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Trial registered on ANZCTR


Registration number
ACTRN12609000209291
Ethics application status
Approved
Date submitted
18/03/2009
Date registered
24/04/2009
Date last updated
15/12/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
Opioids for breathlessness in people with primary hypertension.
Scientific title
Randomised, placebo-controlled,
double-blind, cross-over study of the efficacy of sustained-release low dose morphine in the subjective sensation of dyspnoea due to maximally treated primary pulmonary hypertension in opioid naive participants.
Secondary ID [1] 284417 0
NIL
Universal Trial Number (UTN)
Trial acronym
Opioids in dyspnoea in primary pulmonary hypertension.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dyspnoea in opioid naive participants with primary pulmonary hypertension. 3865 0
Condition category
Condition code
Respiratory 4061 4061 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
One capsule of sustained- release Morphine 20mg taken orally, daily for 7 days, 1-2 tablets of Coloxyl and Senna taken orally, daily for 7 days, then a washout period of one week.
Intervention code [1] 3595 0
Treatment: Drugs
Comparator / control treatment
One capsule of sustained-release Morphine 20 mg placebo taken orally, daily for 7 days.(This placebo capsules will have the same outward appearance as the intervention capsule but will be filled with sugar (sucrose)) and 1-2 tablets of Coloxyl and Senna placebo taken orally, daily for 7(The placebo formulation will be lactose, starch maize. gelatin, magnesium stearate, propyl hydroxybenzoate, opadry brown and carnauba wax and will have the same outward appearance as the intervention tablets.
Control group
Placebo

Outcomes
Primary outcome [1] 4959 0
The relief of breathlessness by the mean of the Dyspnoea Visual Analogue(VAS) scores. This will be calculated separately for morning (am) and evening (pm) scores.
Timepoint [1] 4959 0
On days 5,6and 7, and days 19,20, and 21.
Secondary outcome [1] 8368 0
Systematically evaluate any adverse effects from the use of sustained release morphine in this participant population.
The participant will be visited at home weekly and phoned weekly at times convenient to the patient, visits will last approximately 30-40 minutes. their blood pressure, heart rate and respiratory rate will be measured, their blood oxygen saturation by means of a pulse oximeter and their end tidal cardon dioxide by means of an end tidal carbon dioxide monitor.
Using the Anticipated Adverse Event Assessment frequent side effects of morphine sulphate will be monitored and categorised according to the National Cancer Institute Common Toxicity Criteria for Adverse Events.This will be assessed at both the home and phone contacts.
Adverse events will also be monitored by asking the patient if they have "any other problems" and how they rate the effectiveness of breathlessness control, both assessed twice weekly.They are asked to fill out the Chronic Respiratiory Questionnaire - Dyspnoea Subscale (Mcmaster University) weekly.
Timepoint [1] 8368 0
Days 4,7,14,18,22.
Secondary outcome [2] 8369 0
Changes in respiratory rate, pulse oximetry and end-tidal carbon dioxide.
A study nurse will visit the patient at home, at a time convenient to the patient to measure the respiratory rate and will use a pulse oximeter and an end tidal carbon dioxide monitor (all non invasive procedures).
Timepoint [2] 8369 0
Baseline,Day 7, second baseline (Day 14) and day 22.
Secondary outcome [3] 8370 0
Evaluate any of the descriptive type(s) of the subjective sensation of dyspnoea that are more likely to be associated with primary pulmonary hypertension.
Participant will keep a diary for a maximum of 23 days, anticipated to take 5-10 minutes daily to fill out. they will be asked to indicate twice daily,the intensity of dyspnoea now on a modified Borg scale.the intensity of dyspnoea now, on a Visual Analogue Scale (VAS), to indicate once daily, their average breathlessness, worst breathlessness and best breathlessness in in the last 24 hours, each utilising a VAS scale and their exercise tolerance using the Medical Research Council of Great Britain Scale for Dyspnoea.
They will also be asked to indicate twice in their diary,at the end of each arm, (active and control) the level of dyspnoea control and the overall level of dyspnoea in the last 7 days and the level of satisfaction with medications received in the last 7 days.
(While measurements and analysis will be based upon the data from the last 3 days of each arm participants are also asked to provide responses once or twice daily to make sure they are comfortable with the pattern of participation prior to responding on the key census days).
Timepoint [3] 8370 0
Days 5, 6, 7 and 19, 20, 21.
Secondary outcome [4] 8371 0
Define any changes in quality of life generated by either arm of the study by using the McMaster Chronic Respiratory Questionnaire - Dyspnoea Sub-scale. This will be filled by the patient 4 times at study nurse home visits.( visits will lasting about 30-40 minutes)
Timepoint [4] 8371 0
Baseline, day 7, second baseline (day 14) and Day 22
Secondary outcome [5] 8372 0
To identify the clinical characteristics of people who derive the greatest benefit from sustained release morphine in the setting of maximally treated primary pulmonary hypertension (and whether there is a differential response based on severity of objective cardiorespiratory dysfunction).
This will be assessed from the subjective responses to questions relating to the sensation of breathlessness in the patient diary on the last 3 days of each arm of the study. The clinical characteristics based on objective cardiorespiratory dysfunction will be established from existing results of tests done prior to enrolment. They include an Echocardiogram, a right Heart Cardiac Catherterisation and six minute walk tests.(These tests are routinely done on this patient population as part of their diagnosis and ongoing health care and not specifically done for the study).
Timepoint [5] 8372 0
Baseline and days 5, 6,7,19,20,and 21.
Secondary outcome [6] 8373 0
Determine whether there is blinded preference for the net clinical benefit of one arm in the study. This will be assessed from questions asked of the patient in the daily diary, only asked at the end of both the active and contol arms.These questions will relate to the effectiveness of breathlessness control, the overall level of breathlessness, and their level of satisfaction with the medications received only in the last 7 days of each arm of the study.
Timepoint [6] 8373 0
Days 5,6,7,19,20.and 21.

Eligibility
Key inclusion criteria
English speaking. Participants over the age of 18.Dyspnoea secondary to maximally medically treated primary pulmonary
hypertension as assessed by the person’s respiratory physician. New York Heart Association heart failure grade III or IV.Renal function - calculated creatinine clearance >10mmol/l. Haemoglobin > 10 g/dl, or treating clinician has reviewed the haemoglobin result and confirmed that patient is on maximal treatment. On stable oxygen - no changes to prescription in the last 7 days. On stable medications – no changes to prescription medications in the last 7 days. Able to complete participant diary.Willing and able to give informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Taking regular opioid medications.True adverse reaction(s) to morphine previously. Known hypersensitivity to any of the morphine sulphate capsule components. History of central hypoventilation syndrome.
Use of monoamine oxidase inhibitor(s) (MAOIs) in the last 2 weeks or proposed use during the study.Australian Karnofsky Modified Performance Status (modified AKPS) < 50. Acutely confused (Nursing Delirium Assessment Scale score > 0 at baseline).Cognitive impairment (Mini-Mental State Examination < 24 at baseline). Uncontrolled nausea or vomiting.
.Gastrointestinal obstruction.Pregnancy, risk of pregnancy or breast feeding mothers.
Past history of significant illicit opioid misuse.

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)
Participants will be referred to the study by their treating Respiratory Consultant and screened for eigibility for the study. Allocation involves contacting the holder of the allocation schedule who will be 'off-site".
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be block randomised in a double-blind fashion by the Southern Adelaide Health Service Clinical Trials Pharmacist.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 2306 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 7980 0
3084 - Heidelberg
Recruitment postcode(s) [2] 1212 0
5041

Funding & Sponsors
Funding source category [1] 4790 0
Self funded/Unfunded
Name [1] 4790 0
Southern Adelaide Palliative Services
Address [1] 4790 0
700 Goodwood Road
Daw Park SA 5041
Country [1] 4790 0
Australia
Primary sponsor type
University
Name
Flinders University - Department of Palliative and Support Services
Address
700 Goodwood Road
Daw Park
SA 5041
Country
Australia
Secondary sponsor category [1] 4324 0
None
Name [1] 4324 0
Address [1] 4324 0
Country [1] 4324 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6885 0
Finders Clinical Research Ethics Committee
Ethics committee address [1] 6885 0
Flinders Medical Centre
Bedford Park
Ethics committee country [1] 6885 0
Australia
Date submitted for ethics approval [1] 6885 0
Approval date [1] 6885 0
25/02/2009
Ethics approval number [1] 6885 0
253/08

Summary
Brief summary
Dyspnoea is a source of physical and psychological distress, and is one of the most commonly feared aspects of the dying process. By definition, people with severe primary pulmonary hypertension have breathlessness, despite maximal therapy and recent advances in therapies for primary pulmonary hypertension.
In parallel with attempting to treat the underlying pathology causing breathlessness, the sensation of breathlessness itself must be ameliorated. For many participants there comes a point when there are no further identifiable
reversible components of the disease and the full focus of care moves to reducing
the subjective sensation of breathlessness.
Opioids have been studied for the relief of breathlessness predominantly in people
with chronic obstructive pulmonary disease although people with cancer and heart
failure have been included. [Abernethy, Miriam Johnson] A meta-analysis verified
that overall there is benefit from the use of morphine in people with refractory
breathlessness. [Jennings]
This prospective, randomised, placebo-controlled, double-blind, cross-over study
is modelled on a study successfully undertaken by some members of this research team. The study proposes to specifically study people with primary pulmonary hypertension for whom breathlessness is a significant symptomatic problem to establish whether there is benefit from sustained release morphine, and if so, what magnitude of benefit, and the clinical characteristics of those who are most likely to respond to this intervention. Any toxicity will also be carefully monitored.Study participants will receive either Kapanol 20mg and Coloxyl and Senna 1 to 2 tablets, or kapanol placebo and coloxyl and senna placebo for one week, will receive no intervention medication for the second week then will receive the alternative intervention combination for the third week.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 29055 0
Prof David Currow
Address 29055 0
Department of Palliative and Supportive Services Flinders University 700 Goodwood Road Daw Park SA 5041
Country 29055 0
Australia
Phone 29055 0
+61 8 8275 1871
Fax 29055 0
+61 8 8375 1201
Email 29055 0
david.currow@health.sa.gov.au
Contact person for public queries
Name 12212 0
Prof Professor David Currow
Address 12212 0
Department of Palliative and Supportive Services
Flinders University
700 Goodwood Road
Daw Park
SA 5041
Country 12212 0
Australia
Phone 12212 0
+61 8 8275 1871
Fax 12212 0
+61 8 8374 0350
Email 12212 0
david.currow@health.sa.gov.au
Contact person for scientific queries
Name 3140 0
Prof Professor David Currow
Address 3140 0
Department of Palliative and Support Sevices
Flinders University
700 Goodwood Road
Daw Park
SA 5041
Country 3140 0
Australia
Phone 3140 0
+61 8 8275 1871
Fax 3140 0
+61 8 8375 1201
Email 3140 0
david.currow@health.sa.gov.au

No information has been provided regarding IPD availability
Summary results
No Results