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Trial registered on ANZCTR


Registration number
ACTRN12616001618448
Ethics application status
Approved
Date submitted
21/11/2016
Date registered
23/11/2016
Date last updated
6/12/2021
Date data sharing statement initially provided
16/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Melatonin vs. placebo for prevention of delirium in hospital in people with advanced cancer
Scientific title
Randomised, double-blind, placebo-controlled phase III trial of oral melatonin for the prevention of delirium in hospital in people with advanced cancer
Secondary ID [1] 290476 0
Protocol Number 035/16 v1.1
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Delirium 300850 0
Advanced Cancer 301079 0
Condition category
Condition code
Neurological 300671 300671 0 0
Other neurological disorders
Cancer 300855 300855 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Melatonin prolonged release 2mg oral tablet nightly commenced within 48 hours after hospital admission and continued until delirium occurrence, discharge, or for a maximum of 3 weeks after any acute medical issues imparting a delirium risk have been resolved.

The intervention will be delivered at 20:00 hours. At each dose, the individually labelled bottle will be opened and the prescribed dose taken out. The clinical nurse will observe the participant while the participant swallows the tablet whole, and then record the administration in the medicine record.
Intervention code [1] 296332 0
Treatment: Drugs
Intervention code [2] 296464 0
Prevention
Comparator / control treatment
Placebo
Oral placebo tablet containing identical ingredients except the active ingredient melatonin (amino methacrylate co-polymer, lactose, silicon dioxide, talcum and magnesium stearate) to ensure matching taste, size, shape and colour.
Control group
Placebo

Outcomes
Primary outcome [1] 300097 0
Number of delirium-free days (which occur before delirium onset for any participant who develops delirium).
For each participant, delirium screening will occur every 8 hours on each of the three 8-hour shifts by the ward nurses, using the Nursing Delirium Screening Scale (NuDESC). Participants scoring 2 or higher in the NuDESC will be assessed with The Delirium Rating Scale – Revised 98 (DRS-R-98) to confirm delirium presence and delirium severity.
Timepoint [1] 300097 0
From within 48 hours of hospital admission, until delirium occurrence, discharge or for a maximum of three weeks if patient remains in hospital after any acute medical issues imparting a delirium risk have been resolved
Secondary outcome [1] 329028 0
Delirium profile assessed by DRS-R-98 (Delirium Rating Scale- Revised-98)
Timepoint [1] 329028 0
Eligibility and then daily for the duration of study medication administration
Secondary outcome [2] 329029 0
Toxicity:
- Sedation: assessed by the Richmond Agitation-Sedation Scale - Palliative (RASS - Pal)
- Days in coma defined as RASS - Pal score of -4 or -5.
- Other adverse events: assessed using the National Cancer Institute Common Terminology Criteria
Timepoint [2] 329029 0
From baseline and then daily for the duration of study medication administration
Secondary outcome [3] 329030 0
Regular and administration of ‘as required’ doses of benzodiazepine and antipsychotics will be recorded daily in the participant medication chart (within the medical record)
Timepoint [3] 329030 0
From baseline for the duration of study medication administration
Secondary outcome [4] 329033 0
Delirium precipitating factors measured using the Delirium Etiology Checklist (DEC)
Timepoint [4] 329033 0
At the time of delirium occurrence
Secondary outcome [5] 329034 0
In-hospital complications:
Falls, pneumonia, thromboembolism, pressure areas, changes in performance status (AKPS) and survival will be documented daily in the medical records until participant's hospital discharge and then weekly in the follow-up period (21 days after ceasing study medication).
Timepoint [5] 329034 0
From baseline for the duration of study medication administration
Secondary outcome [6] 329035 0
Family distress using the Delirium Experience Questionnaire
Timepoint [6] 329035 0
After a delirium episode
Secondary outcome [7] 329036 0
Sleep quality measured using the Insomnia Severity Index
Timepoint [7] 329036 0
At baseline and every 5 days during the admission
Secondary outcome [8] 329038 0
Inpatient resource utilisation
variables include duration of admission (days), daily medications, investigations (blood tests, imaging, urine cultures), and level of nursing required for transfers or care (independent, standby assistance, one or two assistants) and use of one to one nursing (hours). This information will be assessed by review of medical records.
Timepoint [8] 329038 0
From baseline until follow-up completion (21 days after ceasing study medication)

Eligibility
Key inclusion criteria
- Aged 18 years or older
- English speaking or availability of a health care interpreter.
- Diagnosis of advanced cancer (histological or clinical diagnosis) defined by the intent of treatment no longer being curative
- Admission to an acute or sub-acute inpatient facility
- Participant is able to give fully informed written consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Inability to take medications orally
- Delirium on admission as defined the cut off score on the delirium rating scale DRS-R-98 of 17.75 or more indicative of delirium
- Australian Karnofsky Performance Status (AKPS) score less than 30 at the beginning of the study
- A known allergy to melatonin or placebo content
- Active seizure disorder defined as seizure within last one month, or seizure disorder not on anticonvulsants
- Concomitant cimetidine use (CYP2D Inhibitor increases melatonin levels by 1.7 fold)
- Current history alcohol abuse (alcohol reduces melatonin levels);
- In people taking warfarin, a markedly nontherapeutic international normalized ratio (less than 1 or greater than 4)
- Moderate to severe dementia as defined by clinical diagnosis of dementia and a Short Blessed Test (SBT) score equal or greater that 10
- Severe hepatic impairment (defined as bilirubin at least 2.5 times upper limit of normal; alkaline phosphatase, aspartate transaminase and/or alanine transaminase more than 3 times upper limit of normal clinically determined to be due to hepatic impairment)
- Current use of melatonin for other indication, melatonin use within last 14 days
- Currently taking agomelatine, or use of agomelatine in the past 7 days
- Pregnant or breastfeeding

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation schedules will be developed for each site using random number tables, generated at an independent central registry. The central registry will supply site randomisation schedules to each site pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Intention-to-treat analysis will be used for all statistical comparisons. For the primary outcome, comparisons between groups for delirium-free days, with adjustment to the length of stay and other potential covariates using a general linear model approach will be undertaken. For potential missing data, multiple imputation technique will be applied to handle the missing data. A proper multiple imputation method will be employed that based on various models of assumption including missing completely at random (MCAR), missing at random (MAR), and missing not at random (MNAR). Sensitivity analysis will apply to examine the effects of these different assumptions on the imputed data structure in order to ascertain the most reliable approach.

For the secondary outcomes, time-to-event analysis will be used to determine differences in time to first episode of delirium. Delirium precipitants, which occur at variable times and for different durations during the study period are time-dependent covariates and Cox proportional hazard modelling will be used.
The incidence rate of delirium will also be calculated and compared between the treatment and control groups. For possible toxicity of the medication, incidence of adverse event will be calculated and reported.

Sample size was calculated based on the information obtained in the pilot study on the primary outcome, namely delirium-free days during a 3 week study period, and an analytical approach of comparing the mean delirium-free days between groups. It has been estimated that a sample size of 110 in each arm (n=220 in total) would provide 90% power to reject the null hypothesis with a 5% type I error rate to detect an increase of 2 delirium-free days allowing for 30% drop out or loss to follow-up and 5% for possible adjustments for covariates.

Two planned interim analyses will be conducted independently and reviewed by the independent data and safety monitoring committee after about 33% and 66% of patients have been enrolled. The primary outcome and adverse events will be compared between groups with p<0.001 required as the threshold of stopping the trial for significant evidence of benefit or harm in either one of the treatment arms.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
3/01/2017
Actual
19/07/2017
Date of last participant enrolment
Anticipated
31/12/2019
Actual
17/12/2020
Date of last data collection
Anticipated
14/02/2020
Actual
12/01/2021
Sample size
Target
220
Accrual to date
Final
221
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,VIC
Recruitment hospital [1] 6892 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 6894 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 6895 0
Sacred Heart Hospice - Darlinghurst
Recruitment hospital [4] 9178 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 9179 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [6] 11998 0
Braeside Hospital - Prairiewood
Recruitment hospital [7] 11999 0
Barwon Health - McKellar Centre campus - North Geelong
Recruitment hospital [8] 12000 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [9] 12001 0
St Vincent's Private Hospital - Kew
Recruitment hospital [10] 12002 0
The Canberra Hospital - Garran
Recruitment hospital [11] 19111 0
Mater Adult Hospital - South Brisbane
Recruitment postcode(s) [1] 14560 0
2170 - Liverpool
Recruitment postcode(s) [2] 14562 0
5042 - Bedford Park
Recruitment postcode(s) [3] 14563 0
2010 - Darlinghurst
Recruitment postcode(s) [4] 17814 0
2139 - Concord Repatriation Hospital
Recruitment postcode(s) [5] 17815 0
3050 - Royal Melbourne Hospital
Recruitment postcode(s) [6] 24154 0
2176 - Prairiewood
Recruitment postcode(s) [7] 24155 0
3215 - North Geelong
Recruitment postcode(s) [8] 24156 0
3065 - Fitzroy
Recruitment postcode(s) [9] 24157 0
2605 - Garran
Recruitment postcode(s) [10] 33670 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 294895 0
University
Name [1] 294895 0
University Technology Sydney
Country [1] 294895 0
Australia
Primary sponsor type
University
Name
University Technology Sydney
Address
Centre for Cardiovascular and Chronic Care
Faculty of Health, University of Technology Sydney
Level 3, 235 Jones Street, Ultimo, NSW 2007
Country
Australia
Secondary sponsor category [1] 293732 0
None
Name [1] 293732 0
Address [1] 293732 0
Country [1] 293732 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296370 0
HREC of South Western Sydney Local Health District
Ethics committee address [1] 296370 0
Ethics committee country [1] 296370 0
Australia
Date submitted for ethics approval [1] 296370 0
21/06/2016
Approval date [1] 296370 0
08/10/2016
Ethics approval number [1] 296370 0
HREC/16/LPOOL/359

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1245 1245 0 0
/AnzctrAttachments/371790-melatonin for delirium prevention phase III protocol_version 1.1_290916_clean.pdf (Protocol)
Attachments [2] 1246 1246 0 0
/AnzctrAttachments/371790-Melatonin Phase III NEAF_210616.pdf (Other)
Attachments [3] 1257 1257 0 0
/AnzctrAttachments/371790-Letter - REO - HE16 186 - Approval - Ethics-signed.pdf

Contacts
Principal investigator
Name 70218 0
Prof Meera Agar
Address 70218 0
Centre for Cardiovascular and Chronic Care
Faculty of Health, University of Technology Sydney
Level 3, 235 Jones Street, Ultimo, NSW 2007
Country 70218 0
Australia
Phone 70218 0
+6129514 4243
Fax 70218 0
Email 70218 0
meera.agar@uts.edu.au
Contact person for public queries
Name 70219 0
Meera Agar
Address 70219 0
Centre for Cardiovascular and Chronic Care
Faculty of Health, University of Technology Sydney
Level 3, 235 Jones Street, Ultimo, NSW 2007
Country 70219 0
Australia
Phone 70219 0
+6129514 4243
Fax 70219 0
Email 70219 0
meera.agar@uts.edu.au
Contact person for scientific queries
Name 70220 0
Meera Agar
Address 70220 0
Centre for Cardiovascular and Chronic Care
Faculty of Health, University of Technology Sydney
Level 3, 235 Jones Street, Ultimo, NSW 2007
Country 70220 0
Australia
Phone 70220 0
+6129514 4243
Fax 70220 0
Email 70220 0
meera.agar@uts.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All data will be available on request to the Lead Investigator
When will data be available (start and end dates)?
Maximum of 5 years post publication.
Available to whom?
Other researchers with research question approved by the study investigator team
Available for what types of analyses?
Those analyses described in approved proposals only
How or where can data be obtained?
Available from the Lead Investigator by email to: Meera.Agar@uts.edu.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.