A Pragmatic, Phase III, Multi-site, Double-blind, Placebo Controlled, Parallel Arm, Dose Increment Randomised Trial of Regular, Low Dose Extended Release Morphine for Chronic Refractory Breathlessness
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 171
- 试验地点
- 15
- 主要终点
- Change from the baseline in the number of steps per day
研究概览
简要总结
Breathlessness is an overwhelming symptom affecting tens of thousands of Australians every day. For many people, it persists even when all the underlying causes have been optimally managed (chronic breathlessness). In these circumstances, it often occurs at rest or with minimal exertion.
Evidence from a number of clinical studies suggests that a small, regular dose of morphine helps to reduce safely the sensation of breathlessness. However, it is not well established which patients derive more benefit and what is the net clinical effect of this treatment (weighing benefits and harms).
This is a phase III, multi-site, randomised, double-blind, placebo-controlled trial with patients with chronic obstructive pulmonary disease (COPD) and severe chronic breathlessness which will explore several important questions:
- Are regular, low doses of morphine at four possible doses over 3 weeks more effective than placebo at improving breathlessness?
- Does increasing the dose in people who already are experiencing some benefit provide even greater reduction in worst breathlessness?
- Does the medication have any effect on daily activity and quality of life?
- What are the common or serious side effects of this intervention?
- Does the benefit from the medication outweigh the side effects it produces?
- Are there specific characteristics of people who are more likely to receive benefit from extended release morphine?
Participants will receive once daily extended release morphine (plus laxative, docusate with senna), or placebo (placebo laxative) in addition to their usual medication for up to 3 weeks at increasing doses.
Participants will have a medical interview and 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 6 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".
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 harms) on chronic refractory breathlessness in people with chronic obstructive pulmonary disease (COPD) and baseline breathlessness of 3 or 4 on the modified Medical Research Council breathlessness scale (mMRC) taking once daily, extended release oral 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
- Parallel
- 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 with the most recent result available defined as a prior post-bronchodilator FEV1/FVC < 0.7 in accordance with the GOLD 2014 criteria.
- •Respiratory physician confirmed optimisation of treatment of COPD.
- •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 three (3) or four (4) on the modified Medical Research Council (mMRC) breathlessness scale.
- •worst breathlessness intensity in the previous 24 hours was at least 3/10 on a 0-10 numerical rating scale (NRS).
- •English speaking with sufficient reading and writing ability to complete the study questionnaires
- •Assessed as competent (using St Louise University Mental Status Examination (SLUMS) score of 27/30 for people whose highest level of education was high school, and 25/30 for people who did not complete high school).
- •Able and willing to give written informed consent.
排除标准
- •On any opioid for breathlessness in the previous seven (7) days.
- •On regularly prescribed opioid medications for other conditions, including codeine preparations at or above 8mg oral morphine equivalent daily dose (MEDD) 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.
- •Current history of abuse of alcohol, 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
Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.
干预措施: Placebo (Drug)
Placebo
Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.
干预措施: Plus placebo laxative (Drug)
Placebo
Double-blind placebo capsule, looking identical to capsules with active treatment, during all three treatment weeks.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine Sulfate (0, 0, 8 mg)
Placebo on weeks one and two. Morphine 8 mg/day on week three.
干预措施: Placebo (Drug)
Morphine Sulfate (0, 0, 8 mg)
Placebo on weeks one and two. Morphine 8 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine Sulfate (0, 0, 8 mg)
Placebo on weeks one and two. Morphine 8 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine Sulfate (0, 0, 8 mg)
Placebo on weeks one and two. Morphine 8 mg/day on week three.
干预措施: Plus placebo laxative (Drug)
Morphine Sulfate (0, 0, 8 mg)
Placebo on weeks one and two. Morphine 8 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (0, 8, 8 mg)
Placebo on week one. Morphine 8 mg/day on weeks two and three.
干预措施: Placebo (Drug)
Morphine sulfate (0, 8, 8 mg)
Placebo on week one. Morphine 8 mg/day on weeks two and three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (0, 8, 8 mg)
Placebo on week one. Morphine 8 mg/day on weeks two and three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (0, 8, 8 mg)
Placebo on week one. Morphine 8 mg/day on weeks two and three.
干预措施: Plus placebo laxative (Drug)
Morphine sulfate (0, 8, 8 mg)
Placebo on week one. Morphine 8 mg/day on weeks two and three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (0, 8, 16 mg)
Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.
干预措施: Placebo (Drug)
Morphine sulfate (0, 8, 16 mg)
Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (0, 8, 16 mg)
Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (0, 8, 16 mg)
Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.
干预措施: Plus placebo laxative (Drug)
Morphine sulfate (0, 8, 16 mg)
Placebo on week one. Morphine 8 mg/day on week two. Morphine 16 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (8, 8, 8 mg)
Morphine 8 mg/day on weeks one, two and three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (8, 16, 16 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on weeks two and three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (8, 8, 8 mg)
Morphine 8 mg/day on weeks one, two and three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (8, 8, 8 mg)
Morphine 8 mg/day on weeks one, two and three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (8, 8, 16 mg)
Morphine 8 mg/day on weeks one and two. Morphine 16 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (8, 8, 16 mg)
Morphine 8 mg/day on weeks one and two. Morphine 16 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (8, 8, 16 mg)
Morphine 8 mg/day on weeks one and two. Morphine 16 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (8, 16, 16 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on weeks two and three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (8, 16, 16 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on weeks two and three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (8, 16, 24 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on week two. Morphine 24 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (8, 16, 24 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on week two. Morphine 24 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (8, 16, 24 mg)
Morphine 8 mg/day on week one. Morphine 16 mg/day on week two. Morphine 24 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (16, 16, 16 mg)
Morphine 16 mg/day on weeks one, two and three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (16, 16, 16 mg)
Morphine 16 mg/day on weeks one, two and three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (16, 16, 16 mg)
Morphine 16 mg/day on weeks one, two and three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (16, 16, 24 mg)
Morphine 16 mg/day on weeks one and two. Morphine 24 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (16, 16, 24 mg)
Morphine 16 mg/day on weeks one and two. Morphine 24 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (16, 16, 24 mg)
Morphine 16 mg/day on weeks one and two. Morphine 24 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (16, 24, 24 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on weeks two and three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (16, 24, 24 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on weeks two and three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (16, 24, 24 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on weeks two and three.
干预措施: FitBit charge HR (Accelerometer) (Device)
Morphine sulfate (16, 24, 32 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on week two. Morphine 32 mg/day on week three.
干预措施: Morphine Sulfate (Drug)
Morphine sulfate (16, 24, 32 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on week two. Morphine 32 mg/day on week three.
干预措施: Plus laxative (Docusate with senna) (Drug)
Morphine sulfate (16, 24, 32 mg)
Morphine 16 mg/day on week one. Morphine 24 mg/day on week two. Morphine 32 mg/day on week three.
干预措施: FitBit charge HR (Accelerometer) (Device)
结局指标
主要结局
Change from the baseline in the number of steps per day
时间窗: Week 3
Difference from the baseline in the number of steps per day measured using the Fitbit(Charge HR). Measured at baseline, end of week 1, and end of week 3. The primary endpoint is: * The difference between morphine sulphate 8mg and placebo (end of week 1) * The difference between morphine sulphate 16mg and placebo (end of week 1) * Comparison between baseline and end of week 3
Change from baseline worst breathlessness intensity over the previous 24 hours
时间窗: Week 1
Rated on a 0-10 numerical rating scale (NRS). Measured at baseline, Stage1-3 (daily diary) and Stage 4 (weekly diary). The primary endpoint is: * The difference between morphine sulphate 8mg and placebo (end of week1) * The difference of morphine sulphate 16 mg and placebo (end of week 1)
次要结局
- Change from baseline intensity of breathlessness "average"(Up to week 15)
- Change from baseline functional impact of breathlessness(Up to week 15)
- Change from baseline in activity levels(Week 3)
- Change from baseline total energy expenditure(Week 3)
- Change from baseline performance status(Up to week 15)
- Change from baseline activities of daily living(Up to week 15)
- Pharmacogenetic opioid profile - Number of participants with UGT2B7*2 and *28 polymorphisms(Baseline (1 day))
- Pharmacogenetic opioid profile - Mu receptor (A118G) polymorphism(Baseline (1 day))
- Change from baseline pulse oximetry(Up to week 15)
- Change from baseline sleep minutes(Week 3)
- Change from baseline in sleep quality(Up to week 15)
- Change from baseline Polysomnography(Week 3)
- Change from baseline Driving ability(Week 3 + 2 days)
- Change from baseline perceived-impact of breathlessness(Up to week 3)
- Change from baseline end-tidal carbon dioxide(Up to week 15)
- Change from baseline sleep activity(Week 3)
- Pharmacogenetic opioid profile - Number of participants with P-glycoprotein polymorphism (ABCB1 5SNPs in a haplotype block)(Baseline (1 day))
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Peak Plasma Concentration [Cmax](Week 1)
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Area Under the Curve (AUC)(Week 1)
- Change from baseline serum testosterone level(Week 15)
- Change from baseline in concurrent symptoms(Up to 15 weeks)
- Change from baseline health-related quality of life(Up to 15 weeks)
- Opioid Withdrawal(Up to week 15 + 3 days)
- Change from baseline distress from breathlessness over the previous 24 hours(Up to week 15)
- Change from baseline in objective sleep testing(Week 3)
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine Area Under the Curve (AUC)(Week 1)
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Peak Plasma Concentration [Cmax](Week 1)
- Change from baseline health-status in COPD(Week 3)
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-6-glucuronide (M6G) Area Under the Curve (AUC)(Week 1)
- Pharmacogenetic opioid profile - Number of participants with 5-hydroxytryptamine type 3B (HTR3B) gene rs7103572 polymorphism(Baseline (1 day))
- Adverse Effects(Up to 15 weeks)
- Change from the baseline anxiety and depression(Up to Week 15)
- Pharmacokinetic (PK)/ Pharmacodynamic (PD) opioid profile: Morphine-3-glucuronide (M3G) Peak Plasma Concentration [Cmax](Week 1)
- Change in baseline global impression of change(Up to 15 weeks)
- Change from baseline caregiver Impact(Up to week 15)
- Blinded-patient preference to continue the treatment [3-point Likert Scale](Up to week 15)
- Economic Evaluation - Cost per responder(Up to week 4)
研究者
David Currow
Professor: Palliative and Supportive Services
Flinders University