Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000436471
Ethics application status
Approved
Date submitted
20/12/2015
Date registered
6/04/2016
Date last updated
22/06/2022
Date data sharing statement initially provided
18/09/2019
Date results information initially provided
18/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised trial of the pro-phylactic use of melatonin in critically ill patients to evaluate if this leads to a reduction in incidence of delirium (Pro-MEDIC study)
Scientific title
Pro-phylactic administration of Melatonin for the prevention of Delirium in Intensive Care units – a randomized placebo controlled trial (Pro-MEDIC study)
Secondary ID [1] 287597 0
Nil
Universal Trial Number (UTN)
U1111-1175-1814
Trial acronym
Pro-MEDIC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Delirium 296400 0
Condition category
Condition code
Neurological 296669 296669 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Melatonin (4mg) to be given once daily at 21:00 (oral or nasogastric medication) to intensive care patients who have an expected ICU length of stay >72 hrs. Patients must be enrolled within 48 hrs of their admission. Given for 14 days or until ICU discharge (whichever is shorter). The decision on whether nasogastric or oral route is used will be left up to the patient and bedside nurse. Melatonin is inexpensive with an excellent safety profile and is widely used in the community. It is a natural hormone stimulated by low light, peaking during the main sleep period. It helps regulate the sleep-wake cycle, which is a problem in ICU. Serum melatonin levels are lower post surgery, in delirious post surgical patients and in those administered opioids. Drops in melatonin levels and fluctuations in its metabolite 6-SMT are associated with delirium. Administered by bedside ICU nurse and adherence will be monitored by the examining the patients medication chart
Intervention code [1] 292995 0
Prevention
Intervention code [2] 293980 0
Treatment: Drugs
Comparator / control treatment
Placebo - similar liquid in appearance - nursing/pharmacy/medical staff will be blinded.
Both formulations - sucrose, glycerol, flavouring and purified water so will be identical in taste (melatonin added to intervention formulation)
Control group
Placebo

Outcomes
Primary outcome [1] 296276 0
Delirium free assessments (as measured by CAM-ICU score)
Timepoint [1] 296276 0
Twice daily assessment - percentage of delirium free assessments during ICU stay or 14 days (whichever is shorter)
Secondary outcome [1] 318034 0
Severity of delirium as measured by CAM-S score
Timepoint [1] 318034 0
Twice daily (if positive for delirium) during ICU stay or 14 days (whichever is shorter)
Secondary outcome [2] 318035 0
Mortality
Timepoint [2] 318035 0
ICU, 28 and 90 day mortality
Secondary outcome [3] 318036 0
Length of ICU stay - this will be assessed by the principal investigator or research co-ordinator at each site using computer results systems linked to medical records
Timepoint [3] 318036 0
Duration of stay in terms of number of days
Secondary outcome [4] 321013 0
Hospital length of stay - this will be assessed by the principal investigator or research co-ordinator at each site using computer results systems linked to medical records or medical records themselves
Timepoint [4] 321013 0
Hospital discharge
Secondary outcome [5] 321014 0
Ventilator days - this is recorded in ICU systems already and will be extracted by the research co-ordinator or principal investigator
Timepoint [5] 321014 0
Number of days ventilated during during ICU stay or 14 days (whichever is shorter)
Secondary outcome [6] 321260 0
Physical restraints - yes/no each day during ICU stay or 14 days (whichever is shorter) - nursing staff will report whether they used physical restraints that day
Timepoint [6] 321260 0
Daily need for physical restraints - each day during ICU stay or 14 days (whichever is shorter)
Secondary outcome [7] 321261 0
Anti-psychotics - these will be recorded as total dose each day - recorded on case report form
Timepoint [7] 321261 0
Daily doses of anti-psychotics required - during ICU stay or 14 days (whichever is shorter)
Secondary outcome [8] 321262 0
Economic cost - costing analysis - If there are differences observed in duration of mechanical ventilation, hospital length of stay or requirements for anti-psychotic medications, a costing analysis will be performed to estimate potential cost savings.
Timepoint [8] 321262 0
Cost-consequence approach based on potential reduction in length of stay and cost of intervention - evaluated after completion of data collection
Secondary outcome [9] 322564 0
Sleep quality - total sleep time by polysomnography
Timepoint [9] 322564 0
Performed on two occasions (days 2-3 and day 5-7) in a subset of 100 patients
Secondary outcome [10] 322565 0
Sleep quality - sleep efficiency on polysomnography
Timepoint [10] 322565 0
Performed on up to two occasions (days 2-3 and day 5-7) in a subset of 50 patients
Secondary outcome [11] 322566 0
Sleep quality - percentage REM sleep by polysomnography
Timepoint [11] 322566 0
Performed on two occasions (days 2-3 and day 5-7) in a subset of 100 patients
Secondary outcome [12] 322567 0
Sleep quality - arousal index by polysomnography
Timepoint [12] 322567 0
Performed on two occasions (days 2-3 and day 5-7) in a subset of 50 patients
Secondary outcome [13] 397066 0
Daily ability to participate in physiotherapy - yes/no - documentation daily from nurse or physiotherapist as to whether patient was able to participate in physio
Timepoint [13] 397066 0
Recorded for duration of study or 14 days (whichever is shorter)
Secondary outcome [14] 397067 0
Patient removal of lines - yes/no - prospective daily documentation by nurse or research coordinator
Timepoint [14] 397067 0
Recorded on daily basis for duration of study or 14 days (whichever is shorter)
Secondary outcome [15] 397068 0
Delirium and coma free days -Delirium= any positive CAM-ICU score that day is positive for delirium. Coma = RASS (Richmond agitation sedation scale) of -5 to -3. Both must be negative to be a delirium and coma free day
Timepoint [15] 397068 0
Recorded for duration of study or 14 days (whichever is shorter)
Secondary outcome [16] 397069 0
Odds ratio product of sleep study - this is a number from 0 (deep sleep) to full wakefulness (2.5) generated from assessing the polysomnography study - looks at the 4 EEG bands relative to each other
Timepoint [16] 397069 0
Measured when patients have sleep studies
Aim to have sleep studies done study day 3-6

Eligibility
Key inclusion criteria
Patients admitted to the Intensive Care Unit, identified by the treating intensivist as expected to have an ICU length of stay >72 hours. Patients must be enrolled within 48 hours of their ICU admission.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1 Patients already on melatonin before their admission to ICU
2 Prior hypersensitivity reaction to any of the components of the study drug
3 Patients expected to be discharged within 72 hrs of their ICU admission
4 Non English speaking
5 Expected or inevitable death within next 48 hours
6 Patients that are not expected to improve adequately to be able to be assessed with a CAM-ICU score during their ICU stay
7 Patients that are not able to be assessed due to neurological problems that would affect their ability to participate in a CAM-ICU assessment (as judged by treating physician)
8 No enteral route – melatonin not available in intravenous formulation
9 Pregnancy or breastfeeding.
10. Hepatic impairment defined as Alanine Transferase (ALT) >500 IU/L, previous liver transplant or liver cirrhosis categories Childs-Pugh B and C.

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)
Computer generated randomisation list by independent statistician. Randomisation will be stratified by site. Melatonin and placebo will be liquid form in sealed bottles, same taste and appearance.
Once allocated, blinding will assist allocation concealment in that at no point in the study will the clinicians, investigators or other study personnel be aware of the allocation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated sequence
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size Estimation
Estimates of sample size were made based on the percentage of delirium free assessments (the primary outcome) and the length of stay in ICU (LOS). LOS was chosen in addition to the percentage of delirium free assessments, as a significant relationship been delirium and LOS has been observed.

An audit of 100 patients at SCGH and JHH was used to provide preliminary data to guide sample size calculations.

Both estimates of sample size were performed with an alpha value of 0.05 and a power of 0.80.

Percentage of delirium free assessments

In the audit, 54% of assessments were deemed delirium free (standard deviation of 45%). The research group is interested in being able to detect a 10% increase in the percentage of delirium free assessments. This would give a sample size calculation of 319 per group. Adjustment for non-parametric test, (15%) increases this to 367 per group. It is expected that 10% of patients recruited in the study will not be assessable for delirium at any point during the study. To account for this, and missing data/loss to follow up, the sample size was increased by 15% to 423 patients per group (total rounded to 850).

Length of stay

LOS using the study criteria did not result in a normal distribution of values but a gamma distribution. Thus using a sample size calculation for a gamma distribution as outlined in Cundill & Alexander, 2015 (67) to detect a difference in length of stay of one day, 387 patients per group will be required.

Sample size: Based on the two sample size calculations a total of 850 patients will be recruited for the study, with 425 patients in each arm.

Statistical Analyses Plan
Analysis
All analyses will be conducted on both an intention-to-treat (ITT) and per-protocol (PP) basis. The ITT sample is defined as all randomized subjects including those who are lost to follow-up or have missing data. If the patient does not receive the assigned intervention post-randomisation, the patient will still be included in the ITT sample and analyzed according to assigned treatment group. The per-protocol sample is defined as all randomized subjects who fulfil the eligibility criteria, receive the correct treatment assignment according to the randomization schedule, and follow the protocol up to the end of the treatment phase.
Demographics will be presented and compared between the two groups. Variables will include age, gender, admission type and diagnosis type.
Primary and secondary outcomes will be analysed as described below.
Where appropriate analysis of primary and secondary outcomes will be analysed by a number of predetermined subgroups. These subgroups will include:
• Percentage of delirium free assessments by age: less than 65 or more than 65 years of age
• Percentage of delirium free assessments by gender
• Percentage of delirium free assessments by delirium subgroup at baseline– hyperactive, hypoactive and mixed and no delirium
• Percentage of delirium free assessments by diagnostic category (respiratory, cardiovascular, gastrointestinal, toxicological, neurological, metabolic, sepsis, trauma, traumatic brain injury)
• Percentage of delirium free assessments by >50% risk or <50% risk as per Pre-Deliric Score (calculated from first 24 hours of ICU admission)
To account for multiple testing on secondary and subgroup analyses multiplicity adjustments will be made as necessary.
Data analysis is to be carried out using the Stata MP, version 15.

Primary Outcome
Delirium
The primary outcome, the percentage of delirium free assessments, will be calculated for each participant. The percentage of delirium free assessments for participants in each group will then be compared using a student’s t-test. Supporting analysis will be using linear regression making adjustments for baseline covariates listed above.
A secondary analysis will look at the comparing the rates of delirium in each group. The number of times an individual is reported with delirium and the total number of assessments will be examined by a comparison of rates. In addition, a poisson regression will be used with the response number of reported positive delirium assessments and offset of total number of assessments. Baseline characteristics will be included as covariates in the model.
Finally, an analysis that looks at whether the individual reported a positive delirium assessment during their stay will be undertaken by comparing proportions between the groups through a logistic regression analysis controlling for variables including age, gender and length of stay.

Secondary Outcomes
Severity and duration of delirium
All analyses in this subsection (with the exception of (ii) Delirium and Coma Free Days) will use either a linear mixed model approach or generalized linear mixed model approach, both of which will include a random individual effect to account for the repeated nature of the data and an appropriate correlation structure. Estimated differences between the groups and 95% confidence intervals will be provided throughout.
(i) CAM-S: Score
CAM-S scores range from 0 (no delirium) to 7 (severe delirium). Linear mixed models will be used to compare CAM-S score as a response between the two treatment groups for individuals who have tested positive using CAM-ICU.
(ii) Delirium and Coma Free Days
Poisson regression will be used to compare the count of delirium and coma free days between the treatment groups using an offset of number of days in ICU.
(iii) Anti-psychotics or sedation
The use of anti-psychotics or sedations will be recorded as a binary outcome labelled ‘used’ or ‘not used’ for each day during the study period. Generalised linear mixed models with logit link will be used to compare the two treatment groups with respect to the binary outcome.
(iv) Physical restraint
Each day during the study period, the use of physical restraints will be recorded as a binary outcome labelled having been ‘used’ or ‘not used’. Generalised linear mixed models with logit link will be used to compare the use of restraints between the two treatment groups with respect to the binary outcome.
(v) Participation with physiotherapy and mobilization
Ability of participate in physiotherapy and mobilisation sessions will be assessed as a binary outcome labelled ‘yes’ or ‘no’. Generalised linear mixed models with logit link will be used to compare the use of the two treatment groups with respect to the binary outcome.
(vi) Patient removal of lines
Each day during the study period, it will be recorded as whether or not the patient has attempted to or successfully removed their lines (binary outcome labelled ‘yes’ or ‘no’). Generalised linear mixed models with logit link will be used to compare the used to compare the use of the two treatment groups with respect to the binary outcome.
(vii) Type of delirium

At each assessment, patients with delirium will be classified as having either hyperactive, hypoactive or mixed delirium. Generalised linear mixed models for ordinal response will be used to compare the use of the two treatment groups with respect to the ordinal outcome.

4Sleep quality
Two types of sleep questionnaire will be utilised during the study. The first, the RCSQ provides a score out of 50. The second (Little’s) involved a mixture of dichotomous questions and five-point rating questions.
Estimated Hours of sleep
For both questionnaire responses, calculated outcomes will be compared between the treatment groups using student’s t-tests and supporting linear regression models to adjust for covariates.
Polysomnography
In the subset of patients with polysomnography, the following will be analysed: total sleep time, sleep efficiency, percentage REM sleep, arousal index, and odds ratio product.
All calculated outcomes will be compared between the treatment groups using student’s t-tests and supporting linear regression models to adjust for covariates.

ICU and hospital length of stay
Initial comparisons between the two groups for ICU and hospital length of stay will be compared using a student’s t-test. Supporting analysis will also be carried out using poisson regression, accounting for previously described covariates.
Length of stay will be analysed in particular with the aforementioned subgroups.

Duration of mechanical ventilation
The total number of hours of mechanical ventilation will be calculated for each participant. Comparison between the two groups will be made using a student’s t-test. Supporting analysis will also be carried out using poisson regression, accounting for covariates such as age, gender, admission type and diagnosis type.

Mortality
Mortality (time to death) will be analysed using Kaplan Meier curves and Cox proportional hazard models, both unadjusted and adjusting for previously described covariates. Individuals who did not experience an event (death) will be censored at the end of the follow-up period of the study. Individuals withdrawn from the study early or lost to follow up will be censored at the date of withdrawal or the last contact visit respectively. Results will be presented using hazard ratios and 95% confidence intervals for relative comparisons between the groups and absolute risk and differences will be estimated at both 28 and 90 days.

Costing Analysis
The cost of ICU care has been estimated at $4,37518 and $5,534 (Medical Division SCGH, 2015) per day based on national and state data respectively. From these figures, any reduction in costs through reduced LOS will be calculated. The cost per melatonin dose ($20 AUD per 30ml bottle of 2mg/ml) as well as consumables (syringe for NGT application) will also be calculated. There would also be a small time cost associated with administration, but we believe it could reasonably be included in the general nursing workload. Costs will be presented in Australian dollars, adjusted to 2020.

If there are differences observed in duration of mechanical ventilation, hospital length of stay or requirements for anti-psychotic medications, a costing analysis will be performed to estimate potential cost savings.

Adverse events
Safety will be evaluated by tabulation of adverse events and will be presented with descriptive statistics at baseline and follow-up visits for each treatment group. With each SAE the study investigator will determine the intensity and causality as per ICH GCP guidelines All SAEs will be discussed at the Data Safety Monitoring Committee meetings to reach a consensus on causality. If this differs from the original decision the local ethics committee is informed.
The number and proportion of patients experiencing at least one AE, and the number and proportion of patients experiencing at least one SAE will be presented descriptively. The mean number of AEs and SAEs per patient will be presented. In addition, the frequencies of patients with (i) adverse events and (ii) serious adverse events, will both be compared between the intervention groups using Fisher’s exact tests or Chi Squared tests.

Missing data
Due to the nature and implementation of the CAM-ICU tool it is expected there will be some missing data. However, such data is expected to be missing at random and consequently appropriate analyses will be carried out. The patterns of data availability for primary and secondary outcomes and reasons for missingness, where known, will be summarised for the two treatment groups. In situations where mixed modelling is the primary analysis missing data will be handled by the likelihood-based estimation used in these analyses where the MAR assumption holds. In other situations of missing data analyses will be carried out, if applicable, using multiple imputation (MI).

Interim Analyses
An interim analysis will be carried out after data has been collected on the first 100 subjects. The interim analysis will be done to examine the primary aim and review the number of adverse events in each group. This will be done to ensure results of the study are in line with the sample size calculations and that the treatment is being well tolerated. If the treatment is having a greater effect than expected, the prevalence is notably higher or lower than expected, or there are high rates of SUSARs in the treatment group the study may be closed before the scheduled completion date.

We have chosen to use the Haybittle-Peto stopping rule. Thus if there is a probability of less than 0.001 in either direction that the treatment and placebo are different the Data Safety Monitoring Board will recommend that the study be ceased. The Haybittle-Peto rule is relatively conservative but as melatonin has an excellent safety profile it is very unlikely that patients will be exposed to harm a result of participating in the trial.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/05/2016
Actual
20/07/2016
Date of last participant enrolment
Anticipated
1/06/2019
Actual
17/08/2019
Date of last data collection
Anticipated
29/11/2019
Actual
29/11/2019
Sample size
Target
850
Accrual to date
Final
850
Recruitment in Australia
Recruitment state(s)
ACT,NSW,WA,VIC
Recruitment hospital [1] 4422 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [2] 4423 0
John Hunter Hospital Royal Newcastle Centre - New Lambton
Recruitment hospital [3] 4424 0
Royal Perth Hospital - Perth
Recruitment hospital [4] 4425 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [5] 4426 0
Joondalup Health Campus - Joondalup
Recruitment hospital [6] 8665 0
St John of God Midland Public Hospital - Midland
Recruitment hospital [7] 8666 0
St John of God Hospital, Murdoch - Murdoch
Recruitment hospital [8] 8667 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [9] 14815 0
The University of Canberra Hospital: Specialist Centre for Rehabilitation, Recovery and Research - Bruce
Recruitment hospital [10] 14816 0
Gosford Hospital - Gosford
Recruitment hospital [11] 14817 0
Wyong Public Hospital - Hamlyn Terrace
Recruitment hospital [12] 14818 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment postcode(s) [1] 28066 0
2250 - Gosford
Recruitment postcode(s) [2] 28067 0
2259 - Hamlyn Terrace
Recruitment postcode(s) [3] 28065 0
2617 - Bruce
Recruitment postcode(s) [4] 28068 0
3220 - Geelong
Recruitment postcode(s) [5] 16778 0
6008 - Subiaco
Recruitment postcode(s) [6] 16777 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 292163 0
Government body
Name [1] 292163 0
State Health Research Advisory Council
Country [1] 292163 0
Australia
Primary sponsor type
Hospital
Name
Sir Charles Gairdner Hospital
Address
Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Western Australia 6009
Country
Australia
Secondary sponsor category [1] 290836 0
None
Name [1] 290836 0
nil
Address [1] 290836 0
Country [1] 290836 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293636 0
Sir Charles Gairdner Hospital Ethics Committee
Ethics committee address [1] 293636 0
Sir Charles Gairdner Hospital Ethics Committee
Hospital Ave
Nedlands
WA 6009
Ethics committee country [1] 293636 0
Australia
Date submitted for ethics approval [1] 293636 0
04/10/2015
Approval date [1] 293636 0
14/03/2016
Ethics approval number [1] 293636 0
205-122

Summary
Brief summary
Aim
Delirium is associated with increased mortality, ventilator time, hospital length of stay, poor functional status and cognitive impairment, use of physical restraints and medical costs. This study will help determine whether the use of melatonin prophylactically decreases the incidence of delirium in Intensive Care patients.

Secondary aims will be to see if melatonin prophylaxis via its effect on delirium and sleep results in reduced mortality, length of stay (hospital and ICU), ventilator days and use of anti-psychotics, sedatives and physical restraints.
The economic analysis will evaluate the cost benefits of the intervention

Participant recruitment
850 patients from Adult Public ICUs who meet all of the inclusion and none of the exclusion criteria. Randomisation and enrolment will only occur Monday-Friday due to limitation of resources although treatment and assessment will occur on weekends and after-hours.

Randomisation and consent
Patients may be unable to consent at time of enrolment. In these cases an emergency waiver of consent will be used, as allowed for in the NHMRC National Statement, in conjunction with acknowledgement from the patient’s next-of-kin that they are not aware of any reason why the patient would have chosen not to participate. All patients will be followed up and provided the opportunity to consent to continued study participation once capacity is regained.

Intervention
Melatonin 4mg in oral suspension or placebo (similar appearance) will be given at 21:00 for 14 days or until discharge from ICU.
A subset of 100 patients will have two separate sleep EEGs done which is the gold standard to assess sleep quality and duration on days 2-3 and 5-7 of their admission

Analysis described earlier. An interim analysis will take place after 100 patients and 400 patients (employing peto-haybittle rule with p value 0.001) and a pre-planned economic analysis

Outcome assessment will be done by trained intensive care registrars. Data recording and management will be done by the principal investigators and research nurses
Trial website
Nil as yet
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 60794 0
Dr Bradley Wibrow
Address 60794 0
Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, WA 6009
Country 60794 0
Australia
Phone 60794 0
+61422410689
Fax 60794 0
Email 60794 0
bradley.wibrow@health.wa.gov.au
Contact person for public queries
Name 60795 0
Dr Bradley Wibrow
Address 60795 0
Intensive Care Unit
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia 6009
Country 60795 0
Australia
Phone 60795 0
+61422410689
Fax 60795 0
Email 60795 0
bradley.wibrow@health.wa.gov.au
Contact person for scientific queries
Name 60796 0
Dr Bradley Wibrow
Address 60796 0
Intensive Care Unit
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
Western Australia 6009
Country 60796 0
Australia
Phone 60796 0
+61422410689
Fax 60796 0
Email 60796 0
bradley.wibrow@health.wa.gov.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?
outcome data
When will data be available (start and end dates)?
post publication
start date - once accepted for publication - expect 2020
end date- no end date determined
Available to whom?
any researcher on permission of authors
Available for what types of analyses?
any purpose - not currently limited to certain type of analyses - again on permission of authors
How or where can data be obtained?
bradley.wibrow@health.wa.gov.au


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Ethical approval  bradley.wibrow@health.wa.gov.au
Informed consent form  bradley.wibrow@health.wa.gov.au
Study protocol https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-016-1751-0bradley.wibrow@health.wa.gov.au 369434-(Uploaded-09-09-2019-22-45-53)-Study-related document.pdf


Results publications and other study-related documents

Documents added manually
TypeIs Peer Reviewed?DOICitations or Other DetailsAttachment
Study results articleYes Wibrow B, Martinez E F, Myers E, Chapman A, Litton... [More Details]
Plain language summaryNo The early use of melatonin did not result in reduc... [More Details]

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProphylactic Melatonin for Delirium in Intensive Care (Pro-MEDIC): Study protocol for a randomised controlled trial.2017https://dx.doi.org/10.1186/s13063-016-1751-0
EmbaseProphylactic melatonin for delirium in intensive care (Pro-MEDIC): a randomized controlled trial.2022https://dx.doi.org/10.1007/s00134-022-06638-9
N.B. These documents automatically identified may not have been verified by the study sponsor.