What this is
- is common in palliative care, affecting up to 88% of patients in their final days.
- This trial tested as a preventive treatment for in patients with advanced cancer.
- It assessed the feasibility of conducting a larger randomized controlled trial (RCT) on this topic.
Essence
- did not show a statistically significant effect on preventing compared to placebo in this feasibility trial. However, the study indicated that a larger RCT is feasible and necessary.
Key takeaways
- The trial enrolled 60 participants out of 616 screened, indicating a recruitment rate of 9.7%. This low rate suggests a need for multisite collaboration in future studies.
- Incident occurred in 11 of 30 (36.7%) in the group vs. 10 of 30 (33%) in the placebo group, showing no significant difference.
- No serious adverse effects related to were reported, suggesting it may be safe for further investigation in larger trials.
Caveats
- The study was not powered to detect efficacy differences, limiting the interpretation of results regarding 's effectiveness.
- High rates of participant withdrawal (35%) and missing data may affect the reliability of the findings.
- The feasibility study's single-site design may not generalize to broader populations, highlighting the need for multisite trials.
Definitions
- delirium: An acute neurocognitive disturbance characterized by decreased awareness and disordered attention.
- melatonin: A natural hormone that regulates sleep-wake cycles, proposed to prevent delirium.
AI simplified
Background
Delirium is a recognized complication of medical illness, particularly in older patients, in whom it is associated with increased mortality, hospitalization and healthcare costs [1]. In inpatient palliative care settings, the prevalence of delirium has been reported in the 20β42% range on admission and up to 88% in the last hours or days of life [2]. Delirium is an acute neurocognitive disturbance in which oneβs awareness of the immediate environment is decreased and disordered attentional capacity is a core feature; other cognitive deficits and perceptual abnormalities may also occur [3]. As a consequence of these features and associated hypo- or hyperactive psychomotor changes, normal communication is impeded. The collective syndromal features of delirium invariably generate distress for patients and their families [4]; for healthcare practitioners, delirium presents a barrier in symptom assessment and a clinical management challenge, particularly when psychomotor agitation occurs [5β7]. This is especially true in the context of advanced disease and end-of-life care, in which patientsβ physical and functional decline confers a high level of baseline vulnerability towards delirium precipitants such as infection and adverse medication effects [6].
The clinical management approach towards an episode of delirium in the palliative care context is to identify and treat correctable precipitating factors, if consistent with the patientβs desired goals of care; in situations where the desired goals of care are solely focussed on comfort, or where the delirium precipitants are refractory to treatment, therapeutic intervention must then focus on symptomatic management of distressing symptoms such as perceptual disturbance or agitation [8]. Antipsychotics have been advocated in the first line pharmacological management of distressing delirium symptoms [9, 10]. However, evidence is emerging that antipsychotics have no preventative role and a limited therapeutic role for delirium in hospitalized adults [11β13]; in a recent trial in palliative care patients, antipsychotics were in fact associated with worsening of mild to moderate delirium when compared to placebo [14]. The recommended overall management approach is shifting towards greater preventive efforts, especially with non-pharmacological interventions and minimizing antipsychotic use where possible [15]. Multi-component non-pharmacological interventions, including maintenance of sleep hygiene have remarkable efficacy in preventing delirium in older people, [16, 17] but similar interventions together with deprescribing showed no benefit in preventing delirium in a palliative care population study [18]. Sleep-wake cycle disturbance is not a core diagnostic criterion for diagnosis of delirium, but its prevalence in cancer patients with delirium has been reported in the 75β100% range [19, 20]. Although the pathophysiology of delirium is complex and not fully understood, melatonin dysregulation and associated sleep-wake cycle disturbance is postulated as one of the mechanisms in the pathogenesis of delirium [21].
Melatonin is a natural hormone that is secreted predominantly by the pineal gland, particularly in response to darkness onset, coinciding with the initiation and maintenance of sleep; it has a major role in both the regulation and synchronization of the sleep-wake cycle and circadian rhythms [22]. In addition to its chronobiotic role, melatonin has diverse and complex oncostatic and immunomodulatory properties [23β25]. Furthermore, altered circadian melatonin levels, particularly a reduction in peak endogenous production, have been reported in relation to various cancers, [26β28] healthy ageing and cognitive impairment [29, 30]. Disturbed circadian production of melatonin has also been reported in postoperative patients and those with critical illness, particularly sepsis [31β33]. Melatonin dysregulation has thus been demonstrated in most of the clinical populations at highest risk of delirium, which is the main hypothetical basis of exogenously administering melatonin to prevent delirium.
Although there is growing interest in the role of melatonin and melatonin receptor agonists in promoting sleep and preventing delirium in critical care and other high-risk populations, [34] heterogeneity among delirium prevention studies with melatonin supplementation precludes broad conclusive recommendations [35]. Although two systematic reviews and meta-analyses failed to show statistically significant benefit in delirium prevention for melatonin or its agonist, ramelteon across postoperative, intensive care and older medical populations, [36, 37] a sub-group analysis estimated that melatonin administration decreased the incidence of delirium by 75% in older (> 65 years) medical patients [36]. Meanwhile, delirium prevention studies with melatonin supplementation have not been published to date in the palliative care population, whose clinical characteristics are likely to have a shared overlap with the older medical population.
Given the rationale for a randomized controlled trial (RCT) to evaluate the role of melatonin in preventing delirium in the palliative care population, and prior to conducting such a trial, hereafter referred to as the main study, a preliminary study was conducted to examine its feasibility. The primary objectives of this feasibility study were to determine (1) estimates of participant recruitment and retention, (2) the appropriateness of the main studyβs outcome measures, based on both the frequency of protocol violation and ascertainment of preliminary data on time to onset of first incident episode of delirium, cumulative incidence of delirium, incident rate of delirium and the severity of delirium and insomnia (3) the acceptability of study procedures, including assessment tools to patients, their families and palliative care unit staff. The secondary objectives of this feasibility study were to (a) assess the feasibility of data collection regarding predisposing and precipitating risk factors for delirium, (b) facilitate the initial implementation of standard delirium prevention and management guidelines on the palliative care unit, and (c) assess the safety of the study interventions, based on preliminary estimates of adverse events.
Methods
The methods have been described in detail in a previous protocol publication and will be summarized here [38].
Study setting, design and sample size
The feasibility study was conducted in a 31-bed inpatient, university teaching palliative care unit (PCU) at Γlisabeth BruyΓ¨re Hospital, Ottawa, Canada. The study was a double-blind, randomized, parallel arm, placebo-controlled, single centre trial of once daily, orally administered melatonin to prevent delirium in patients with advanced cancer. The proposed primary outcome of the main study is time-to-event survival (survival in this context refers not to life survival but to remaining delirium-free, albeit at risk of delirium) analysis for first incident episode of delirium. This means that participants who do not develop delirium by the end of the study period would be censored in the analysis; similarly, those participants who might leave the study without developing delirium before the designated study period ends would contribute at-risk time to the time-to-event survival analysis, but would be censored at the time of their leaving the study.
For time-to-event survival analysis, we anticipated a 25% incidence of delirium in the placebo arm of the main study. Accounting for censoring, we estimated a sample size requirement of N = 410 to detect an effect size (hazard ratio) of 0.5, given an alpha level of 0.05 and power of 80% in the main study. Consistent with literature recommendations, [39] a sample size requirement of 60 (30 in each arm) was estimated for the feasibility study, which was 15% of the sample size (N = 410) of the main study. Feasibility targets were not formally pre-specified for this single site study in anticipation that the main study would likely require multisite participation.
The feasibility study assessed the proposed primary and secondary outcomes of the main study: time in days from study enrollment to first inpatient episode of delirium (event) for 50% (often referred to as median survival time) of each study group in the at-risk population; cumulative incidence of delirium within the study period of 28βdays; incidence rate of delirium per person-time, also known as incidence rate density; severity of incident delirium and perceived sleep satisfaction. The use of person-time incidence and time-to-event survival outcomes rather than cumulative incidence within a certain time interval accounts for those situations where the observation time differs between participants, or the population at risk varies with time.
Study eligibility
Inclusion criteria: age β₯ 18 years; documented diagnosis of advanced cancer; admitted to the inpatient PCU; a rating β₯ 30% on the Palliative Performance Scale (PPS) [40]; cognitive capacity to give informed consent, as assessed by the attending physician, or if cognitively impaired, access of the study team to a substitute decision maker (SDM) to obtain informed written consent.
Exclusion criteria: delirium present on admission, based on a positive CAM assessment; known psychotic disorder other than dementia; inability to take medications sublingually or via gastrostomy tube; known allergy to melatonin or placebo content; use of melatonin within the 2 weeks preceding admission; patients on warfarin or other oral anticoagulants; on other investigational agents or treatments or on immunosuppressant medication in the context of autoimmune disease or post organ transplantation; communication problems that could not be accommodated in the course of study assessments, including deafness, tracheostomy, aphasia, dysarthria or emotional distress; severe visual impairment or designated legally blind; and pregnancy or lactation.
Recruitment and randomization
Consecutive potential study participants were approached within 72βh of admission and assessed by their attending physician regarding study eligibility criteria; those eligible were referred to either a trained clinical research nurse (CRN) or trained clinical research assistant (CRA) from the study team, who provided information verbally and in writing, and obtained informed written consent before study enrollment of all participants.
Using the Ottawa Hospital Research Institute (OHRI) Data Management Services (a web-based randomization system), a central randomization master list, incorporating a 1:1 ratio for melatonin to placebo, was pre-generated by an independent statistician and sent by secure electronic communication to the hospitalβs Director of Pharmacy. The melatonin drug and identical placebo were packaged, and numbered as per the master list. This list was kept confidential and secure by OHRI Data Management Services, the Director of Pharmacy and the specific pharmacy technician who prepackaged the study (melatonin or placebo) medication. The label of the study medications only broadly identified the contents as βMelatonin/ Placebo Study Drugβ. Allocation of study group (melatonin or placebo) was concealed: the study investigators, research nurse and assistant, the PCU pharmacist, nurses, physicians, dispensing pharmacist and technician, and study participants were blinded to the exact study medication.
Study drug administration protocol and safety monitoring
Enrolled subjects were randomised to receive melatonin 3βmg (immediate release) or an identical (size, shape and taste) placebo at 21:00 (+/ββ1βh) on study day 1 (D1) and daily thereafter until D28 or earlier in the event of death, discharge, study withdrawal or diagnosis of incident delirium. The study drugs were supplied by Jamieson Laboratories Ltd., Windsor, Ontario, Canada.
The National Cancer Instituteβs Common Terminology Criteria for Adverse Events (NCI-CTAE, v 4.03) format was used for adverse event recording and reporting [41]. An independent Data and Safety Monitoring Board (DSMB) was established for the study and received regular standardized reports from the study team.
Additional measures and data recording
Routine physician assessments on the day of PCU admission include the Confusion Assessment Method (CAM), [42, 43] a validated tool to screen for and diagnose delirium, and the Short Orientation Memory Concentration Test (SOMCT), [44] a validated tool to assess cognition. Routine nursing assessments included 8-hly delirium screening on a daily basis with the Nursing Delirium Screening Scale (Nu-DESC), a validated observational tool (score range 0β10) that was completed in relation to each 8-hour nursing shift [45]. A score β₯ 2 on the Nu-DESC prompted an attending physician CAM rating within 24 h. Symptom intensity is routinely rated using the revised Edmonton Symptom Assessment System (ESAS-r) [46] and cancer pain is classified using the Edmonton Classification System for Cancer Pain (ECS-CP) [47].
Specific study assessments included the following: the Insomnia Severity Index (ISI), [48] which was conducted on D1 (Study Day 1), D14 Β± 2 days and D28 Β± 2 days; the Memorial Delirium Assessment Scale (MDAS), [49] which was rated on weekdays (with reference to the preceding 24 h) by the CRN within 24 Β± 8 h of incident delirium diagnosis; and the Clinician Global Rating (CGR) of delirium severity (mild, moderate or severe), which was rated by the attending physician at the time of incident delirium diagnosis.
The designated goals of care, based on consensual input from patient and/or SDM, were recorded at admission and at the day of diagnosis of incident delirium. Consistent with patient and family wishes, the designated goals of care help to determine the degree of intensity applied to the investigation and treatment of an episode of delirium. This approach is consistent with the Canadian Guidelines on the Assessment and Treatment of Delirium in Older Adults at the End of Life, [50] which were adapted and introduced at the commencement of this feasibility study. The goals of care categories were as follows: βRβ for full resuscitation; βM + Tβ for medical and transfer (indicating full medical investigation and treatment on the PCU with the option to transfer out to tertiary acute care as necessary for additional investigations or treatments); βMβ for medical investigation and treatment without transfer out; and βCβ for comfort only care.
Data relating to baseline or predisposing factors (at D1) and acute onset precipitating factors at the time of incident delirium were collected by the CRN or CRA using standard checklists (see Additional files 1 and 2, Table S1 and Table S2 with checklists for baseline/predisposing factors and acute onset precipitating factors, respectively). Within 3 days of delirium diagnosis, the CRN or CRA also interviewed the attending physician of those study patients who developed incident delirium and systematically recorded a checklist of potential precipitant risk factors (categorized as definite, probable, possible, present but apparently not contributory, and either ruled out or not present or not relevant) associated with the episode of incident delirium. Laboratory and other investigations were conducted as per routine practice on the PCU and consistent with the designated goals of care. Laboratory abnormalities were designated as such based on their being outside of the local laboratory reference range in all cases. The total opioid dose in morphine oral equivalent, the corticosteroid daily dose in prednisone oral equivalent, the diazepam oral equivalent benzodiazepine daily dose and the total anticholinergic drug scale (ADS) score at D1 were calculated in accordance with standard tables and references [51β53]. The Charlson Co-morbidity Index was rated on D1 [54].
Data analysis
The data analysis for the feasibility study was largely descriptive. Categorical data were summarized as proportions or percentages with 95% confidence intervals (CIs), unless otherwise stated; continuous data were summarized as medians with interquartile (Q1-Q3) ranges, as most were not normally distributed. As a preliminary report, statistically significant differences between the study groups were analyzed using the Pearson Chi Square or Fisherβs Exact Tests for categorical variables and the Mann-Whitney Test for continuous variables. Similarly, preliminary data regarding the time to event of the first episode of delirium in the two study groups was compared using a Kaplan-Meier analysis. Statistical analyses reported in this paper were conducted using Stata 14.1 (StataCorp LP, College Station, TX, USA).
Ethical approval and oversight requirements
A no objection letter was obtained from the Therapeutic Products Directorate of Health Canada to proceed with the study, which was sponsored by BruyΓ¨re Research Institute. The study received ethical approval from the Ottawa Health Sciences Network and BruyΓ¨re Research Ethics Boards. In addition to providing regular reports to the DSMB, an independent study monitor, who conducted a site visit and review of procedures at the times of 20th, 40th and 60th subject recruitment, was also appointed. The trial was registered on July 21st 2014 with ClinicalTrials.govβ: NCT02200172β. The study adheres to CONSORT guidelines for randomized pilot and feasibility trials [55].
Results
Recruitment, retention and demographic characteristics of participants
Of the 556 excluded patients, 396 failed to meet the study eligibility requirements, most commonly due to delirium on admission in 124/396 (31%), low PPS rating (n = 67, 17%) and communication problems in (n = 59, 15%). Seven (23.3%; 9.9β42.3%) of the melatonin and 11 (36.7%; 19.9β56.1%) of the placebo study groups, a total of 18 (30%; 18.9β43.2%) completed the study to its designated full duration of 28 days without developing incident delirium. Among the remaining 21 (35%; 23.1β48.4%) participants whose study participation ended before 28 days without incident delirium being recorded, 1 from the placebo group died; 6 versus 3 were withdrawn and 6 versus 5 were discharged in the melatonin and placebo groups, respectively. The study exit for all of these participants was within the first 21 days.
CONSORT Flow Diagram. PPS: Palliative Performance Scale; SDM: Substitute Decision Maker; IC: Informed Consent
| Characteristic | Study Group | All patients | valueP | |
|---|---|---|---|---|
| Placebo=β30 (%)n | Melatonin=β30 (%)n | Total=β60 (%)n | ||
| Age, yrsa | 67 (60β76) | 67 (59β75) | 67 (60β75) | 0.531 |
| Sex: female | 13 (43.3) | 14 (46.7) | 27 (45.0) | 0.795 |
| Primary cancer | ||||
| Lung | 12 (40.0) | 8 (26.7) | 20 (33.3) | 0.531 |
| Gastrointestinal | 7 (23.3) | 9 (30.0) | 16 (26.7) | |
| Genitourinary | 4 (13.3) | 4 (13.3) | 8 (13.3) | |
| Breast | 4 (13.3) | 2 (6.7) | 6 (10.0) | |
| Hematologic | 1 (3.3) | 1 (3.3) | 2 (3.3) | |
| Head & Neck | 1 (3.3) | 0 (0.0) | 1 (1.67) | |
| Primary Brain | 0 (0.0) | 2 (6.7) | 2 (3.3) | |
| Other | 1 (3.3) | 4 (13.3) | 5 (8.3) | |
| Metastatic sites of cancer | ||||
| Lung | 8 (26.7) | 12 (40.0) | 20 (33.3) | 0.273 |
| Liver | 12 (40.0) | 14 (46.7) | 26 (43.3) | 0.602 |
| Brain | 12 (40.0) | 8 (26.7) | 20 (33.3) | 0.273 |
| Leptomeningeal | 5 (16.7) | 1 (3.3) | 6 (10.0) | 0.195 |
| Bone | 17 (56.7) | 14 (46.7) | 31 (51.7) | 0.438 |
| Palliative Performance Scale (PPS)a | 40 (30β50) | 40 (30β50) | 40 (30β50) | 0.613 |
| Charlson Comorbidity Index (CCI)a | 10 (9β11) | 10 (9β13) | 10 (9β12) | 0.27 |
| Baseline Goals of Care | ||||
| Comfort only | 6 (20.0) | 7 (23.3) | 13 (21.7) | 0.75 |
| Medical | 19 (63.3) | 18 (60.0) | 37 (61.7) | |
| Medical & Transfer | 5 (16.7) | 4 (13.3) | 9 (15.0) | |
| Full Resuscitation | 0 (0.0) | 1 (3.3) | 1 (1.67) | |
| ECS-CPPain mechanismb | ||||
| No pain syndrome | 4 (13.3) | 8 (26.7) | 12 (20.0) | 0.076 |
| Nociceptive | 18 (60.0) | 9 (30.0) | 27 (45.0) | |
| Neuropathic | 8 (26.7) | 12 (40.0) | 20 (33.3) | |
| Unknown or missing | 0 (0) | 1 (3.3) | 1 (1.67) | |
| ECS-CPIncident painb | ||||
| Present | 15 (50.0) | 13 (43.3) | 28 (46.7) | 0.606 |
| Absent | 14 (46.7) | 17 (56.7) | 31 (51.7) | |
| Unknown or missing | 1 (3.3) | 0 (0) | 1 (1.67) | |
| ESAS-r symptom intensity,c | ||||
| Paina | 3 (2β3) | 2 (0β5) | 2.5 (1β4) | 0.786 |
| Tirednessa | 5 (3β6) | 4.5 (2β6.5) | 5 (3β6) | 0.525 |
| Drowsinessa | 3 (1β6) | 4.5 (2β6.5) | 4 (1β6) | 0.413 |
| Nauseaa | 0 (0β2) | 0 (0β0.5) | 0 (0β1) | 0.486 |
| Lack of appetitea | 3.5 (0β7) | 3.5 (0β7) | 3.5 (0β7) | 0.923 |
| Short of breatha | 2 (0β4) | 0 (0β2) | 1 (0β3) | 0.072 |
| Depressiona | 1 (0β3) | 0 (0β3) | 0.5 (0β3) | 0.584 |
| Anxietya | 1 (0β4) | 2 (0β5) | 2 (0β4) | 0.787 |
| Well beinga | 4.5 (2β6) | 3.5 (2β5.5) | 4 (2β6) | 0.644 |
| Sleepa | 4 (0β6) | 3.5 (0β6) | 4 (0β6) | 0.847 |
Baseline neurocognitive assessment
| Characteristic | Study Group | All patients | valueP | |
|---|---|---|---|---|
| Placebo=β30 (%)n | Melatonin=β30 (%)n | Total=β60 (%)n | ||
| Highest educational level achieved | ||||
| Elementary | 0 (0.0) | 2 (6.7) | 2 (3.3) | 0.369 |
| Junior High School | 2 (6.7) | 1 (3.3) | 3 (5.0) | |
| High School | 4 (13.3) | 5 (16.7) | 9 (15.0) | |
| University / 3rd level | 8 (26.7) | 12 (40.0) | 20 (33.3) | |
| Unknown | 16 (53.3) | 10 (33.3) | 26 (43.3) | |
| Consent obtained | ||||
| Patient | 24 (80.0) | 26 (86.7) | 50 (83.3) | 0.731 |
| Substitute | 6 (20.0) | 4 (13.3) | 9 (15.0) | |
| Dementia diagnosis documenteda | 2 (6.7) | 2 (6.7) | 4 (6.7) | 1 |
| Cognitive impairment without dementia | ||||
| Documented present | 2 (6.7) | 2 (6.7) | 4 (6.7) | 0.748 |
| Unknown | 1 (3.3) | 2 (6.7) | 3 (5.0) | |
| Short Orientation Memory Concentration Test Score (SOMCT)b | 2 (0β5) | 3 (0β7) | 2 (0β6) | 0.307 |
| Previous delirium episode | ||||
| Documented record of occurrence | 7 (23.3) | 6 (20.0) | 13 (21.7) | 0.521 |
| Unknown | 7 (23.3) | 4 (13.3) | 11 (18.3) | |
| Mood disorder diagnosis documenteda | 2 (6.7) | 6 (20.0) | 8 (13.3) | 0.357 |
| Anxiety disorder documenteda | 3 (10.0) | 3 (10.0) | 6 (10.0) | 0.891 |
| Recent neurocognitive symptoms (per history from patient or substitute)c | ||||
| Perceptual disturbance | 3 (10.0) | 3 (10.0) | 6 (10.0) | 0.665 |
| Delusional disturbance | 0 (0) | 0 (0) | 0 (0) | 0.385 |
| Attention problemsa | 5 (16.7) | 7 (23.3) | 12 (20.0) | 0.658 |
| Sleep pattern disturbeda | 8 (26.7) | 2 (6.7) | 10 (16.7) | 0.08 |
| Insomnia severity index (ISI) scoreb | 11 (4β15) | 7.5 (2β13) | 9 (3β13) | 0.199 |
| Psychoactive medications at admission | ||||
| Number prescribedb | 3 (1β4) | 2 (1β3) | 2 (1β4) | 0.125 |
| Morphine equivalent daily dose (MEDD)bd | 60 (6β90) | 37.5 (4β240) | 54 (4.5β132) | 0.645 |
| Diazepam equivalent daily dosebd | 0 (0) | 0 (0) | 0 (0) | 0.931 |
| Prednisone equivalent daily dosebd | 11 (0β40) | 16.25 (0β45) | 12.25 (0β40.0) | 0.757 |
Preliminary data on the outcome measures chosen for main study
In regard to the severity of incident delirium, there were 9 participants with missing MDAS ratings for their first 24 h of incident delirium; comparison of the six available MDAS ratings in each group revealed higher severity in the melatonin versus placebo group: 18 (16β20) versus 13.5 (11β17), (p = 0.09). There were no missing CGRs of delirium severity and rating categories (mild, moderate and severe) were not statistically different in the study groups. Similarly, there were no statistically significant study group differences in the maximum Nu-DESC score either during the day of incident delirium diagnosis or in the 72-h period that included the day before the day of incident delirium diagnosis, the day of incident delirium diagnosis and the day following this.
In rating the severity of insomnia, there were 28 (53%) of participants with missing D14 ISI ratings and 43 (72%) with missing D28 ISI ratings. Apart from a reported ISI baseline comparison, in which treatment group differences were not statistically significant, no further study group comparisons were made in view of the extent of missing data.
There was one protocol violation in the placebo group: two doses of the placebo medication were missed in one participant. There were 31 protocol deviations in the placebo group and 18 in the melatonin group, mostly relating to documentation and timing of assessments.
Kaplan-Meier plots of cumulative incidence of delirium in study groups
| Characteristic | Study Groups | All patients | valueP | |
|---|---|---|---|---|
| Placebo=β30 (%)n | Melatonin=β30 (%)n | Total=β60 (%)n | ||
| Incident Delirium Diagnosis (IDD) | ||||
| Cumulative 28-day incidence | 10 (33.3) | 11 (36.7) | 21 (35.0) | 0.787 |
| Total person-days at risk | 521 | 411 | 932 | |
| Incidence rate per person-day [95% Confidence interval] | 0.019 [0.010β0.036] | 0.027 [0.015β0.048] | 0.023[0.015β0.036] | 0.227 |
| First quartile delirium-free survival time (days) | 18 | 9 | 10 | 0.433 |
| Severity measures at IDD | ||||
| MDAScompletedβ<Β 24βh of IDDa | 6 (60.0) | 6 (54.5) | 12 (57.1) | 0.331 |
| MDAS scoreb | 13.5 (11β17) | 18 (16β20) | 16.5 (12β18) | 0.09 |
| Clinician Global Rating (CGR) | ||||
| Mild | 2/10 [20.0] | 3/11 [27.3] | 5/21 [23.8] | 0.632 |
| Moderate | 6/10 [60.0] | 8/11 [72.7] | 14/21 [66.7] | |
| Severe | 2/10 [20.0] | 0/11 [0] | 2/21 [9.5] | |
| Nu-DESC ratingsc | ||||
| Total number of ratings available over 72βhat IDDdb | 7 (6β9) | 8 (6β9) | 8 (6β9) | 0.462 |
| Maximum total Nu-DESC score over 72βhat IDDdb | 4 (3β6) | 3 (1β5) | 3 (2β5) | 0.191 |
| Maximum total Nu-DESC score during day of IDDb | 6 (4β7) | 3 (3β5) | 4 (3β6) | 0.144 |
Acceptability of study procedures
Field notes were made by the CRN and CRA regarding the acceptability of core study procedures. Apart from issues with assessment tools, the study procedures were otherwise considered acceptable. Missing assessments occurred most frequently in relation to the MDAS ratings and ISI ratings. Missing MDAS ratings were attributed to lack of weekend CRN/CRA assessor coverage in 3 participants and patient fatigue or distress in the remainder. In the case of participants with missing ISI ratings, many had either been discharged or become delirious before their ISI assessments that were scheduled on D14 or D28, or were noted to be too fatigued to complete the assessment.
Secondary objectives
Data collection regarding delirium risk factors
Categorized precipitants of delirium for 20 participants with incident delirium. β Data were not recorded in this category for two participants
| Characteristic | Study Group | All patients | valueP | |
|---|---|---|---|---|
| No Delirium=β39 (%)n | Delirium=β21 (%)n | Total=β60 (%)n | ||
| Age, yrsa | 67 (60β75) | 68 (61β75) | 67 (60β75) | 0.687 |
| Sex: female | 20 (51.3) | 7 (33.3) | 27 (45.0) | 0.183 |
| Primary cancer | ||||
| Lung | 13 (33.3) | 7 (33.3) | 20 (33.3) | 0.544 |
| Gastrointestinal | 9 (23.1) | 7 (33.3) | 16 (26.7) | |
| Genitourinary | 6 (15.4) | 2 (9.5) | 8 (13.3) | |
| Breast | 5 (12.8) | 1 (4.8) | 6 (10.0) | |
| Primary Brain | 1 (2.6) | 1 (4.8) | 2 (3.3) | |
| Hematologic | 0 (0) | 2 (9.5) | 2 (3.3) | |
| Head & Neck | 1 (2.6) | 0 (0) | 1 (1.7) | |
| Other | 4 (10.3) | 1 (4.8) | 5 (8.3) | |
| Metastatic sites of cancer | ||||
| Lungs | 14 (35.9) | 6 (28.6) | 20 (33.3) | 0.566 |
| Liver | 17 (43.6) | 9 (42.9) | 26 (43.3) | 0.956 |
| Brain | 11 (28.2) | 9 (42.9) | 20 (33.3) | 0.251 |
| Leptomeninges | 3 (7.7) | 3 (14.3) | 6 (10.0) | 0.078 |
| Bone | 21 (53.9) | 10 (47.6) | 31 (51.7) | 0.645 |
| Charlson Comorbidity Index (CCI)a | 10 (9β12) | 10 (9β13) | 10 (9β12) | 0.919 |
| Palliative Performance Scorea | 40 (30β50) | 40 (30β40) | 40 (30β50) | 0.036 |
| Baseline Goals of Care | ||||
| Comfort only | 7 (17.9) | 6 (28.6) | 13 (21.7) | 0.301 |
| Medical | 23 (59.0) | 14 (66.7) | 37 (61.7) | |
| Medical & Transfer to Acute Care | 8 (20.5) | 1 (4.8) | 9 (15.0) | |
| Full Resuscitation | 1 (2.6) | 0 (0) | 1 (1.7) | |
| Highest educational level achieved | ||||
| Elementary | 1 (2.6) | 1 (4.76) | 2 (3.3) | 0.959 |
| Junior High School | 2 (5.13) | 1 (4.76) | 3 (5.00) | |
| High School | 6 (15.4) | 3 (14.3) | 9 (15) | |
| University / 3rd level | 12 (30.8) | 8 (38.1) | 20 (33.3) | |
| Unknown | 18 (46.5) | 8 (38.1) | 26 (43.3) | |
| Cognitive and psychiatric status at admission | ||||
| Short Orientation Memory Concentration Test Score (SOMCT)a | 2 (0β4) | 6 (2β10) | 2 (0β6) | 0.013 |
| Recent neurocognitive symptoms (per admission history and assessments)b | ||||
| Perceptual disturbance | 3 (7.7) | 3 (14.3) | 6 (10.0) | 0.417 |
| Delusional disturbance | 0 (0) | 0 (0) | 0 (0) | |
| Attention problemsc | 4 (10.3) | 8 (38.1) | 12 (20.0) | 0.003 |
| Sleep pattern disturbedc | 7 (18.0) | 3 (14.3) | 10 (16.7) | 0.443 |
| Insomnia severity index (ISI) scorea | 10 (3β14) | 5.5 (1β12.5) | 9 (3β13) | 0.336 |
| Previous delirium episode | ||||
| Documented occurrence | 7 (18.0) | 6 (28.6) | 13 (21.7) | 0.562 |
| Unknown | 7 (18.0) | 4 (19.1) | 11 (18.3) | |
| Dementia diagnosisc | 3 (7.7) | 1 (4.8) | 4 (6.7) | 0.536 |
| Cognitive deficits without dementia | ||||
| Documented | 2 (5.1) | 3 (14.3) | 5 (8.3) | 0.601 |
| Unknown | 2 (5.1) | 1 (4.8) | 3 (5.0) | |
| Mood disorder diagnosisc | 7 (18.0) | 1 (4.8) | 8 (13.3) | 0.268 |
| Anxiety disorder diagnosisc | 3 (7.7) | 3 (14.3) | 6 (10.0) | 0.546 |
| Metabolic abnormalities at admission | ||||
| Hypoalbuminemia | 23 (59.0) | 16 (76.2) | 39 (65.0) | 0.258 |
| Hyponatremia | 4 (10.3) | 4 (19.1) | 8 (13.3) | 0.433 |
| Hypercalcemia | 2 (5.1) | 1 (4.8) | 3 (5.0) | 1 |
| Low Hemoglobin (<β 100βg/L) | 9 (23.1) | 8 (38.1) | 17 (28.3) | 0.243 |
| Hypoxia requiring Oxygen therapy | 7 (18.0) | 5 (23.8) | 12 (20.0) | 0.737 |
| Medications at admission | ||||
| Number of medications prescribeda | 12 (10β16) | 10.5 (8β14) | 12 (8β15) | 0.187 |
| Psychoactive medicationsa | 2 (1β4) | 2 (1β4) | 2 (1β4) | 0.641 |
| Morphine equivalent daily dose (MEDD)a | 30 (5β150) | 60 (2.5β90) | 54 (4.5β132) | 0.944 |
| Diazepam equivalent daily dosea | 0 (0) | 0 (0) | 0 (0) | 0.487 |
| Prednisone equivalent daily dosea | 12.25 (0β40) | 13 (0β50) | 12.5 (0β40) | 0.868 |
Implementation of delirium assessment and management guidelines
The conduct of this feasibility study was used as an opportunity to implement standard clinical practice guidelines regarding delirium assessment and management on our PCU. These guidelines were implemented for all members of the inter-professional team in a modular fashion, with a focus on delirium screening, nonpharmacological interventions, and improving communication and support for patients and their families. Recommendations for antipsychotic prescribing were derived from recently published RCT evidence.
Safety evaluation
Although the total number of participants with at least one CTCAE Grade 3β5 serious adverse event was 17 (57%) in the placebo study group and 20 (67%) in the melatonin study group, these were considered to be not related (n = 15) or unlikely to be related (n = 2) in the placebo group and not related (n = 17) or unlikely to be related (n = 3) in the melatonin group.
Discussion
There is a general consensus that a pilot or feasibility study is practically a prerequisite requirement prior to proceeding with a larger study, especially in palliative care settings, whose population are particularly vulnerable [56, 57]. Although the literature distinction between pilot and feasibility studies is somewhat unclear, [58, 59] there is some consensus that pilot studies are a subset of feasibility studies [60]. In meeting its primary and secondary objectives, the current study, although referred to as a feasibility study, provides useful information from both the pilot and feasibility perspectives prior to conducting the main RCT.
Primary feasibility of study objectives
Recruitment and retention
The presence of delirium at inpatient admission in 31% of those not meeting inclusion criteria was the most frequent reason for study exclusion. Of the 616 screened subjects, 160 (26%) either declined to give informed consent or declined contact from the CRN/CRA. Approximately 10% of all screened subjects (N = 616) were recruited in this study and although there was no specific, a priori defined recruitment rate target, the recruitment at our single site required a lengthy period of approximately 16 months. From a recruitment perspective, these data indicate that a larger RCT would clearly require multisite collaboration.
Although a change in the study inclusion criteria to include participants with non-cancer end-of-life conditions might broaden the study target population and boost recruitment, it might also introduce a high degree of heterogeneity and add further challenges in terms of analyses. Nonetheless, this warrants consideration. The feasibility study recruited patients with advanced cancer that required inpatient PCU admission. It should be acknowledged that targeting patients earlier in their cancer disease trajectory might enhance recruitment potential for a community-based study (as opposed to an inpatient PCU study), but the validity of screening for and diagnosing delirium as an outcome in a community-based setting would also pose major challenges.
In terms of retention, 21 (35%) study participants contributed at-risk time from a time-to-event analysis perspective and exited the study prior to 21βdays without developing delirium, thus requiring right censoring in the analysis. Of those who developed incident delirium, all but 2 did so by 21βdays. These data suggest that we could consider shortening the duration of the main study to 21βdays with minimal loss of data, which might be an acceptable trade-off, as multisite collaboration might be more attractive with a shorter study duration.
Preliminary data on outcome measures for the main study
Although the extent of missing assessment score data was substantial, this related mainly to outcomes that are designated as secondary outcome measures in the main study. The minimal protocol violation or deviation encountered in relation to the main studyβs designated primary outcome measure supports its choice as primary outcome measure for the main study. Meanwhile, preliminary data obtained from the study regarding efficacy of study medications and sample size estimates warrant careful evaluation.
The study was remarkably informative regarding the time-to-event for the occurrence of incident delirium. However, caution should be exercised in relation to any hypothesis testing or interpreting efficacy differences between the study groups, as this study was not adequately powered to do so. Nonetheless, the signal highlights the importance of a DSMB and careful tracking of trends in both arms in the main study.
The study provided helpful pilot data in relation to the sample size requirement for the main study, originally estimated at 410. Although the 35% cumulative incidence of delirium in the study sample was higher than our pre-study projection of 25%, we under-estimated the need to censor cases in the time-to-event analysis: instead of the projected 10% withdrawal rate, there were 21 (35%) study participants who contributed at-risk time and required right censoring, albeit at varying times within the first 21βdays of the study. Furthermore, our pre-study effect size change, reflected by a hazard ratio of 0.5 (a 50% reduction in hazard) and based on a previous study in a medical geriatric population, appears to be overly optimistic. Using a more conservative estimate for hazard ratio change to 0.7 (30% reduction in hazard), conducting a 21-day study and applying our feasibility/pilot data to our sample size estimation, together indicate a sample size requirement of 724 with 362 in each arm and 253 events (incident delirium) for the main study. This sample size requirement, 304 (72%) greater than the pre-study projection, highlights yet again the need for multisite collaboration in the main study, assuming that survival analysis with time-to-event (incident delirium diagnosis) is used as the primary outcome. An alternative approach, as adopted in a current Australian multi-site RCT designed to examine the role of melatonin in preventing delirium in PC settings, and in which members of our study team (MA, SB, PL, DC) are also involved, is to use delirium-free days as the primary outcome, while adjusting for length of inpatient stay. Using this as primary outcome has the advantage of having a smaller sample size requirement.
The severity of incident delirium (based on Nu-DESC, MDAS and CGR) and the severity of insomnia (based on ISI scores) are two secondary outcomes in the main study. The completion rates of Nu-DESC scores and ratings of CGR were acceptable and their respective scores were similar in the two study treatment groups, with the caveat that this study was not powered to detect a group difference. The proportions of missing MDAS scores (43%) and ISI scores for D14 (53%) and D28 (72%) precluded meaningful analyses in relation to both of these measures. The missing MDAS scores due to lack of CRN/CRA availability at weekends could be corrected by funding more extensive CRN/CRA coverage, whereas extreme patient fatigue and the consequent burden of conducting the MDAS assessment in such patients is less easily amenable to modification, albeit that based on available scores, pro-rating of scores for burdensome individual MDAS items has been reported [61]. Given that delirium severity measurement is a secondary rather than primary objective, consideration could be given to omitting the MDAS assessments in the main study for valid reasons: delirium severity is already captured by the CGR and the Nu-DESC, and our having previously reported moderate correlation between MDAS (as gold standard) and Nu-DESC scores in a Nu-DESC validation study [62]. The missing ISI scores due to patientsβ discharge prior to reaching 28 days of the study could be addressed in the main study by omitting D14 and D21 ratings, and instead either conduct ratings on D7 of the study or rely solely on ESAS-r ratings for sleep.
Acceptability of study procedures and assessments
Acceptability of study procedures were reflected by a single protocol violation and a moderate degree of protocol deviations, mostly in relation to assessment tool ratings. Although CRN/CRA field notes indicated good acceptability of core study procedures from a patient and healthcare staff perspective, there were some remarkable instances of missing data, particularly in relation to the MDAS and ISI ratings, both amenable to solutions as previously discussed.
Secondary objectives of the feasibility study
The study facilitated the implementation of delirium assessment and management guidelines, which will be reported separately. Safety evaluation of the study medication revealed no serious medication related adverse events. Although the discontinuation of melatonin in two participants with drowsiness was attributed as most likely due to other observed illness complications, we cannot exclude the potential for some contribution of melatonin to the drowsiness. The feasibility examination of collecting delirium risk factor data was highly informative towards planning a main study.
Although few studies have reported risk models for delirium in palliative care settings or palliative care eligible populations, [63] the baseline delirium risk factors identified in this study, poorer functional and cognitive performance and a higher frequency of baseline deficits in attentional capacity, are consistent with existing data from oncology settings [64, 65]. Data regarding CRP and ADS were not obtained as pre-planned. Although increasing anticholinergic drug burden in palliative care patients has been reported in association with delirium in a retrospective case-control study, [66] and cognitive impairment towards death in a secondary analysis of longitudinal data from an RCT, [67] there are remarkably conflicting data in many elderly and critical care studies regarding the role of anticholinergic drug burden, serum anticholinergic activity and scales to assess anticholinergic drug burden in relation to delirium risk [68β71]. In view of such uncertainty, anticholinergic drug burden evaluation could be omitted in the main study. In the case of low availability of CRP data, the goals of care on admission, designated as comfort only in 13 (22%) patients may have influenced physiciansβ decision not to request CRP levels.
Moreover, the study demonstrated a temporal trend towards an increasing focus on comfort only: of the 21 participants who developed incident delirium, 12 (57%) had their goals of care designated as comfort only at that time. This trend is consistent with increasing awareness of disease progression and is in accordance with the fundamental principles of palliative care. However, the evaluation of predisposing and precipitating risk factors for delirium in a research study is compromised in this context, as confounding may occur due to the goals of care designation and its change over time. One ethically acceptable solution is to restrict investigation and evaluation of delirium risk factors to those whose goals of care are designated as βmedicalβ, βmedical and transferβ or βfull resuscitationβ.
In a larger RCT on delirium prevention, it is advisable to have good baseline data on covariates, pending patient consent for investigation, and adjust for them in the study analyses. More comprehensive epidemiological evaluation of delirium risk factors warrants a prospective cohort study to obtain robust data. The number of risk factors evaluated in the feasibility study was very large; it is possible that examination of existing databases may allow the selection of a smaller number of factors for either the planned RCT on prevention or a more comprehensive prospective cohort study of delirium risk factors [63].
Strengths and limitations
This study met all of its clearly defined objectives and provided very useful feasibility and pilot data to inform the planning and conduct of a larger double blind RCT, albeit with some important modifications. The sample size of 60 was consistent with literature recommendations of at least 9% of the projected sample size of the main RCT and adequate to meet the objectives of the study. The study provided useful preliminary information to be cautiously interpreted in accordance with literature recommendations [72]. The feasibility studyβs randomization process resulted in two study groups that were well balanced and comparable. The study had some important limitations apart from the limited ability to evaluate efficacy. First, although we did not survey patients regarding the effectiveness of blinding process, there were no signs of any deficits in this regard. Second, although the study identified substantive areas of missing data, particularly in relation to follow-up assessment tool scores and the recording of risk factors, this has enabled more appropriate planning towards a larger RCT. Overall, the distribution of missing baseline neurocognitive and other data across the main study groups was similar and likely of a random nature. Third, the potential for underdiagnosis of delirium among study participants at baseline cannot be excluded and could be reduced by gaining information from the addition of a more elaborate assessment tool such as the Delirium Rating-Revised-98 (DRS-98) [73] or MDAS at the baseline assessment.
Conclusion
In meeting its pre-defined objectives, this study adequately assessed the feasibility of conducting a double blind RCT to examine the role of exogenous melatonin to prevent delirium in patients with advanced cancer who were admitted to an inpatient palliative care unit. A larger double-blind RCT is feasible, but subject accrual and withdrawal rates signal a need for adjustment in sample size and multisite collaboration. Although not powered for efficacy evaluation, the trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial. The ethically acceptable evaluation of risk factors for delirium in research studies warrants careful consideration in light of the agreed goals of care and their temporal shift towards more comfort focussed care.
Supplementary information
Additional file 1 : Table S1. Baseline Risk Profile for Delirium in the Cancer Trajectory (BRP-DICT)Additional file 2 : Table S2. Precipitant Profile for Delirium in the Cancer Trajectory (PP-DICT)Additional file 3 : Table S3. Aggregated frequency of delirium precipitants and their estimated role in incident delirium