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Trial registered on ANZCTR


Registration number
ACTRN12617001619336
Ethics application status
Approved
Date submitted
21/11/2017
Date registered
11/12/2017
Date last updated
22/11/2018
Date data sharing statement initially provided
22/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Reduction Of Chronic Post-surgical Pain with Ketamine - ROCKet Trial
Scientific title
The effect of perioperative ketamine on the risk of development of chronic post-surgical pain in patients undergoing elective or expedited surgery and anaesthesia for major orthopaedic, abdominal or non cardiac thoracic surgery.
Secondary ID [1] 293420 0
NHMRC Project Grant 1120848
Universal Trial Number (UTN)
Not applicable
Trial acronym
ROCKet Trial
Linked study record
ACTRN12614000247673

Health condition
Health condition(s) or problem(s) studied:
Chronic post-surgical pain 304072 0
Condition category
Condition code
Anaesthesiology 303408 303408 0 0
Pain management
Surgery 304802 304802 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The effect of intravenous ketamine administered prior to and for up to 72 hours following surgical incision on the incidence of chronic post-surgical pain at 12 months post-operatively.
Ketamine or placebo dosage is intravenous 0.5 mg/kg bolus, followed by 0.125 mg/kg/hr intra-operatively, then 0.125 mg/kg/hr continued for up to 72 hours post-operatively.

The initial bolus dose will be administered after induction and prior to surgical incision.
The trial infusion will be continued for 72 hours after the commencement of surgery, or until:
1. the patient no longer requires opioid analgesia (IV or oral) for acute pain management, or
2. IV access is discontinued by the treating surgical unit, or
3. the patient is deemed ready for discharge home by the treating surgical unit.
The research staff will liaise daily with the treating ward staff and acute pain service to coordinate trial solution administration with the patient care plan for each day.

Trial solution rate dose escalation: In the case of severe postoperative pain that is not responding adequately to standard postoperative analgesia (NRS or VAS pain score >5/10 with functional impairment of postoperative mobilization), the trial solution infusion rate can be doubled to 0.25 mg/kg/hr (ketamine or placebo equivalent) by the treating acute pain team. This should be reviewed daily and returned to the standard rate where pain control becomes satisfactory or if side effects which are considered possibly related to the study drug are found to be dose limiting.

Trial solution rate dose reduction: If the patient is experiencing symptoms such as hallucinations, unpleasant dreams, delirium, confusion or drowsiness which the research staff in consultation with the treating clinicians suspect may be due to ketamine administration and which are causing distress or impeding patient’s postoperative mobilisation or recovery, the trial solution can be ceased for 2 hours and re-commenced at half the rate administered previously.

Trial solution cessation: Following dose reduction of >6 hours, if there are persisting postoperative symptoms such as hallucinations, unpleasant dreams, delirium, confusion or drowsiness which the research staff in consultation with the treating clinicians suspect may be due to ketamine administration and which are causing distress or impeding patient’s postoperative mobilisation or recovery, the trial solution can be ceased

Dose escalation, reduction or cessation will be captured in the eCRF and be centrally monitored via the database. Site monitoring will occur early in the trial and allow for education of research staff.
Intervention code [1] 298638 0
Treatment: Drugs
Comparator / control treatment
0.9% sodium chloride
Control group
Placebo

Outcomes
Primary outcome [1] 302793 0
The incidence of chronic post-surgical pain (CPSP) reported by the patient at telephone follow-up structured interview and adjudicated as CPSP by the endpoint adjudication committee.
CPSP will be defined as pain reported by the patient in the area of the index surgery, experienced in the week prior to the 3 and 12 month follow up calls, which either was not present, or is different in site or nature to any pain present prior to surgery. Details of reported pain will be reviewed by three members of the EAC for blinded assessment of whether they meet the criteria for CPSP. EAC members will be clinicians practicing in the field of pain medicine with expertise in chronic pain assessment.
Timepoint [1] 302793 0
12 months post-surgery
Secondary outcome [1] 337009 0
The incidence of chronic post-surgical pain as reported by the patient at telephone follow-up structured interview and adjudicated as CPSP by the adjudication committee.
Where participants are successfully contacted, a structured interview will be conducted to determine the incidence and nature of CPSP reported by the participant. The participant will be asked if "in the last week, have you experienced pain in the area of the operation you had 3 months ago". If the participant answers "Yes", then a series of questionnaires will be asked.
Timepoint [1] 337009 0
3 months post-surgery
Secondary outcome [2] 337021 0
Severity of chronic post-surgical pain assessed using 'average' and 'worst' Numerical Rating Scale pain score in the last 24 hours, obtained from the adapted modified brief pain inventory short form (mBPI-sf).
Timepoint [2] 337021 0
3 and 12 months post-surgery
Secondary outcome [3] 337022 0
Incidence of moderate chronic post-surgical pain, defined as 'average' and 'worst' Numerical Rating Scale pain score 3-5/10 in the last 24 hours respectively, obtained from the adapted modified brief pain inventory short form (mBPI-sf).
Timepoint [3] 337022 0
3 and 12 months post-surgery
Secondary outcome [4] 337023 0
Incidence and severity of neuropathic symptoms and pain, assessed using the Neuropathic Pain Questionnaire summary score.
Timepoint [4] 337023 0
3 and 12 months
Secondary outcome [5] 337024 0
Quality of life estimates and their relationship to incidence of chronic post surgical pain assessed using the EQ-5D-3L and adapted modified brief pain inventory short form (mBPI-sf) questionnaires. The incidence will be measured by asking the participant if "in the last week, have you experienced pain in the area of the operation you had".
Timepoint [5] 337024 0
3 and 12 months post-surgery
Secondary outcome [6] 337025 0
Severity of acute post-operative pain in the first 3 days, and their relationships to pain incidence and severity. Pain will be measured by the documented patient pain scores using a numerical rating scale of 0-10.
Timepoint [6] 337025 0
3 and 12 months post-surgery
Secondary outcome [7] 337026 0
Relationship of incidence and severity of chronic post-surgical pain to duration of study drug infusion. The incidence of CPSP will be captured during the follow up call and the severity will be assessed using the mBPI-sf questionnaire. The duration of study drug will be captured in the eCRF and calculated in the database.
Timepoint [7] 337026 0
3 and 12 months
Secondary outcome [8] 337027 0
Quality of recovery from anaesthesia, assessed using the Quality of Recovery questionnaire (QoR-15)
Timepoint [8] 337027 0
Day 1 post-surgery
Secondary outcome [9] 337028 0
Length of hospital stay
Timepoint [9] 337028 0
Defined as time from surgery start to hospital discharge
Secondary outcome [10] 337029 0
Incidence of post-operative delirium in patients aged >65 years, assessed using the Montreal Cognitive Assessment (MoCA), brief cognitive screen with Confusion Assessment method (3D-CAM) and Richmond Agitation-Sedation Scale (RASS).
Timepoint [10] 337029 0
Hospital discharge
Secondary outcome [11] 337030 0
Incidence of adverse/side effects which are considered possibly related to the study drug during hospital admission for index surgery (assessed by capturing side effects and adverse events).
Side effects/reactions to study drug include agitation, delirium, confusion, hallucinations, unpleasant dreams. These will be captured in the eCRF.
Timepoint [11] 337030 0
Time of surgery to discharge
Secondary outcome [12] 337031 0
Depression after surgery, assessed using Kessler Psychological Distress Scale (K-10).
Timepoint [12] 337031 0
3 and 12 months
Secondary outcome [13] 337035 0
Perioperative and long term health expenditure measured using Medicare data
Timepoint [13] 337035 0
12 months
Secondary outcome [14] 337037 0
The relationship of incidence and severity of chronic post-surgical pain to potential predictors of chronic post-surgical pain risk, including pre-operative and early post-operative pain severity and catastrophizing, insurance status, and preoperative quality of life estimates using the EQ-5D-3L and adapted modified pain inventory short form (mBPI-sf) and Kessler Psychological distress Scale (K-10) and Pain Catastrophizing Scale (PCS).
Timepoint [14] 337037 0
3 and 12 months
Secondary outcome [15] 337038 0
The relationship of incidence of chronic post-surgical pain to postoperative quality of life estimates using the EQ-5D-3L and adapted modified pain inventory short form (mBPI-sf), post-operative Pain Catastrophizing Scale (PCS), Neuropathic Pain Questionnaire (NPQ) and Kessler Psychological Distress Scale (K-10), and perioperative and long term health expenditure.
Timepoint [15] 337038 0
3 and 12 months
Secondary outcome [16] 340850 0
Incidence of severe chronic post-surgical pain, defined as 'average' and 'worst' Numerical Rating Scale pain score >5/10 in the last 24 hours respectively, obtained from the adapted modified brief pain inventory short form (mBPI-sf).
Timepoint [16] 340850 0
3 and 12 months
Secondary outcome [17] 340851 0
Quality of life estimates and their relationship to severity of chronic post surgical pain, assessed using the EQ-5D-3L and adapted modified brief pain inventory short form (mBPI-sf) questionnaires.
Timepoint [17] 340851 0
3 and 12 months
Secondary outcome [18] 340852 0
Opioid and other analgesic consumption in the first 3 days, and their relationships to pain incidence and severity. Opioid and other analgesia medications and doses will be captured in the eCRF.
Timepoint [18] 340852 0
3 and 12 months after surgery
Secondary outcome [19] 340853 0
Adverse events in the first 3 days, and their relationships to pain incidence and severity.
Emergence reactions: hallucinations, agitation, delirium, confusion, unpleasant dreams.
These events will be captured in the Case Report Form. The participant will be reviewed daily by research staff to monitor reactions/events that may have occurred. Information will be obtained from clinical notes and discussion with the participant.
Timepoint [19] 340853 0
3 and 12 months post surgery
Secondary outcome [20] 340854 0
Psychological distress after surgery, assessed using the Pain Catastrophizing Scale (PCS).
Timepoint [20] 340854 0
3 and 12 months
Secondary outcome [21] 340855 0
The relationship of severity of chronic post-surgical pain to postoperative quality of life estimates using the EQ-5D-3L and adapted modified pain inventory short form (mBPI-sf), post-operative Pain Catastrophizing Scale (PCS), Neuropathic Pain Questionnaire (NPQ) and Kessler Psychological Distress Scale (K-10), and perioperative and long term health expenditure.
Timepoint [21] 340855 0
3 and 12 months

Eligibility
Key inclusion criteria
Patients with ASA 1-3 undergoing elective or expedited surgery and anaesthesia for abdominal surgery involving an expected skin incision at least 8cm in length and including open herniorraphy; non-cardiac thoracic surgery, including mastectomy and breast reconstruction surgery, and including all video-assisted thoracoscopic surgery; hip and knee joint arthroplasty and spinal surgery involving an expected skin incision at least 8cm; plan for postoperative opioid analgesia; planned hospital stay of at least one night post-operatively.
Minimum age
18 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients unable to provide written informed consent
Patients who are pregnant or lactating
Body mass index (BMI) over 40 kg/m2 or weight over 130kg
ASA physical status 4 or 5
Planned use of intraoperative remifentanil or intravenous lignocaine infusion
Uncontrolled hypertension (SBP >180mmHg) on admission
Poorly controlled atrial fibrillation (ventricular response rate >120/min) on admission
Uncontrolled heart failure
Intracranial surgery or raised intracranial pressure
History of haemorrhagic stroke
Severe impairment of liver function
Previous adverse reaction to ketamine
Documented complex regional pain syndrome
History of epilepsy or convulsions
History of psychosis, or of illicit drug use or known illegal activities

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)
Central randomisation via secure login to trial database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block randomisation with 1:1 allocation.
Stratification will be by site and presence of preoperative chronic pain, measured by Numerical Rating Scale (NRS) score for average pain in last 24 hours of greater than of equal to 3/10 on the adapted modified brief pain inventory short form (mBPI-sf).
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 3 / Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Based on data from the ENIGMA and ENIGMA-II trials, the pilot study, and meta-analysis, an incidence of chronic post-surgical pain (CPSP) of approximately 12% in the placebo arm is expected from a broad sample of major surgical patients. Assuming that a 25% reduction in incidence of CPSP by ketamine (i.e., a decrease from 12% to 9%, equivalent to a RR of 0.75) is considered clinically significant and using a two-sided type I error of 4.9% and a type II error of 10%, in total 4396 patients are required. A correction is applied to the type I error for including one planned interim analysis that allows stopping for efficacy early in case of an unexpected strong efficacy outcome. Allowing for a 10% lost to follow-up rate (similar to that encountered in the ENIGMA 2 follow up study), this leads to a final sample size of 4,884 in total, or 2,442 patients per treatment arm.
Analysis will be undertaken on an intention to treat basis. The analysis set will consist of all randomised patients who underwent anaesthesia for surgery, irrespective of whether trial solution was administered during surgery or not. Analysis of the efficacy outcomes will be undertaken according to their randomised treatment assignment (i.e., “as randomised”) while analysis of the safety outcomes will be “as treated”.
If the participant is randomised and surgery is cancelled and not to return for further surgery, the patient will be withdrawn from the intention to treat analysis.

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)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 12499 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 12500 0
Frankston Hospital - Frankston
Recruitment hospital [3] 12501 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 12502 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [5] 12503 0
Westmead Hospital - Westmead
Recruitment hospital [6] 12504 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [7] 12505 0
The Northern Hospital - Epping
Recruitment hospital [8] 12506 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [9] 12507 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [10] 12508 0
Goulburn Valley Health - Shepparton campus - Shepparton
Recruitment hospital [11] 12509 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 24879 0
3084 - Heidelberg
Recruitment postcode(s) [2] 24880 0
3199 - Frankston
Recruitment postcode(s) [3] 24881 0
3050 - Parkville
Recruitment postcode(s) [4] 24882 0
3220 - Geelong
Recruitment postcode(s) [5] 24883 0
2145 - Westmead
Recruitment postcode(s) [6] 24884 0
4102 - Woolloongabba
Recruitment postcode(s) [7] 24885 0
3076 - Epping
Recruitment postcode(s) [8] 24886 0
6008 - Subiaco
Recruitment postcode(s) [9] 24887 0
5000 - Adelaide
Recruitment postcode(s) [10] 24888 0
3630 - Shepparton
Recruitment postcode(s) [11] 24889 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 9065 0
New Zealand
State/province [1] 9065 0
Country [2] 9066 0
Hong Kong
State/province [2] 9066 0

Funding & Sponsors
Funding source category [1] 297025 0
Government body
Name [1] 297025 0
National Health and Medical Research Council
Address [1] 297025 0
16 Marcus Clarke Street
Canberra City ACT 2600
Country [1] 297025 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
Parkville VIC 3010
Country
Australia
Secondary sponsor category [1] 297116 0
None
Name [1] 297116 0
Address [1] 297116 0
Country [1] 297116 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298210 0
Austin Health HREC
Ethics committee address [1] 298210 0
Austin Health
145 Studley Road
Heidelberg VIC 3084
Ethics committee country [1] 298210 0
Australia
Date submitted for ethics approval [1] 298210 0
05/04/2017
Approval date [1] 298210 0
10/05/2017
Ethics approval number [1] 298210 0
HREC/17/Austin/161

Summary
Brief summary
Chronic post-surgical pain (CPSP) is among the most common and debilitating complications of major surgery, with enormous long term costs to the economy and patients’ quality of life. Primary prevention is now seen as the “Holy Grail” of anaesthesiology. There is a well established physiological and pharmacological basis for the proposition that the widely used, potent analgesic ketamine given perioperatively reduces the development of CPSP in patients undergoing major surgery, and this is supported by meta-analysis of data from small placebo controlled published studies. The potential benefits in reducing the healthcare cost and the quality of life burden of chronic pain in the community are substantial. A large clinical trial of perioperative ketamine analgesia is urgently needed in patients undergoing general anaesthesia for major surgery. Proof of effectiveness would transform routine anaesthetic practice worldwide with huge economic and humanitarian benefits.
Trial website
www.medicine.unimelb.edu.au/visit/rocket-trial
Trial related presentations / publications
Peyton PJ, Wu C, Jacobson T, Hogg M, Zia F, Leslie K. The effect of a perioperative ketamine infusion on the incidence of chronic post-surgical pain - a pilot study. Anaesthesia and Intensive Care 2017 Jul; 45(4):459-465.
Public notes

Contacts
Principal investigator
Name 76350 0
Prof Philip Peyton
Address 76350 0
Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084
Country 76350 0
Australia
Phone 76350 0
+61402282398
Fax 76350 0
Email 76350 0
phil.peyton@austin.org.au
Contact person for public queries
Name 76351 0
Prof Philip Peyton
Address 76351 0
Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084
Country 76351 0
Australia
Phone 76351 0
+61402282398
Fax 76351 0
Email 76351 0
phil.peyton@austin.org.au
Contact person for scientific queries
Name 76352 0
Prof Philip Peyton
Address 76352 0
Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084
Country 76352 0
Australia
Phone 76352 0
+61402282398
Fax 76352 0
Email 76352 0
phil.peyton@austin.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable