A Multi-site, Double-blind, Parallel Arm, Block Randomised, Placebo Controlled, Factorial Phase III Study of Opioids for Chronic Refractory Breathlessness in People With Chronic Obstructive Pulmonary Disease.

Flinders University0 个研究点开始时间: 2015年5月最近更新: 2016年1月12日

适应症

干预措施

试验速览

阶段: 3 期
状态: 撤回
发起方: Flinders University
主要终点: Change from baseline intensity of breathlessness over the previous 24 hours

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者记录与标识符相似试验

研究概览

简要总结

Breathlessness, the sensation of breathing discomfort, is a major problem in people with chronic obstructive pulmonary disease (COPD). Breathlessness that persists despite optimal management of the underlying disease(s) is said to be refractory.

Preliminary evidence suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, this research on morphine for breathlessness has not defined the best way to adjust the dose of the medication, or refined which people are most likely to have benefit, no response or side effects.

This is a randomized, double-blind phase III trial in people with COPD and significant refractory breathlessness, which will explore several important questions:

Are regular, low dose opioids (morphine) at four possible doses over 3 weeks more effective than placebo medication (containing no active ingredient) at improving breathlessness?
Does the medication have any effect on daily activity, breathlessness, and quality of life?
What are the common side effects of this intervention?
Does the benefit from the drug outweigh the side effects it produces?
Are there specific characteristics of people who are more likely to receive benefit from sustained release morphine?

Participants will be allocated to receive three weeks of morphine sulfate (and laxative, docusate with senna), or placebo (and placebo laxative). The dose of morphine may be increased each week for weeks two and three. All medicines will appear the same (blinded) and neither the doctor nor the participant will know which medication the participant is receiving.

Participants will have a medical interview, physical examination to collect some general health information, and baseline measurements including; daily activity, symptoms, and quality of life. A small amount of blood may be required to check eligibility. Further blood samples may be taken at week 1 and 3 to enable testing on how individuals respond to opioids, further consent will be obtained for these samples. Data on benefits, side effects, and medical care will be collected during comprehensive weekly visits. Participants will also fill out a simple diary twice daily for weeks one to three of the study, and for one day each week during an optional 3 month extension stage.

The outcome of this study may enable better management of symptoms and activity in people COPD with medicines that are shown to be effective and safe.

详细描述

Background: Three hundred thousand (300,000) Australians are breathless at rest or on minimal exertion, often for years, despite optimal treatment of the underlying cause(s). This includes more than 70,000 people who are too breathless to leave their homes often for long periods of time. Underlying causes for such severe and ongoing breathlessness include chronic obstructive pulmonary disease (COPD), interstitial lung disease, heart failure, neurodegenerative diseases such as motor neurone disease and cachexia from any cause. The prevalence of chronic refractory breathlessness will continue to increase as the population ages because the chronic progressive diseases where breathlessness is common are increasing in prevalence. Nearly one half of all people experience distressing breathlessness during the last year of life.

The American Thoracic Society defines breathlessness as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity". The term 'dyspnoea' is used interchangeably with breathlessness, shortness of breath, breathing difficulty and laboured breathing.

Internationally, no medication is registered for the symptomatic reduction of chronic refractory breathlessness despite recommendations from the American Thoracic Society, the American College of Physicians, the Canadian Thoracic Society and the American College of Chest Physicians that regular, low-dose morphine is the evidence-based pharmaceutical option.

Aim: To enhance the evidence base for the pharmacological treatment of chronic refractory breathlessness using potential therapies compared to placebo.

Primary objective: To compare the difference of the net clinical effect (benefits and side effects) on chronic refractory breathlessness in people with chronic obstructive pulmonary disease (COPD) taking once daily, sustained release morphine at two different doses when compared to placebo.

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Factorial
主要目的: Treatment
盲法: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

入排标准

年龄范围: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•18 years of age or older.
•Physician diagnosed COPD confirmed by spirometry, defined as a prior post-bronchodilator FEV1/FVC < 0.7 in accordance with the GOLD 2014 criteria
•On stable medications relating to the optimal treatment of COPD or its symptomatic management over the prior week except routine "as needed" medications.
•Breathlessness of a level two (2) or higher on the modified Medical Research Council (mMRC) dyspnoea scale
•English speaking with sufficient reading and writing ability to complete the study questionnaires
•Assessed as competent (using SLUMS score of 27 for high school, and 25 for less than high school)
•Able and willing to give written informed consent

排除标准

•On regularly prescribed opioid medications, including codeine preparations at or above 8mg oral morphine equivalent daily in the previous seven (7) days.
•History of adverse reactions to any of the study medications or constituents in the placebo;
•Australian-modified Karnofsky performance score (AKPS) less than 50 at the beginning of the study.
•Respiratory or cardiac event in the previous one week (excluding upper respiratory tract infections). Illness must have resolved completely prior to baseline evaluation, as judged by the person's treating physician.
•Evidence of respiratory depression with resting respiratory rate <8/min.
•Documented central hypoventilation syndrome.
•Chronic alcoholism, or previous or recent history of substance misuse.
•Uncontrolled nausea, vomiting or evidence of a gastrointestinal tract obstruction.
•Renal dysfunction with creatinine clearance calculated (MDRD) less than 20 mls/minute.
•Evidence of severe hepatic impairment defined as transaminases or bilirubin >4x normal (Excluding Gilbert's syndrome)
•Pregnant or breastfeeding.

研究组 & 干预措施

Placebo

Placebo Comparator

Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.

干预措施: Placebo (Drug)