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Trial registered on ANZCTR


Registration number
ACTRN12619000669190
Ethics application status
Approved
Date submitted
30/04/2019
Date registered
6/05/2019
Date last updated
27/05/2019
Date data sharing statement initially provided
6/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Clonidine at Low dosage postOperatively to Nocturnally Enhance Sleep
Scientific title
A randomised, double-blind, single-centre, placebo-controlled trial of low-dose clonidine infusion to improve sleep in postoperative patients in the High Dependency Unit
Secondary ID [1] 297703 0
None
Universal Trial Number (UTN)
U1111-1229-9703
Trial acronym
CLONES
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postoperative sleep disturbance 312007 0
Postoperative delirium 312008 0
Condition category
Condition code
Anaesthesiology 310571 310571 0 0
Anaesthetics
Neurological 310572 310572 0 0
Other neurological disorders
Surgery 310573 310573 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Single intravenous infusion of clonidine hydrochloride at 0.3 mcg/kg/hr (up to a maximum dosing weight of 100 kg) from 20:00 on the evening of surgery until 06:00 the following morning (10 hours total). Subjects will be followed from admission to the high dependency unit until discharge from the high dependency unit.
Intervention code [1] 313935 0
Treatment: Drugs
Comparator / control treatment
Intravenous infusion of sodium chloride 0.9% placebo at the same volume rate (0.03 mL/kg/hr) and duration (10 hours).
Control group
Placebo

Outcomes
Primary outcome [1] 319427 0
Total sleep time (hours) assessed using a FitBit Alta HR
Timepoint [1] 319427 0
Night of surgery
Secondary outcome [1] 368095 0
Sleep - number of awakenings assessed using a FitBit Alta HR
Timepoint [1] 368095 0
Night of surgery
Secondary outcome [2] 368096 0
Sleep - Sleep fragmentation index (awakenings / total sleep time) assessed using a FitBit Alta HR
Timepoint [2] 368096 0
Night of surgery
Secondary outcome [3] 368097 0
Sleep - REM sleep time (hours; % of total sleep) assessed using a FitBit Alta HR
Timepoint [3] 368097 0
Night of surgery
Secondary outcome [4] 368098 0
Sleep - Light sleep time (hours; % of total sleep) assessed using a FitBit Alta HR
Timepoint [4] 368098 0
Night of surgery
Secondary outcome [5] 368099 0
Sleep - Deep sleep time (hours; % of total sleep) assessed using a FitBit Alta HR
Timepoint [5] 368099 0
Night of surgery
Secondary outcome [6] 368102 0
Sleep - Awake time (hours) assessed using a FitBit Alta HR
Timepoint [6] 368102 0
Night of surgery
Secondary outcome [7] 368103 0
Sleep - Sleep efficiency (%) assessed using a FitBit Alta HR
Timepoint [7] 368103 0
Night of surgery
Secondary outcome [8] 368104 0
Sleep - Subjective sleep quality reported by subject using Richards-Campbell Sleep Questionnaire (RCSQ) plus additional scale item of Noise
Timepoint [8] 368104 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [9] 368105 0
Sleep - Subjective sleep quality reported by bedside nurse using Richards-Campbell Sleep Questionnaire (RCSQ) plus additional scale item of Noise
Timepoint [9] 368105 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [10] 368106 0
Delirium - Presence of post-operative delirium using Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)
Timepoint [10] 368106 0
1. Admission to the High Dependency Unit following surgery
2. Between 07:00 and 09:00 the morning after surgery
Secondary outcome [11] 368107 0
Delirium - Presence of post-operative agitation measured using Richmond Agitation-Sedation Scale (RASS)
Timepoint [11] 368107 0
1. Admission to the High Dependency Unit following surgery
2. Between 07:00 and 09:00 the morning after surgery
Secondary outcome [12] 368108 0
Delirium - need for supplementary antipsychotic medications including but not limited to haloperidol, olanzapine, quetiapine (yes/no) assessed using hospital records
Timepoint [12] 368108 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [13] 368109 0
Delirium - need for supplementary sedatives including but not limited to benzodiazepams, propofol (yes/no) assessed using hospital records
Timepoint [13] 368109 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [14] 368110 0
Delirium - nursing reports of delirium during High Dependency Unit admission (yes/no)
Timepoint [14] 368110 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [15] 368111 0
Delirium - nursing reports of agitation during High Dependency Unit admission (yes/no)
Timepoint [15] 368111 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [16] 368112 0
Fever - incidence of fever >38.0°C between 20:00 and 06:00 (yes/no) recorded in the observation chart
Timepoint [16] 368112 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [17] 368114 0
Fever - time patient was febrile >38.0°C between 20:00 and 06:00 (hours) recorded in the observation chart
Timepoint [17] 368114 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [18] 368115 0
Duration of study drug infusion (hours) recorded in hospital records
Timepoint [18] 368115 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [19] 368117 0
Total opioid use in ESHDU between 20:00 and 06:00 (fentanyl equivalent in mcg) recorded in hospital records
Timepoint [19] 368117 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [20] 368118 0
High Dependency Unit length of stay (hours) recorded in hospital records
Timepoint [20] 368118 0
Discharge from the High Dependency Unit
Secondary outcome [21] 368119 0
Acute hospital length of stay (days) recorded in hospital records
Timepoint [21] 368119 0
Discharge from hospital
Secondary outcome [22] 368120 0
Safety - number of instances of the blinded study medication being prematurely ceased, based on hospital records
Timepoint [22] 368120 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [23] 368121 0
Safety - indications for doctors prematurely ceasing blinded study medication (exploratory outcome) reported in medical notes
Timepoint [23] 368121 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [24] 368122 0
Safety - treatments given in association with prematurely ceasing study medication reported in the medical notes
Timepoint [24] 368122 0
Morning after surgery between 07:00 and 09:00
Secondary outcome [25] 369947 0
Safety - complications associated with prematurely ceasing study medication reported in the medical notes
Timepoint [25] 369947 0
Morning after surgery between 07:00 and 09:00

Eligibility
Key inclusion criteria
1. Post-operative elective surgical patients admitted to the RBWH Elective Surgery High Dependency Unit (ESHDU).

2. ESHDU doctor (registrar or consultant) agrees to the subject’s participation.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age less than 18 years.

2. Pregnancy or breastfeeding.

3. Patients admitted to ICU (instead of ESHDU).

4. ICU research coordinators not be available for enrolment (e.g. after 20:00) or completion of study assessments (Saturday morning – i.e. Friday admissions).

5. Patients who are expected to be discharged home directly from ESHDU the day after surgery.

6. Patients who take clonidine as a regular medication prior to surgery.

7. Patients prescribed an a2 agonist (e.g. clonidine or dexmedetomidine) during the current admission (e.g. as premedication, perioperatively as an adjunct to anaesthesia, or as a PCA/PCEA adjunct)... except:
* IV or oral clonidine up to maximum total dose of 1 mcg/kg administered either intraoperatively or in the Post Anaesthesia Care Unit will be permitted.

8. Advanced dementia (in the premorbid state requiring professional nursing care)

9. The patient has previously been enrolled in a clinical trial of a sedative, antipsychotic or anti-delirium medication during this admission.

10. Severe bradyarrhythmia resulting from either sick sinus syndrome or AV block of second or third degree.

11. Known allergy to alpha2-agonists including clonidine or dexmedetomidine.

12. End-stage kidney disease or use of dialysis (prior to or during current admission).

13. Comorbidities that will prevent or interfere with sleep measurement via the FitBit Alta HR, i.e. disease or condition such that wearing the device is either not possible (e.g. bilateral amputee, burns, loss of skin, etc), or will not be effective due to abnormal limb movement (e.g. quadriplegia, severe motor neuron disease, etc).

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 by computer (REDCap Randomization Module)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple stratified randomisation using a scheme generated by the Robust Randomization App (RRApp) with four strata based on two binary variables:

1. Intraoperative or PACU administration of either IV or oral clonidine up to a maximum total dose of 1 mcg/kg (yes; no)

2. Expected frequent awakenings, i.e. one or more of the following: known or suspected Obstructive Sleep Apnoea, two-hourly or more frequent neurological or neurovascular monitoring (yes; no)
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 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Power analysis indicates that 120 patients are needed to show a 30-minute difference in Total Sleep Time between treatment groups using a two-tailed Student’s t-test with two independent groups, alpha of 0.05, power of 0.90. Effect size was calculated based on a mean Total Sleep Time of 407.1 minutes (SD 50.1 minutes) reported in a healthy population of middle aged adults using polysomnography [Fonseca, Weysen, Goelema, et al. Sleep. 2017;40(7)].

This study is not powered to detect statistically significant differences in incidence of delirium (based on CAM-ICU assessment) between treatment groups. However, findings from this study will be used to determine sample sizes required for future studies where delirium incidence is a primary outcome.

A detailed Statistical Analysis Plan will be developed before completion of recruitment. All analyses will be conducted on an intention-to-treat basis.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 13370 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 25970 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 302226 0
Charities/Societies/Foundations
Name [1] 302226 0
RBWH Foundation: The Foundation of Royal Brisbane and Women’s Hospital
Address [1] 302226 0
Block 20, Central Drive,
Royal Brisbane and Women’s Hospital,
Butterfield Street,
Herston, QLD, 4006
Country [1] 302226 0
Australia
Funding source category [2] 302228 0
Government body
Name [2] 302228 0
Queensland Health
Address [2] 302228 0
Health Innovation, Investment and Research Office
Level 13, 33 Charlotte Street,
Brisbane QLD 4000
Country [2] 302228 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
UQ Centre for Clinical Research
Building 71/918
Royal Brisbane & Women's Hospital Campus
Herston, QLD, 4029
Country
Australia
Secondary sponsor category [1] 302083 0
None
Name [1] 302083 0
Address [1] 302083 0
Country [1] 302083 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302906 0
The Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 302906 0
The Prince Charles Hospital
Research, Ethics and Governance Unit
Building 14
The Prince Charles Hospital
Rode Road, Chermside, Qld 4032
Ethics committee country [1] 302906 0
Australia
Date submitted for ethics approval [1] 302906 0
13/09/2018
Approval date [1] 302906 0
05/11/2018
Ethics approval number [1] 302906 0
HREC/2018/QPCH/44026
Ethics committee name [2] 302908 0
The University of Queensland Human Ethics Research Office
Ethics committee address [2] 302908 0
Cumbrae-Stewart Building #72
The University of Queensland
St Lucia, QLD 4072
Ethics committee country [2] 302908 0
Australia
Date submitted for ethics approval [2] 302908 0
20/11/2018
Approval date [2] 302908 0
11/12/2018
Ethics approval number [2] 302908 0
2018002382 / 44026

Summary
Brief summary
Postoperative delirium is a common surgical complication associated with major long-term morbidity and mortality. No single pharmacological agent has been conclusively shown to reduce or prevent postoperative delirium, but recent trials with dexmedetomidine – a highly selective alpha2- adrenoreceptor agonist – have been promising. A low-dose infusion on the night of surgery appears to have a lasting effect at reducing delirium for the week post infusion, and improved both the quantity and quality of sleep. If these findings could be replicated with clonidine (the prototypical alpha2-adrenoreceptor agonist), this – and subsequent – studies could have substantial implications for future perioperative delirium risk management.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91802 0
Dr David Liu
Address 91802 0
UQ Centre for Clinical Research
Building 71/918 – Level 8
Royal Brisbane and Women's Hospital
Herston QLD 4029
Country 91802 0
Australia
Phone 91802 0
+61736468111
Fax 91802 0
Email 91802 0
d.liu3@uq.edu.au
Contact person for public queries
Name 91803 0
Dr David Liu
Address 91803 0
UQ Centre for Clinical Research
Building 71/918 – Level 8
Royal Brisbane and Women's Hospital
Herston QLD 4029
Country 91803 0
Australia
Phone 91803 0
+61736468111
Fax 91803 0
Email 91803 0
d.liu3@uq.edu.au
Contact person for scientific queries
Name 91804 0
Prof Michael Reade
Address 91804 0
The University of Queensland
Level 9, UQ Health Sciences
Royal Brisbane & Women’s Hospital
Herston QLD 4029
Country 91804 0
Australia
Phone 91804 0
+61733651111
Fax 91804 0
Email 91804 0
m.reade@uq.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?
Individual participant data underlying published results only.
When will data be available (start and end dates)?
Beginning 3 months and ending 5 years following main results publication.
Available to whom?
Only researchers who provide a methodologically sound proposal.
Available for what types of analyses?
Only to achieve the aims in the approved proposal, e.g. for IPD meta-analyses.
How or where can data be obtained?
Access subject to approvals by Principal Investigator.
What supporting documents are/will be available?
No other documents available
Summary results
No Results