Melatonin to prevent delirium in patients with advanced cancer: a double blind, parallel, randomized, controlled, feasibility trial.

BACKGROUND: Delirium is highly problematic in palliative care (PC). Preliminary data indicate a potential role for melatonin to prevent delirium, but no randomized controlled trials (RCTs) are reported in PC. METHODS: Patients aged ≥18 years, with advanced cancer, admitted to an inpatient Palliative Care Unit (PCU), having a Palliative Performance Scale rating ≥ 30%, and for whom consent was obtained, were included in the study. Patients with delirium on admission were excluded. The main study objectives were to assess the feasibility issues of conducting a double-blind RCT of exogenous melatonin to prevent delirium in PC: recruitment, retention, procedural acceptability, appropriateness of outcome measures, and preliminary efficacy and safety data. Study participants were randomized in a double-blind, parallel designed study to receive daily melatonin 3 mg or placebo orally at 21:00 over 28 days or less if incident delirium, death, discharge or withdrawal occurred earlier. Delirium was diagnosed using the Confusion Assessment Method. Efficacy endpoints in the melatonin and placebo groups were compared using time-to-event analysis: days from study entry to onset of incident delirium. RESULTS: Over 16 months, 60/616 (9.7%; 95% CI: 7.5-12.4%) screened subjects were enrolled. The respective melatonin (n = 30) vs placebo (n = 30) outcomes were: incident delirium in 11/30 (36.7%; 95%CI: 19.9-56.1%) vs 10/30 (33%; 95% CI: 17.3-52.8%); early discharge (6 vs 5); withdrawal (6 vs 3); death (0 vs 1); and 7 (23%) vs 11 (37%) reached the 28-day end point. The 25th percentile time-to-event were 9 and 18 days (log rank, χ2 = 0.62, p = 0.43) in melatonin and placebo groups, respectively. No serious trial medication-related adverse effects occurred and the core study procedures were acceptable. Compared to those who remained delirium-free during their study participation, those who developed delirium (n = 21) had poorer functional (p = 0.036) and cognitive performance (p = 0.013), and in particular, poorer attentional capacity (p = 0.003) at study entry. CONCLUSIONS: A larger double-blind RCT is feasible, but both subject accrual and withdrawal rates signal a need for multisite collaboration. The apparent trend for shorter time to incident delirium in the melatonin group bodes for careful monitoring in a larger trial. TRIAL REGISTRATION: Registered on July 21st 2014 with ClinicalTrials.gov : NCT02200172 .

Pilot observational prospective cohort study on the use of a novel home-based urinary pregnanediol 3-glucuronide (PDG) test to confirm ovulation when used as adjunct to fertility awareness methods (FAMs) stage 1.

RATIONALE: Ovulation confirmation is a fundamental component of the evaluation of infertility. PURPOSE: To inform the design of a larger clinical trial to determine the effectiveness of a new home-based pregnanediol glucuronide (PDG) urine test to confirm ovulation when compared with the standard of serum progesterone. METHODS: In this observational prospective cohort study (single group assignment) in an urban setting (stage 1), a convenience sample of 25 women (aged 18-42 years) collected daily first morning urine for luteinisinghormone (LH), PDG and kept a daily record of their cervical mucus for one menstrual cycle. Serum progesterone levels were measured to confirm ovulation. Sensitivity and specificity were used as the main outcome measures. Estimation of number of ultrasound (US)-monitored cycles needed for a future study was done using an exact binomial CI approach. RESULTS: Recruitment over 3 months was achieved (n=28) primarily via natural fertility regulation social groups. With an attrition rate of 22%, specificity of the test was 100% for confirming ovulation. Sensitivity varied depending on whether a peak-fertility mucus day or a positive LH test was observed during the cycle (85%-88%). Fifty per cent of participants found the test results easy to determine. A total of 73 US-monitored cycles would be needed to offer a narrow CI between 95% and 100%. CONCLUSION: This is first study to clinically evaluate this test when used as adjunct to the fertility awareness methods. While this pilot study was not powered to validate or test efficacy, it helped to provide information on power, recruitment and retention, acceptability of the procedures and ease of its use by the participants. Given this test had a preliminary result of 100% specificity, further research with a larger clinical trial (stage 2) is recommended to both improve this technology and incorporate additional approaches to confirm ovulation. TRIAL REGISTRATION NUMBER: NCT03230084.

The preventative role of exogenous melatonin administration to patients with advanced cancer who are at risk of delirium: study protocol for a randomized controlled trial.

BACKGROUND: Delirium is a very common and distressing neuropsychiatric syndrome in palliative care. Increasing age, the presence of dementia and advanced cancer are well-known predisposing risk factors for delirium development. Sleep-wake cycle disturbance is frequently seen during delirium and melatonin has a pivotal role in the regulation of circadian rhythms. Current evidence across various settings suggests a potential preventative role for melatonin in patients at risk of delirium, but no studies are currently reported in patients with advanced cancer. The aim of this article is to describe the design of a feasibility study that is being conducted to inform a larger randomized, placebo-controlled, double-blind trial (RCT) to evaluate the role of exogenously administered melatonin in preventing delirium in patients with advanced cancer. METHODS/DESIGN: Adult patients with a cancer diagnosis who are admitted to the palliative care unit will be randomized into a treatment or placebo group. The pharmacological intervention consists of a single daily dose of immediate-release melatonin (3 mg) at 21:00 ± 1 h, from day 1 to day 28 of admission. The primary objective of this initial study is to assess the feasibility of conducting the proposed RCT by testing recruitment and retention rates, appropriateness of study outcome measures, acceptability of study procedures and effectiveness of the blinding process. The primary outcome measure of the proposed larger RCT is time to first inpatient incident episode of delirium. We also plan to collect data on incident rates of delirium and patient-days of delirium, adjusting for length of admission. DISCUSSION: The outcomes of this feasibility study will provide information on recruitment and retention rates, protocol violation frequency, effectiveness of the blinding process, acceptability of the study procedures, and safety of the proposed intervention. This will inform the design of a fully powered randomized controlled trial to evaluate the preventative role of melatonin administration in patients with advanced cancer. TRIAL REGISTRATION: Registered with ClinicalTrials.gov: NCT02200172 Registered on 21 July 2014. Health Canada protocol number: BRI-MELAT-2013 (Final approved protocol version (Version 3): 18 June 2014) (Notice of Amended Authorization (NOA) received 14 November 2014).