A randomised double-blind multi-site parallel arm controlled trial to assess relief of refractory breathlessness comparing fixed doses of morphine and placebo.

Brief Summary

Breathlessness continues to be a major clinical problem for many people with advanced progressive illnesses such as chronic obstructive pulmonary disease, end-stage cardiac failure, and cancer, even when they are receiving the best treatment for their underlying disease. There are phase II/III data and one meta-analysis which support the use of morphine in this setting, but further good phase III data are needed in order to that this is a well tolerated and effective intervention suitable for a .... Breathlessness continues to be a major clinical problem for many people with advanced progressive illnesses such as chronic obstructive pulmonary disease, end-stage cardiac failure, and cancer, even when they are receiving the best treatment for their underlying disease. There are phase II/III data and one meta-analysis which support the use of morphine in this setting, but further good phase III data are needed in order to that this is a well tolerated and effective intervention suitable for a broad range of people with refractory breathlessness. It is also important to establish that the overall net benefit outweighs any toxicity encountered. Further, a particular concern to many clinicians is the theoretical risk that opioids may cause respiratory depression. In steady state, at the relatively low regular doses proposed, there are no data to support this concern, but this study will specifically address this question through careful collection of non-invasive measures of respiratory function regularly throughout the study including end-tidal carbon dioxide at the beginning and the end of the study. Objectives: Among participants with refractory breathlessness: 1) To compare the efficacy for relieving the sensation of dyspnoea, level of function, safety and quality of life (QOL) of opioids (sustained release morphine) with placebo; 2) To identify clinical and pharmacogenomic parameters that predict which individuals will achieve the greatest benefit from the intervention and establish any blinded participant preference. Secondary objectives focus of the impact of the intervention on improving quality of life, adverse effects, function, use of breakthrough opioids and clinical predictors of benefit. Study design: This is a phase III, multi-site, randomised double-blind parallel arm fixed dose controlled trial studying treatment approaches for the palliative relief of breathlessness in participants with refractory dyspnoea. Participants will be randomised to fixed dose identical-appearing sustained release morphine (20 mg every 24 hours), or placebo for one week. The intervention period will run for 7 days; participants will receive study interventions at target doses and blinded therapy for constipation with each active arm together with identical appearing placebo for constipation for the placebo arm. Read more

Key Inclusion Criteria

Adults (age >18) Refractory dyspnoea where the underlying cause of the dyspnoea has been maximally treated. Refractory dyspnoea does not have a minimum duration and can have been present for any period of time. A medical specialist must document that all identified reversible causes of the dyspnoea are being optimally managed. Breathlessness of a level 2 or higher on the modified MRC dyspnoea scale On stable medications over the prior week except routine “as needed” medications Prognosis of at l .... Adults (age >18) Refractory dyspnoea where the underlying cause of the dyspnoea has been maximally treated. Refractory dyspnoea does not have a minimum duration and can have been present for any period of time. A medical specialist must document that all identified reversible causes of the dyspnoea are being optimally managed. Breathlessness of a level 2 or higher on the modified MRC dyspnoea scale On stable medications over the prior week except routine “as needed” medications Prognosis of at least 2 months in the opinion of the treating clinician English-speaking and able to read study questionnaires (5th grade level) Read more

Key Exclusion Criteria

On regular opioid medications, including codeine preparations at or above the dose being studied in the previous 7 days. Anemia for which transfusion is not indicated within one month of baseline evaluation. Severely restricted performance status with Australian Karnofsky Performance score of <40 at baseline Uncontrolled nausea, vomiting and/or gastrointestinal obstruction. Renal dysfunction with creatinine clearance calculated as less than 25 mls/minute. Medical history of severe hepatic impair .... On regular opioid medications, including codeine preparations at or above the dose being studied in the previous 7 days. Anemia for which transfusion is not indicated within one month of baseline evaluation. Severely restricted performance status with Australian Karnofsky Performance score of <40 at baseline Uncontrolled nausea, vomiting and/or gastrointestinal obstruction. Renal dysfunction with creatinine clearance calculated as less than 25 mls/minute. Medical history of severe hepatic impairment defined as ‘3 times upper limit of normal for 2 or more hepatic enzymes', or clotting via International Normalisation Ratio (INR) >1.2 – not treated with warfarin. Evidence of respiratory depression with resting respiratory rate <8. Active respiratory or cardiac event in the previous week, not including upper respiratory tract infections. Illness must have resolved completely prior to baseline evaluation, as judged by a doctor involved in the care of the person. Documented previous respiratory failure induced by any opiate medication. Unable to give informed consent or complete diary entries. Pregnant or breastfeeding Read more

Can healthy volunteers participate?

No