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Trial registered on ANZCTR


Registration number
ACTRN12614000411640
Ethics application status
Approved
Date submitted
24/02/2014
Date registered
15/04/2014
Date last updated
1/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The Post Anaesthesia N-Acetycysteine Cognitive Evaluation trial, investigating the potential for N-Acetylcysteine to reduce cognitive dysfunction following major elective non-cardiac surgery
Scientific title
Randomised controlled trial of N-Acetyl-Cysteine vs placebo for the prevention of Post Operative Cognitive Dysfunction in major elective non-cardiac surgery
Secondary ID [1] 283978 0
Barwon Health HREC project number 13/111
Universal Trial Number (UTN)
U1111-1152-5499
Trial acronym
PANACEA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post Operative Cognitive Dysfunction
 291008 0
Surgical Stress Response 291009 0
Post Operative Mood Disorder 291010 0
Post surgical pain 295184 0
Condition category
Condition code
Anaesthesiology 291353 291353 0 0
Anaesthetics
Mental Health 291354 291354 0 0
Studies of normal psychology, cognitive function and behaviour
Surgery 292035 292035 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
N-Acetyl-Cysteine
600mg oral capsules
dosage regimen = 1200mg twice daily, commencing 1-2 hours prior to surgery, continuing for 4 days, with a resultant total dose of 9600mg
Adherence to be monitored by trial coordinators via daily patient visits, medication chart review, and clinical effect to be correlated with biomarker evidence of antioxidant action.
Intervention code [1] 288667 0
Treatment: Drugs
Comparator / control treatment
Placebo
Oral starch capsules, matched in appearance
dosage regimen to match intervention group
Control group
Placebo

Outcomes
Primary outcome [1] 291351 0
A between-groups difference in the severity of early Post-operative Cognitive Dysfunction (POCD) as measured by the psychomotor-attention composite score of the CogState Brief Battery, adjusted for baseline values.
Timepoint [1] 291351 0
Post Operative Day 7
Secondary outcome [1] 306568 0
A between-groups difference on the individual tasks of the CogState Brief Battery
Timepoint [1] 306568 0
Post Operative Day 7
Secondary outcome [2] 306569 0
A between-groups difference on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Timepoint [2] 306569 0
Post Operative Day 7
Secondary outcome [3] 306570 0
A between-groups difference on the Controlled Oral Word Association Test (COWAT)
Timepoint [3] 306570 0
Post Operative Day 7
Secondary outcome [4] 306571 0
A between-groups difference on Trail Making A & B tasks
Timepoint [4] 306571 0
Post Operative Day 7
Secondary outcome [5] 306572 0
A decrease in the severity of late POCD, as defined by between groups differences in scores within the neuropsychological test battery outlined above, adjusted for baseline values
Timepoint [5] 306572 0
3 months post operation
Secondary outcome [6] 306573 0
A decrease in the incidence of post-operative delirium, as measured by between groups differences in scores on the Confusion Assessment Method
Timepoint [6] 306573 0
Post Operative Days 2 and 7
Secondary outcome [7] 306574 0
A decrease in mood disturbance, as measured by between group’s differences in scores on the Hospital Anxiety and Depression Scale, adjusted for baseline values.
Timepoint [7] 306574 0
7 days and 3 months post operation
Secondary outcome [8] 306575 0
An improvement in function and quality of life, as measured by between groups differences in scores on the WHOQOL-BREF Scale
Timepoint [8] 306575 0
3 months and 12 months post operation
Secondary outcome [9] 306576 0
A between-groups difference in serum levels of Interleukin-1, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [9] 306576 0
Post operative day 2
Secondary outcome [10] 307811 0
A between-groups difference in serum levels of Tumor Necrosis Factor alpha, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [10] 307811 0
Post operative day 2
Secondary outcome [11] 307812 0
A between-groups difference in serum levels of Thiobarbituric acid reactive substances, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [11] 307812 0
Post operative day 2
Secondary outcome [12] 307813 0
A between-groups difference in serum levels of Protein Carbonyls, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [12] 307813 0
Post operative day 2
Secondary outcome [13] 307814 0
A between-groups difference in serum levels of 8-Hydroxydeoxyguanosine, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [13] 307814 0
Post operative day 2
Secondary outcome [14] 307815 0
A between-groups difference in serum levels of Glutathione, as measured by enzyme-linked immunosorbent assay (ELISA)
Timepoint [14] 307815 0
Post operative day 2
Secondary outcome [15] 314934 0
A between-groups difference in acute post surgical pain, as measured by the Numerical Rating Scale (NRS)
Timepoint [15] 314934 0
Post operative day 2 and 7
Secondary outcome [16] 314935 0
A between-groups difference in persisting post surgical pain, as measured by the Modified Brief Pain Inventory
Timepoint [16] 314935 0
3 months post operation
Secondary outcome [17] 314936 0
A between-groups difference in persisting post surgical pain, as measured by the Neuropathic Pain Questionnaire
Timepoint [17] 314936 0
12 months post operation

Eligibility
Key inclusion criteria
Patients above the age of 60 years undergoing major elective non cardiac surgery, defined as surgery expected to last at least 1 hour in duration and requiring admission to hospital.
Minimum age
60 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be ineligible to take part if they;
* Have known contraindications to NAC including allergies and concomitant nitrate therapy
* Are unable to comply with the requirements of informed consent or the study protocol
* Are already taking NAC
* Require subsequent procedures necessitating general anaesthesia prior to completion of testing procedures
* Are undergoing carotid endarterectomy, due to the high incidence of perioperative cerebrovascular accidents
* Experience major perioperative morbidity, or mortality, that precludes them from completing post-operative cognitive testing within the prescribed time frame.

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)
Recruitment

Research nurses will identify eligible participants at surgical outpatient clinics, and approach them to obtain written informed consent.

Allocation Concealment

Randomisation will be performed by contacting the holder of the allocation schedule who is at a central administration site, which will be the institution's pharmacy.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
To be randomised to either the intervention or placebo group in 1:1 fashion, stratified by age (greater or less than 80 years) and surgery type (orthopaedic or non-orthopaedic surgery), via centralised computer sequence generation.
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
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size calculations:
There is limited literature pertaining to the detection and quantification of POCD utilising the CogState Brief Battery. The few studies that are available suggest that the acute effect of POCD is likely to be small, somewhere in the region of d is equal to .2 to .4. The Pyschomotor-attention composite (detection and identification tasks) of the CogState Brief Battery has demonstrated sensitivity to differentiating between healthy controls, mild cognitive impairment (MCI), and Alzheimer's disease. MCI is the closest approximation for POCD currently available in the literature, and is comparable to POCD in the perioperative setting. Effect sizes and variance from Lim et al. (2012) suggest a a composite effect size of .96 and resultant post-operative effect size of .51. Given the likely strong correlation (r is likely to be greater than or equal to .5; Silbert et al. 2004) between pre- and post-operative scores, and with consultation with the trial statistician, a sample size of 370 participants is anticipated.


Data analysis:
Primary analyses will include analysis of covariance (ANCOVA) to examine post-surgical differences while controlling for pre-surgical scores. Cognitive outcomes, quality of life measurements, and serum levels of biomarkers will all be examined using a liner mixed effects models, and the magnitude of difference between treatment groups will be calculated at Cohen's d.
Mood and Delirium measurements will be treated as dichotomous variables, and analyzed using Chi-square tests.
Pearson's R will be used to examine correlations between biomarkers of oxidative stress and scores from the neuropsych battery.

Exploratory analyses will be conducted to examine risk factors and latent variables (such as demographics, surgery type, other distinguishing factors) that may contribute to the incidence or severity of POCD. This will be examined using a multilevel modelling approach. This approach will also be used to examine the roles of other measures of participant experience, such as delirium, quality of life, or mood dysfunction. For dichotomous outcomes (such as delirium and mood dysfunction), McNamars test can be used to compare proportions across time points.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/06/2014
Actual
29/04/2015
Date of last participant enrolment
Anticipated
25/06/2019
Actual
Date of last data collection
Anticipated
25/06/2020
Actual
Sample size
Target
370
Accrual to date
297
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 2025 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment postcode(s) [1] 7728 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 288636 0
Hospital
Name [1] 288636 0
The Geelong Hospital
Country [1] 288636 0
Australia
Funding source category [2] 291352 0
Government body
Name [2] 291352 0
CRC for Mental Health
Country [2] 291352 0
Australia
Funding source category [3] 291353 0
Charities/Societies/Foundations
Name [3] 291353 0
Sydney Parker Smith Scholarship
Country [3] 291353 0
Australia
Primary sponsor type
Hospital
Name
The Geelong Hospital
Address
Ryrie Street
Geelong
Victoria 3220
Country
Australia
Secondary sponsor category [1] 287754 0
None
Name [1] 287754 0
Address [1] 287754 0
Country [1] 287754 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290491 0
Barwon Health Human Research Ethics Committee
Ethics committee address [1] 290491 0
Ryrie Street
Geelong 3220
Victoria
Ethics committee country [1] 290491 0
Australia
Date submitted for ethics approval [1] 290491 0
01/04/2014
Approval date [1] 290491 0
16/07/2014
Ethics approval number [1] 290491 0
13/111
Ethics committee name [2] 292915 0
Deakin University Human Research Ethics Committee
Ethics committee address [2] 292915 0
Deakin University
Pigdon Road
Waurn Ponds
Victoria 3216
Ethics committee country [2] 292915 0
Australia
Date submitted for ethics approval [2] 292915 0
04/08/2014
Approval date [2] 292915 0
15/09/2014
Ethics approval number [2] 292915 0
2014-213

Summary
Brief summary
Aims:

* To examine the effectiveness of NAC in reducing POCD (primary aim)

* To investigate the effectiveness of NAC in reducing biomarkers of neuroinflammation and oxidative stress in the perioperative setting
* To examine the correlation between cognition and biomarkers
* To identify possible predictors of POCD

Hypotheses:

* The administration of NAC in a perioperative setting is more effective than placebo in reducing the severity of early POCD, as measured by performance changes on a neuropsychological battery (primary hypothesis)

* The administration of NAC in a perioperative setting is more effective than placebo in reducing the severity of long term POCD

* The administration of NAC in a perioperative setting is more effective than placebo in reducing the incidence of post operative delirium

* The administration of NAC in a perioperative setting is more effective than placebo in reducing the incidence of post operative mood disorders

* The administration of NAC in a perioperative setting is more effective than placebo in improving quality of life

* The administration of NAC in a perioperative setting is more effective than placebo in improving post surgical pain

* The administration of NAC in a perioperative setting is more effective than placebo in reducing serum levels of biomarkers of neuroinflammation and oxidative stress
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 45846 0
Dr Andrew John Marriott
Address 45846 0
Department of Anaesthesia, Perioperative Medicine and Pain Management
The Geelong Hospital
Ryrie Street
Geelong 3220
Victoria
Country 45846 0
Australia
Phone 45846 0
+613 42151916
Fax 45846 0
Email 45846 0
[email protected]
Contact person for public queries
Name 45847 0
Andrew John Marriott
Address 45847 0
Department of Anaesthesia, Perioperative Medicine and Pain Management
The Geelong Hospital
Ryrie Street
Geelong 3220
Victoria
Country 45847 0
Australia
Phone 45847 0
+613 42151916
Fax 45847 0
Email 45847 0
[email protected]
Contact person for scientific queries
Name 45848 0
Andrew John Marriott
Address 45848 0
Department of Anaesthesia, Perioperative Medicine and Pain Management
The Geelong Hospital
Ryrie Street
Geelong 3220
Victoria
Country 45848 0
Australia
Phone 45848 0
+613 42151916
Fax 45848 0
Email 45848 0
[email protected]

No information has been provided regarding IPD availability


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
SourceTitleYear of PublicationDOI
EmbaseThe Post-Anaesthesia N-acetylcysteine Cognitive Evaluation (PANACEA) trial: Study protocol for a randomised controlled trial.2016https://dx.doi.org/10.1186/S13063-016-1529-4
N.B. These documents automatically identified may not have been verified by the study sponsor.