ANZCTR - Registration

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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

25/10/2023

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]

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

Condition category

Condition code

Anaesthesiology

Pain management

Surgery

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.

1. If the trial solution is stopped or is interrupted for whatever reason by clinical staff, and upon review it is considered that the trial solution should be recommenced, this can occur.
2. Trial solution rate dose escalation: This should be reviewed at least daily, or more urgently or frequently if required, for example due to refractory severe pain or suspected side effects.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

0.9% sodium chloride

Control group

Placebo

Outcomes

Primary outcome [1]

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, nature or of greater intensity (VAS =2/10 above pre-operative pain score) than 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]

3 months post-surgery.

Secondary outcome [1]

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]

12 months post-surgery.

Secondary outcome [2]

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]

3 and 12 months post-surgery

Secondary outcome [3]

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]

3 and 12 months post-surgery

Secondary outcome [4]

Incidence and severity of neuropathic symptoms and pain, assessed using the Neuropathic Pain Questionnaire summary score.

Timepoint [4]

3 and 12 months

Secondary outcome [5]

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 that measured as the primary endpoint of the trial.

Timepoint [5]

3 and 12 months post-surgery

Secondary outcome [6]

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]

3 and 12 months post-surgery

Secondary outcome [7]

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]

3 and 12 months

Secondary outcome [8]

Quality of recovery from anaesthesia, assessed using the Quality of Recovery questionnaire (QoR-15)

Timepoint [8]

Day 1 post-surgery

Secondary outcome [9]

Length of hospital stay

Timepoint [9]

Defined as time from surgery start to hospital discharge

Secondary outcome [10]

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]

Hospital discharge

Secondary outcome [11]

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]

Time of surgery to discharge

Secondary outcome [12]

Depression after surgery, assessed using Kessler Psychological Distress Scale (K-10).

Timepoint [12]

3 and 12 months

Secondary outcome [13]

Perioperative and long term health expenditure measured using Medicare data

Timepoint [13]

12 months

Secondary outcome [14]

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]

3 and 12 months

Secondary outcome [15]

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]

3 and 12 months

Secondary outcome [16]

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]

3 and 12 months

Secondary outcome [17]

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]

3 and 12 months

Secondary outcome [18]

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]

3 and 12 months after surgery

Secondary outcome [19]

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]

3 and 12 months post surgery

Secondary outcome [20]

Psychological distress after surgery, assessed using the Pain Catastrophizing Scale (PCS).

Timepoint [20]

Psychological distress after surgery, assessed using the Pain Catastrophizing Scale (PCS) is only being measured at 12 months post-surgery.

Secondary outcome [21]

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]

3 and 12 months

Secondary outcome [22]

The incidence of chronic post-surgical discomfort 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 discomfort in the area of the operation you had 3 or 12 months ago". If the participant answers "Yes", then a series of questionnaires will be asked.

Timepoint [22]

3 and 12 months after surgery

Secondary outcome [23]

Severity of chronic post-surgical discomfort 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 [23]

3 and 12 months after surgery

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, knee and shoulder 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; expected to be alive at 12 months post index surgery.

Minimum age

18 Years

Maximum age

85 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Patients unable to provide written informed consent
Patients who are pregnant or lactating
Body mass index (BMI) over 40 kg/m2 and weight over 130kg
ASA physical status 4 or 5
Planned use of intra or postoperative continuous 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
Previously randomised to the ROCKet trial

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 blinded data collected for the planned interim analysis at n = 1,500, the observed incidence of CPSP at 3 months post-surgery was approximately 24% (95% confidence interval 22% to 27%) and the observed lost to follow-up rate at 3 months post-surgery was about 4%. Using 22% as a conservative estimate of the overall incidence of CPSP at 3-months post-surgery, the power to detect an approximate 15% or 25% reduction in incidence of CPSP at 3 months post-surgery by ketamine (i.e., a decrease from 24% to 20% or 25% to 19%, or approximate RR of 0.85 or 0.75, respectively) is 82% and 99%, respectively, with a two-sided type I error of 4.9% (based on the existing alpha-spending allowance for the interim analysis performed at n = 1,500). This assumes a final sample size of 4,000 after allowing for a conservative final lost-to-follow-up rate at 3 months post-surgery of 10% by the end of the trial.
Subsequently in June 2023, top up funding has been secured in the form of NHMRC CTCS Grant 2023989 (submitted in August 2022), which will allow recruitment to continue to achieve the original target of n = 4396 patients (plus allowance for loss to follow up of up to 10% above this target as originally forecast, total n = 4,884).
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

11/12/2017

Actual

19/12/2017

Date of last participant enrolment

Anticipated

31/10/2024

Actual

Date of last data collection

Anticipated

31/12/2026

Actual

Sample size

Target

4884

Accrual to date

4202

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [2]

Frankston Hospital - Frankston

Recruitment hospital [3]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [4]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [5]

Westmead Hospital - Westmead

Recruitment hospital [6]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [7]

The Northern Hospital - Epping

Recruitment hospital [8]

St John of God Hospital, Subiaco - Subiaco

Recruitment hospital [9]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [10]

Goulburn Valley Health - Shepparton campus - Shepparton

Recruitment hospital [11]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [12]

Ballarat Health Services (Base Hospital) - Ballarat Central

Recruitment hospital [13]

Royal Perth Hospital - Perth

Recruitment hospital [14]

Mackay Base Hospital - Mackay

Recruitment hospital [15]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [16]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [17]

Redcliffe Hospital - Redcliffe

Recruitment hospital [18]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [19]

Gosford Hospital - Gosford

Recruitment hospital [20]

Nepean Hospital - Kingswood

Recruitment hospital [21]

Box Hill Hospital - Box Hill

Recruitment hospital [22]

The Alfred - Melbourne

Recruitment hospital [23]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [24]

Monash Medical Centre - Moorabbin campus - East Bentleigh

Recruitment hospital [25]

Maroondah Hospital - Ringwood East

Recruitment hospital [26]

The Tweed Hospital - Tweed Heads

Recruitment hospital [27]

Lyell McEwin Hospital - Elizabeth Vale

Recruitment hospital [28]

Dandenong Hospital - Dandenong

Recruitment hospital [29]

Wollongong Hospital - Wollongong

Recruitment hospital [30]

John Hunter Hospital - New Lambton

Recruitment hospital [31]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [32]

Royal Darwin Hospital - Tiwi

Recruitment postcode(s) [1]

3084 - Heidelberg

Recruitment postcode(s) [2]

3199 - Frankston

Recruitment postcode(s) [3]

3050 - Parkville

Recruitment postcode(s) [4]

3220 - Geelong

Recruitment postcode(s) [5]

2145 - Westmead

Recruitment postcode(s) [6]

4102 - Woolloongabba

Recruitment postcode(s) [7]

3076 - Epping

Recruitment postcode(s) [8]

6008 - Subiaco

Recruitment postcode(s) [9]

5000 - Adelaide

Recruitment postcode(s) [10]

3630 - Shepparton

Recruitment postcode(s) [11]

2050 - Camperdown

Recruitment postcode(s) [12]

3350 - Ballarat Central

Recruitment postcode(s) [13]

6000 - Perth

Recruitment postcode(s) [14]

4740 - Mackay

Recruitment postcode(s) [15]

3000 - Melbourne

Recruitment postcode(s) [16]

3065 - Fitzroy

Recruitment postcode(s) [17]

4020 - Redcliffe

Recruitment postcode(s) [18]

6150 - Murdoch

Recruitment postcode(s) [19]

2250 - Gosford

Recruitment postcode(s) [20]

2747 - Kingswood

Recruitment postcode(s) [21]

3128 - Box Hill

Recruitment postcode(s) [22]

3004 - Melbourne

Recruitment postcode(s) [23]

3168 - Clayton

Recruitment postcode(s) [24]

3165 - East Bentleigh

Recruitment postcode(s) [25]

3135 - Ringwood East

Recruitment postcode(s) [26]

2485 - Tweed Heads

Recruitment postcode(s) [27]

5112 - Elizabeth Vale

Recruitment postcode(s) [28]

3175 - Dandenong

Recruitment postcode(s) [29]

2500 - Wollongong

Recruitment postcode(s) [30]

2305 - New Lambton

Recruitment postcode(s) [31]

6009 - Nedlands

Recruitment postcode(s) [32]

0810 - Tiwi

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Country [2]

Hong Kong

State/province [2]

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

16 Marcus Clarke Street
Canberra City ACT 2600

Country [1]

Australia

Funding source category [2]

Government body

Name [2]

Research Grants Council (Hong Kong) (14112718)

Address [2]

7/F, Shui On Centre, 6-8 Harbour Road, Wanchai, Hong Kong Special Administrative Region

Country [2]

Hong Kong

Funding source category [3]

Charities/Societies/Foundations

Name [3]

ANZCA Research Foundation

Address [3]

ANZCA, Ulimaroa, 630 St Kilda Rd, Melbourne VIC 3000

Country [3]

Australia

Funding source category [4]

Government body

Name [4]

NHMRC

Address [4]

16 Marcus Clarke Street Canberra City ACT 2600

Country [4]

Australia

Primary sponsor type

University

Name

The University of Melbourne

Address

Parkville VIC 3010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health HREC

Ethics committee address [1]

Austin Health
145 Studley Road
Heidelberg VIC 3084

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

05/04/2017

Approval date [1]

10/05/2017

Ethics approval number [1]

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.

Schug S, Peyton P. Does Perioperative Ketamine have a Role in the Prevention of Chronic Postsurgical Pain – The ROCKet Trial. Editorial. Br J Pain. 2017 Nov;11(4):166-168

Public notes

Contacts

Principal investigator

Name

Prof Philip Peyton

Address

Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61402282398

Fax

[email protected]

Contact person for public queries

Name

Philip Peyton

Address

Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61402282398

Fax

[email protected]

Contact person for scientific queries

Name

Philip Peyton

Address

Austin Health
Department of Anaesthesia
145 Studley Road
Heidelberg VIC 3084

Country

Australia

Phone

+61402282398

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Applications to access data for secondary studies or other research purposes can be forwarded to the Steering Committee for consideration.

When will data be available (start and end dates)?

From 12 months after the publication of primary trial results. No end date determined.

Available to whom?

Applications from outside investigators to access data for secondary studies or other research purposes can be forwarded to the Steering Committee for consideration.

Available for what types of analyses?

Applications to access data for secondary studies or other research purposes can be forwarded to the Steering Committee for consideration.

How or where can data be obtained?

Applications to access data for secondary studies or other research purposes can be forwarded to the Steering Committee for consideration, by contacting [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Other Details
13590	Study protocol	TBA
13591	Statistical analysis plan	TBA
13592	Informed consent form	TBA
13593	Clinical study report	TBA
13594	Ethical approval	TBA
13595	Analytic code	TBA

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.

Trial Review

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