial. The participant, if willing, will then be required to sign a consent form so that the screening procedures can begin, which include:

• Blood sample: Approximately a 20ml sample (4 teaspoons) taken from their arm, for further investigation including full blood count (FBC), brain natriuretic peptide (BNP) and kidney function.

• Questionnaires: 5 different questionnaires that ask about symptoms and how they affect daily life, a physical activity questionnaire, quality of life questionnaire and a MRI safety questionnaire.

• Spirometry: A simple blowing test to assess the participants' breathing which is performed three times.

• 12 lead ECG.

• a hand grip dynamometer to assess muscle strength

• timed up and go test: a test used to measure gait speed, where participants are asked to get up from a chair and walking to 3 meters and back, whilst being timed.

• to wear a step counter (Sensewear armband) for a week during waking hours to record steps.

Provided the ECG, step count (<10,000 steps) and other screening elements are ok, the participant will proceed to Study visit 1.

Strength and exercise test protocol:

The participant will be required to abstain from strenuous exercise for the 48 hours prior to the visit and also from alcohol and caffeine for 24 hours prior. Upon arrival they will perform a knee extension exercise so we can establish the muscle strength in the legs, specifically 3 maximal knee extensions with a 30 second rest in between. We will also measure fatigue by dong 20 extensions after a short break.

After a break they will then undergo an exercise test using an MRI compatible stepper device (Ergospect Cardiostepper) whilst in a supine position. This has been adapted to be similar to how they will exercise in the MRI scanner. Volunteers will start off stepping at a frequency of 65-70 steps a minute at the minimum workload and every 3 minutes get gradually a little harder until exhaustion is reached. Heart rate at rest and in response to exercise will be measured using a heart monitor. Participants will be given the option to have their expired gases also measured during exercise using a face mask, though this is not necessary if not tolerated. In the final minute of each workload we will take a finger prick test to measure the gases in the patients blood. A 3 lead ECG and oxygen saturation probe will be attached during exercise as safety measures and the protocol will be halted if oxygen saturation falls below 80% or if any relevant rhythm abnormalities are seen on the ECG trace.

The second study visit will be used to confirm the exercise and strength parameters measured in the first study visit.

MRI protocol:

A series of scans of the brain and heart will be taken at rest and then whilst stepping on the stepper machine within the MRI. The exercise will be at a steady state low level intensity determined by calculating the workload at which a fraction of maximum heart rate was achieved during first 2 study visits.

The MRI scan itself will take about ¾ hour but upto 2 hours is allowed for preparation and introducing the scan to the participant. The scanner is quite noisy and so the participant will wear ear defenders during the scan. Because the scanner is built around a large magnet, the participant will be instructed to remove all metal from their body, including jewellery. There is no radiation involved.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: September 30, 2020
• Est. primary completion date: September 30, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 75 Years

Eligibility

Inclusion Criteria:

• Patients aged 65-75 years old,

• >10 pack years smoking,

• FEV1/FVC <0.7 and FEV1<60% predicted (for COPD participants only)

• Sedentary lifestyle (<10,000 steps per day)

• Able to give informed consent

• Able to read, understand and communicate coherently in English

Exclusion Criteria:

• Doctor diagnosis of ischaemic heart disease or heart failure

• Doctor diagnosis of dementia or Alzheimers disease

• History of previous cerebrovascular disease (stroke or TIA) or malignancy

• Pregnancy or childbearing in the last 6 months

• Maintenance oral corticosteroids in the past 6 months

• Requirement for oral corticosteroids or antibiotics in the past 6 weeks

• Active arthritis or other muscular condition limiting exercise

• Surgical intervention in the last 12 weeks

• Long term oxygen therapy requirement

• Other formal current respiratory diagnosis

• Thyroid disease

• Diabetes Mellitus

• Neurological or cognitive impairment

• Significant physical disability

• Any other conditions in addition to the above that the investigators consider may affect study measurements or safety

• Inability to understand verbal and/or written explanation of the study requirements

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Cognitive Impairment
• COPD

Locations

Country	Name	City	State
United Kingdom	NIHR Nottingham BRC Respiratory Theme, University of Nottingham and NUH Trust	Nottingham	Nottinghamshire

Sponsors (1)

Lead Sponsor	Collaborator
University of Nottingham

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA. 1989 Nov 3;262(17):2395-401. — View Citation

Erickson KI, Leckie RL, Weinstein AM. Physical activity, fitness, and gray matter volume. Neurobiol Aging. 2014 Sep;35 Suppl 2:S20-8. doi: 10.1016/j.neurobiolaging.2014.03.034. Epub 2014 May 14. Review. — View Citation

John M, Hussain S, Prayle A, Simms R, Cockcroft JR, Bolton CE. Target renal damage: the microvascular associations of increased aortic stiffness in patients with COPD. Respir Res. 2013 Mar 5;14:31. doi: 10.1186/1465-9921-14-31. — View Citation

McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA; TORCH Clinical Endpoint Committee. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007 May;62(5):411-5. Epub 2007 Feb 20. — View Citation

Sabit R, Bolton CE, Edwards PH, Pettit RJ, Evans WD, McEniery CM, Wilkinson IB, Cockcroft JR, Shale DJ. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007 Jun 15;175(12):1259-65. Epub 2007 Mar 15. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Resting white and grey matter structural integrity	Grey and white matter volume (mm3) using the MRI MPRAGE sequences will be measured at rest	up to 12 weeks
Primary	Cardiac structural integrity	Cardiac output (L/min) will be measured using the MRI sequence (Short axis Cine) at rest.	up to 12 weeks
Primary	Cardiac structural integrity	Cardiac fibrosis (%) will be measured using the MRI MOLLI T1 sequence at rest.	up to 12 weeks
Primary	Cardiac structural integrity	Myocardial strain (%) will be measured using the MRI cardiac tagging sequence at rest.	up to 12 weeks
Primary	Whole body fat and muscle quantification	Whole body fat and muscle quantification (%) will be measured using the MRI whole body mdixon sequence at rest.	up to 12 weeks
Primary	Aortic flow	Aortic flow (ml/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls	up to 12 weeks
Primary	Cerebral blood flow	Cerebral blood flow (ml/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls	up to 12 weeks
Primary	Cerebral perfusion	Cerebral artery perfusion (ml/100g/min) will be measured during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls	up to 12 weeks
Primary	Oxygen extraction fraction	Oxygen extraction fraction (%) will be derived from the difference between arterial and venous cerebral oxygenation measured via TRUST MRI scan sequence during rest, low level steady-state exercise and following cessation of exercise and compared between COPD and age and gender matched controls	up to 12 weeks
Secondary	Muscle isometric strength (MVC)	Isometric muscle torque of the quadriceps (Nm) assessed using the cybex dynamometer	up to 6 weeks
Secondary	Muscle isokinetic fatigue	Fatiguability test of the quadriceps (Nm) assessed using the cybex dynamometer	up to 6 weeks
Secondary	Quality of life (SGRQ)	Assessed using the St Georges Respiratory Questionnaire. min value: 0, max value: 84, higher score means worse outcome	1 week
Secondary	Physical activity level (IPAQ Physical activity questionnaire)	Assessed using the International Physical activity questionnaire. min value: 0, max value: 66000, higher score means better outcome	1 week
Secondary	Montreal Cognitive Assessment (MoCA) cognition level	Assessed using the Montreal cognitive assessment questionnaire. min value: 0, max value: 30, higher score means better outcome	1 week
Secondary	Hospital anxiety and depression scale (HADS)	min value: 0, max value: 21, higher score means worse outcome	1 week
Secondary	Hand grip strength	Composite of hand grip strength (Kg), measured by a hand held dynamometer,	1 week
Secondary	Timed up and go test	Timed up and go test (seconds) will be measured to assess degree of frailty.	1 week
Secondary	Serum markers of inflammation for research purposes (likely to include IL-1, IL-6, and TNFa)	Blood test	1 week
Secondary	Heart rate response to exercise	Heart rate response (Beats per minute) will be measured at rest and during incremental exercise to assess cardio-respiratory fitness.	up to 6 weeks