Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611001182987
Ethics application status
Approved
Date submitted
8/11/2011
Date registered
15/11/2011
Date last updated
15/12/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Does blocking the body's own morphine-like chemicals during exercise change the perception of breathlessness?
Scientific title
The role of peripheral opioid receptors in modulating breathlessness. An in vivo placebo controlled, triple arm, cross over , double blind study of naloxone and methylnaltrexone on breathlessness during exercise in people with Chronic Obstructive Airway Disease.
Secondary ID [1] 262684 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breathlessness during exercise in people with Chronic Obstructive Pulmonary Disease. 268388 0
Condition category
Condition code
Respiratory 268528 268528 0 0
Chronic obstructive pulmonary disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The main object of the study is to compare the effects of i.v. administration of naloxone, methylnaltrexone and normal saline on ratings of dyspnoea during contant work rate treadmil exercise. 30 minutes prior to each test the participant will be administered 5mg of salbutamol in 2.5 of normal saline via a nebuliser. At visit 1( baseline) this test is for maximal incremental cardiopulmonary exercise test (iCPET) according to the modified Balke protocol. This iCPET may take up to 25 minutes depending on the participant's endurance but will be ceased when the individual’s perception of dyspnoea or leg fatigue prevents them from maintaining the required minimum speed.
At the subsequent 4 weekly visits a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort.
Throughout each exercise test and for 30 minutes after stopping, the participant will be attached to a 12 lead cardiac safety monitor and their blood pressure will be recorded regularly. Ventilatory and metabolic measurements of exercise will be recorded using a portable gas exchange monitor (COSMED model) through which patients will breathe allowing physiologic and metabolic parameters to be recorded in real time. A medical officer, 2-3 nurses and respiratory technician will be present throughout each visit and the tests will be performed in the cardiology department .

Arm 1 - once only dose of naloxone, 0.1mg/kg (10mg maximum) diluted to a standard volume, given intravenously 15 minutes a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort.

Arm 2 -once only dose methylnaltrexone,0.3mg/kg (30mg maximum) diluted to a standard volume, given intravenously 15 minutes prior to a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort.


There will be a 7 days wash out period between each arm and the placebo.
Intervention code [1] 267032 0
Treatment: Drugs
Comparator / control treatment
Once only dose of normal saline diluted to a standard volume given intravenously 15 minutes prior to a constant rate cardio pulmonary exercise test (cCPET) of optimal training intensity, 75%WRmax will be undertaken to exhaustion with the aim that this will be at least 10 minutes of effort.
Control group
Placebo

Outcomes
Primary outcome [1] 269274 0
Intensity of dyspnoea measured by the Dyspnoea 100mm Visual Analogue Scale (VAS).
Timepoint [1] 269274 0
At one minute intervals during a 15 minute exercise test at Visits 3,4 and 5.
Primary outcome [2] 269275 0
Unpleasantness of dyspnoea measured by the Dyspnoea 100mm Visual Analogue Scale (VAS).
Timepoint [2] 269275 0
At one minute intervals during a 15 minute exercise test at Visits 3,4 and 5.
Secondary outcome [1] 279265 0
Oxygen consumption regression curve from analysis of expired gas looking at minute ventilation, oxygen consumption, changes in oxygen concentration and carbon dioxide generation.This will be measured and recorded by using a portable gas exchange monitor (COSMED model) through which patients will breath allowing physiologic and metabolic parameters to be recorded in real time.
Timepoint [1] 279265 0
Continously throughout each exercise test, lasting 15 minutes.
Secondary outcome [2] 279266 0
Plasma b-endorphin and adrenocorticotorphic hormone levels will be measured by taking 3 samples of blood.
Timepoint [2] 279266 0
At visit 2 one sample of blood is taken prior to commencing exercise test, one at maximally tolerated exercise and one 30 minutes after exercise.
Secondary outcome [3] 279267 0
Ventilatory effort will be measured by using a spirometer before and 30 minutes after inhaling 5mg of ventolin, a bronchodilator .
Timepoint [3] 279267 0
At each visit prior to exercise test.
Secondary outcome [4] 287727 0
Participant preference blinded summary question after all three arms measured by asking the question, " on which day of the study was your breathlessness worst?"
Timepoint [4] 287727 0
After completing the exercise test at visit 5.

Eligibility
Key inclusion criteria
On stable medications for breathlessness over the prior one week except routine “as needed” medications. Able to provide written and dated informed consent.Moderate / severe COPD. (FEV1 30%-80% of predicted for age in spirometry performed approximately 10-15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via a metered dose inhaler (MDI) with a valved-holding chamber. The FEV1/FVC ratio and FEV1 percent predicted values will be calculated using NHANES III reference equations) [Hankinson 1999]. Subjects will have COPD which complies with the definition of the American Thoracic. Society/European Respiratory Society. [Celli, 2004). Modified Medical Research Council breathlessness scale of 3 or 4. >50 years of age. >10 pack year history of smoking (number of pack years = (number of cigarettes per day/20) x number of years smoked). Able to use a treadmill.
Minimum age
51 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
On regular or ‘as needed’ opioids in the week before commencing the study and at any time during the study.
Unable to give informed consent or complete evaluation tool entries. Cognitively impaired (Mini Mental State < 24). [Folstein]. Calculated creatinine clearance of < 30mls using MDRD. [Levey 1999] . Known or suspected bowel obstruction (specific contra-indications in methylnaltrexone) or known or suspected GI lesions.
Participants with any of the following clinical conditions:
a history of myocardial infarction, unstable angina or untreated severe left anterior descending coronary artery compromise within 1 year of screening visit, cardiac arrhythmia causing symptoms or haemodynamic compromise, atrioventricular block, hospitalized for heart failure within the past year, claudication, known active tuberculosis or other chronic lung infection, a history of life-threatening pulmonary obstruction, a history of cystic fibrosis, clinically evident bronchiectasis.
Contraindications for exercise testing which would include
active endocarditis, myocarditis or pericarditis, hypertrophic cardiomyopathy, symptomatic moderate to severe aortic stenosis, severe untreated arterial hypertension (>160 mmHg systolic, >110 mmHg diastolic), significant pulmonary hypertension, untreated venous thromboembolism, active systemic infection, uncontrolled hyperthyroidism, body mass index (BMI) >35, physical limitations due to arthritis, joint replacement, people on monoamine oxidase inhibitors. Participants who are currently under going pulmonary rehabilitation or have completed a pulmonary rehabilitation program in the previous six weeks. Participants with an endurance time > 25 minutes during the training (visit 2)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves contacting the pharmacist at the central administration who is the holder of the allocated schedule.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation developed by a statastician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/11/2011
Actual
11/11/2011
Date of last participant enrolment
Anticipated
30/12/2017
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 267523 0
Charities/Societies/Foundations
Name [1] 267523 0
Flinders Medical Centre foundation
Country [1] 267523 0
Australia
Funding source category [2] 267528 0
Commercial sector/Industry
Name [2] 267528 0
Mundipharma Pty Ltd
Country [2] 267528 0
Australia
Primary sponsor type
University
Name
Flinders University- Deptment of Palliative and Supportive Services
Address
700 Goodwood Road
Daw Pary SA 5041
Country
Australia
Secondary sponsor category [1] 266569 0
None
Name [1] 266569 0
Address [1] 266569 0
Country [1] 266569 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269488 0
Southern Adelaide Flinders Clinical Human Research Ethics Committee (SAFC HREC
Ethics committee address [1] 269488 0
Flinders Medical Centre
Flinders Drive
Bedford Park
South Australia SA 5042
Ethics committee country [1] 269488 0
Australia
Date submitted for ethics approval [1] 269488 0
Approval date [1] 269488 0
11/04/2011
Ethics approval number [1] 269488 0
42/11

Summary
Brief summary
The aim of the study is to understand the role of endogenous opioids ( the body's own morphine-like chemicals) in regulating breathlessness in people with Chronic Obstructive Airways Disease and to answer the question "Does blocking these endogenous opioids during exercise change the perseption of breathlessness.
Trial details
Participants with moderate to severe Chronic Obstructive Pulmonary Airways (COPD) disease, if eligible will be asked to attend the clinic up to 5 times over the study period and each visit will take about 2 hours. After a baseline exercise test on a treadmill participants will have 4 subsequent standardised treadmill exercise sessions.Each test will comprise of up to 15 minutes on the treadmill with the aim of walking as far as possilbe at a steady pace. Visits will be weeklyand a doctor and nurse will be present at all times during the proceedure. Bloods will be taken on visit 3 to measure two chemicals that the body routinely makes- beta endorphin and adrenocorticotrophin.
30 minutes before each exercise test the participant will be administered 5mg of salbutamol through an inhaler.
On the 3th,4th and 5th exercise test participants will receive a double blind injection on different visits of each of saline, methylnaltrexone and naloxone, in a random ( by chance) order.
During the 15 minute exercise tests, participants will be asked to record the intensity and unpleasantness of their breathlessness and how tired their legs feel, every minute by means of a touch pad screen.
Throughout each test and for 30 minutes after stopping the participant will be attached to cardiac monitor and their blood pressure will be monitored regularly.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32910 0
Prof David Currow
Address 32910 0
Department of Palliative and Supportive Services Flinders University 700 Goodwood Rd Daw Park SA 5041
Country 32910 0
Australia
Phone 32910 0
+61 8 8275 1057
Fax 32910 0
+61 8 8375 1201
Email 32910 0
david.currow@health.sa.gov.au
Contact person for public queries
Name 16157 0
David Currow
Address 16157 0
Department of Palliative and Supportive Services
Flinders University
700 Goodwood Rd
Daw Park
SA 5041
Country 16157 0
Australia
Phone 16157 0
+61 8 8275 1057
Fax 16157 0
+61 8 8375 1201
Email 16157 0
david.currow@health.sa.gov.au
Contact person for scientific queries
Name 7085 0
David Currow
Address 7085 0
Department of Palliative and Supportive Services
Flinders University
700 Goodwood Rd
Daw Park
SA 5041
Country 7085 0
Australia
Phone 7085 0
+61 8 8275 1057
Fax 7085 0
+61 8 8375 1201
Email 7085 0
david.currow@health.sa.gov.au

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseIsolating peripheral effects of endogenous opioids in modulating exertional breathlessness in people with moderate or severe copd: A randomised controlled trial.2019https://dx.doi.org/10.1183/23120541.00153-2019
N.B. These documents automatically identified may not have been verified by the study sponsor.