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A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

ABSTRACT: INTRODUCTION:Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. METHODS AND ANALYSIS:The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. ETHICS AND DISSEMINATION:Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. TRIAL REGISTRATION NUMBER:NCT02720822; Pre-results.

SUBMITTER: Currow D

PROVIDER: S-EPMC5726102 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

Currow David D Watts Gareth John GJ Johnson Miriam M McDonald Christine F CF Miners John O JO Somogyi Andrew A AA Denehy Linda L McCaffrey Nicola N Eckert Danny J DJ McCloud Philip P Louw Sandra S Lam Lawrence L Greene Aine A Fazekas Belinda B Clark Katherine C KC Fong Kwun K Agar Meera R MR Joshi Rohit R Kilbreath Sharon S Ferreira Diana D Ekström Magnus M

BMJ open 20170717 7

<h4>Introduction</h4>Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended- release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, paralle ...[more]

PMID: 28716797

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Project description:AimsMorphine is shown to relieve chronic breathlessness in chronic obstructive pulmonary disease. There are no definitive data in people with heart failure. We aimed to determine the effectiveness and cost-effectiveness of 12 weeks morphine therapy for the relief of chronic breathlessness in people with chronic heart failure compared with placebo.Methods and resultsParallel group, double-blind, randomized, placebo-controlled, phase III trial of 20 mg daily oral modified release morphine was conducted in 13 sites in England and Scotland: hospital/community cardiology or palliative care outpatients. The primary analysis compared between-group numerical rating scale average breathlessness/24 hours at week 4 using a covariance pattern linear mixed model. Secondary outcomes included treatment-emergent harms (worse or new). The trial closed early due to slow recruitment, randomizing 45 participants [average age 72 (range 39-89) years; 84% men; 98% New York Heart Association class III]. For the primary analysis, the adjusted mean difference was 0.26 (95% confidence interval, -0.86 to 1.37) in favour of placebo. All other breathlessness measures improved in both groups (week 4 change-from-baseline) but by more in those assigned to morphine. Neither group was excessively drowsy at baseline or week 4. There were no between-group differences in quality of life (Kansas) or cognition (Montreal) at any time point. There was no exercise-related desaturation and no change between baseline and week 4 in either group. There was no change in vital signs at week 4. The natriuretic peptide measures fell in both groups but by more in the morphine group [morphine 2169 (1092, 3851) pg/mL vs. placebo 2851 (1694, 5437)] pg/mL. There was no excess serious adverse events in the morphine group. Treatment-emergent harms during the first week were more common in the morphine group; all apart from 1 were ? grade 2.ConclusionsWe could not answer our primary objectives due to inadequate power. However, we provide novel placebo-controlled medium-term benefit and safety data useful for clinical practice and future trial design. Morphine should only be prescribed in this population when other measures are unhelpful and with early management of side effects.

Project description:IntroductionThis study presents an empirical method to model the high-energy photon beam percent depth dose (PDD) curve by using the home-generated buildup function and tail function (buildup-tail function) in radiation therapy. The modeling parameters n and μ of buildup-tail function can be used to characterize the Collimator Scatter Factor (Sc) either in a square field or in the different individual upper jaw and lower jaw setting separately for individual monitor unit check.Methods and materialsThe PDD curves for four high-energy photon beams were modeled by the buildup and tail function in this study. The buildup function was a quadratic function in the form of [Formula: see text] with the main parameter of d (depth in water) and n, while the tail function was in the form of e-μd and was composed by an exponential function with the main parameter of d and μ. The PDD was the product of buildup and tail function, PDD = [Formula: see text]. The PDD of four-photon energies was characterized by the buildup-tail function by adjusting the parameters n and μ. The Sc of 6 MV and 10 MV can then be expressed simply by the modeling parameters n and μ.ResultsThe main parameters n increases in buildup-tail function when photon energy increased. The physical meaning of the parameter n expresses the beam hardening of photon energy in PDD. The fitting results of parameters n in the buildup function are 0.17, 0.208, 0.495, 1.2 of four-photon energies, 4 MV, 6 MV, 10 MV, 18 MV, respectively. The parameter μ can be treated as attenuation coefficient in tail function and decreases when photon energy increased. The fitting results of parameters μ in the tail function are 0.065, 0.0515, 0.0458, 0.0422 of four-photon energies, 4 MV, 6 MV, 10 MV, 18 MV, respectively. The values of n and μ obtained from the fitted buildup-tail function were applied into an analytical formula of Sc = nE(S)0.63μE to get the collimator to scatter factor Sc for 6 and 10 MV photon beam, while nE, μE, S denotes n, μ at photon energy E of field size S, respectively. The calculated Sc were compared with the measured data and showed agreement at different field sizes to within ±1.5%.ConclusionsWe proposed a model incorporating a two-parameter formula which can improve the fitting accuracy to be better than 1.5% maximum error for describing the PDD in different photon energies used in clinical setting. This model can be used to parameterize the Sc factors for some clinical requirements. The modeling parameters n and μ can be used to predict the Sc in either square field or individual jaws opening asymmetrically for treatment monitor unit double-check in dose calculation. The technique developed in this study can also be used for systematic or random errors in the QA program, thus improves the clinical dose computation accuracy for patient treatment.

Project description:ImportanceMorphine is used as palliative treatment of chronic breathlessness in patients with advanced chronic obstructive pulmonary disease (COPD). Evidence on respiratory adverse effects and health status is scarce and conflicting.ObjectiveTo assess the effects of regular, low-dose, oral sustained-release morphine on disease-specific health status (COPD Assessment Test; CAT), respiratory outcomes, and breathlessness in patients with COPD.InterventionsParticipants were randomly assigned to 10 mg of regular, oral sustained-release morphine or placebo twice daily for 4 weeks, with the possibility to increase to 3 times daily after 1 or 2 weeks.Design, setting, and participantsThe Morphine for Treatment of Dyspnea in Patients With COPD (MORDYC) study was a randomized, double-blind, and placebo-controlled study of a 4-week intervention. Patients were enrolled between November 1, 2016, and January 24, 2019. Participants were recruited in a pulmonary rehabilitation center and 2 general hospitals after completion of a pulmonary rehabilitation program. Outpatients with COPD and moderate to very severe chronic breathlessness (modified Medical Research Council [mMRC] breathlessness grades 2-4) despite optimal pharmacological and nonpharmacological treatment were included. A total of 1380 patients were screened, 916 were ineligible, and 340 declined to participate.Main outcomes and measuresPrimary outcomes were CAT score (higher scores represent worse health status) and arterial partial pressure of carbon dioxide (Paco2). Secondary outcome was breathlessness in the previous 24 hours (numeric rating scale). Data were analyzed by intention to treat. Subgroup analyses in participants with mMRC grades 3 to 4 were performed.ResultsA total of 111 of 124 included participants were analyzed (mean [SD] age, 65.4 [8.0] years; 60 men [54%]). Difference in CAT score was 2.18 points lower in the morphine group (95% CI, -4.14 to -0.22 points; P = .03). Difference in Paco2 was 1.19 mm Hg higher in the morphine group (95% CI, -2.70 to 5.07 mm Hg; P = .55). Breathlessness remained unchanged. Worst breathlessness improved in participants with mMRC grades 3 to 4 (1.33 points lower in the morphine group; 95% CI, -2.50 to -0.16 points; P = .03). Five participants of 54 in the morphine group (9%) and 1 participant of 57 in the placebo group (2%) withdrew because of adverse effects. No morphine-related hospital admissions or deaths occurred.Conclusions and relevanceIn this randomized clinical trial, regular, low-dose, oral sustained-release morphine for 4 weeks improved disease-specific health status in patients with COPD without affecting Paco2 or causing serious adverse effects. The worst breathlessness improved in participants with mMRC grades 3 to 4. A larger randomized clinical trial with longer follow-up in patients with mMRC grades 3 to 4 is warranted.Trial registrationClinicalTrials.gov Identifier: NCT02429050.

Project description:The Breathlessness Intervention Service is a novel service for patients with intractable breathlessness regardless of aetiology. It is being evaluated using the Medical Research Council's framework for the evaluation of complex interventions. This paper describes the feasibility results of Phase II: a single-blinded fast-track pragmatic randomised controlled trial.A single-blinded fast-track pragmatic randomised controlled trial was conducted for patients with chronic obstructive pulmonary disease referred to the service. Patients were randomised to either receive the intervention immediately for an eight-week period, or receive the intervention after an eight-week period on a waiting list during which time they received standard care. Outcomes examined included: response rates to the trial; response rates to the individual questionnaires and items; comments relating to the trial functioning made during interviews with patients, carers, referrers and service providers; and, researcher fieldwork notes.16 of the 20 eligible patients agreed to participate in a recruitment visit (16/20); 14 respondents went on to complete a recruitment visit/baseline interview. The majority of those who completed a recruitment visit/baseline interview completed the RCT protocol (13/14); 12 of their carers were recruited and completed the protocol. An unblinding rate of 6/25 respondents (patients and carers) was identified. Missing data were minimal and only one patient was lost to follow up. The fast-track trial methodology proved feasible and acceptable. Two of the baseline/outcome measures proved unsuitable: the WHO performance scale and the Schedule for the Evaluation of Individual Quality of Life-Direct Weighting (SEIQoL-DW).This study adds to the evidence that fast-track randomised controlled trials are feasible and acceptable in evaluations of palliative care interventions for patients with non-malignant conditions. Reasonable response rates and low attrition rates were achieved. Further, with adequate preparation of the research and randomisation teams, clinicians, and responders, and effective liaison with the clinicians, single-blinding proved possible. Methods were identified to reduce unblinding through careful attention to the type of data collected at unblinded measurement points; the content of interviews should be carefully considered when designing blinded-trial protocols.Clinical Trials.gov NCT00711438.

Project description:BackgroundBreathlessness in advanced disease causes significant distress to patients and carers and presents management challenges to health care professionals. The Breathlessness Intervention Service (BIS) seeks to improve the care of breathless patients with advanced disease (regardless of cause) through the use of evidence-based practice and working with other healthcare providers. BIS delivers a complex intervention (of non-pharmacological and pharmacological treatments) via a multi-professional team. BIS is being continuously developed and its impact evaluated using the MRC's framework for complex interventions (PreClinical, Phase I and Phase II completed). This paper presents the protocol for Phase III.Methods/designPhase III comprises a pragmatic, fast-track, single-blind randomised controlled trial of BIS versus standard care. Due to differing disease trajectories, the service uses two broad service models: one for patients with malignant disease (intervention delivered over two weeks) and one for patients with non-malignant disease (intervention delivered over four weeks). The Phase III trial therefore consists of two sub-protocols: one for patients with malignant conditions (four week protocol) and one for patients with non-malignant conditions (eight week protocol). Mixed method interviews are conducted with patients and their lay carers at three to five measurement points depending on randomisation and sub-protocol. Qualitative interviews are conducted with referring and non-referring health care professionals (malignant disease protocol only). The primary outcome measure is 'patient distress due to breathlessness' measured on a numerical rating scale (0-10). The trial includes economic evaluation. Analysis will be on an intention to treat basis.DiscussionThis is the first evaluation of a breathlessness intervention for advanced disease to have followed the MRC framework and one of the first palliative care trials to use fast track methodology and single-blinding. The results will provide evidence of the clinical and cost-effectiveness of the service, informing its longer term development and implementation of the model in other centres nationally and internationally. It adds to methodological developments in palliative care research where complex interventions are common but evidence sparse.Trial registrationClinicalTrials.gov: NCT00678405ISRCTN: ISRCTN04119516.

Dataset Information

A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

Publications

A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness: Breathlessness, Exertion And Morphine Sulfate (BEAMS) study protocol.

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