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Trial registered on ANZCTR


Registration number
ACTRN12618001767291
Ethics application status
Approved
Date submitted
5/10/2018
Date registered
26/10/2018
Date last updated
26/10/2018
Date data sharing statement initially provided
26/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A trial to look at whether certain anaesthetic medications can affect post operative pain for women who have surgery for endometriosis
Scientific title
An investigation of the effects of different anaesthesia protocols on the incidence of pain after laparoscopic surgery for moderate to severe endometriosis: a randomized pilot study
Secondary ID [1] 296258 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PASE Trial
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
chronic pelvic pain 309928 0
endometriosis 309929 0
Condition category
Condition code
Anaesthesiology 308702 308702 0 0
Pain management
Reproductive Health and Childbirth 308703 308703 0 0
Other reproductive health and childbirth disorders
Renal and Urogenital 308728 308728 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pre-op: Pregabalin 75-150 mg orally + Paracetamol 1g orally

During Induction and Maintenance: standard anaesthetic protocol + Ketamine 0.5 mg/kg bolus at induction followed by infusion (0.2 mg/kg/hr) + Lignocaine 1.5 mg/kg bolus followed by infusion (1 mg/kg/hr)

Post-op: Pregabalin 75 mg twice per day orally for 5 days

The approximate duration of the induction/maintenance phase will differ from case to case as it mainly depends on the severity of the endometriosis encountered which will impact on the case complexity and therefore the duration. The minimum time would be expected to be around 6o minutes, and the maximum time would be approximately 150 minutes.

We will monitor drug adherence via follow up phone call by our trial nurse.

Description of full intervention protocol:

Pre-operative:
Pregabalin 75-150 mg orally (dose at discretion of anaesthetist)
Paracetamol 1g orally

Intra-operative:
Induction and Maintenance:
Ketamine 0.5 mg/kg bolus at induction followed by infusion (0.2 mg/kg/hr)
Lignocaine 1.5 mg/kg bolus followed by infusion (1 mg/kg/hr)

Post operative:
Pregabalin 75 mg twice per day orally for 5 days
Post operative nausea and vomiting will be treated using the standard King Edward Memorial Hospital Post Operative Nausea and Vomiting protocol.
Intervention code [1] 312589 0
Prevention
Comparator / control treatment
Pre-op: Placebo single dose orally

During Induction and Maintenance: standard anaesthetic protocol

Post-op: Placebo twice per day orally for 5 days

All placebos will consist of a gelatine capsule filled with corn starch.

Description of standard anaesthetic protocol:

Standardised anaesthetic protocol
All patients will receive a standardised anaesthetic regimen including the following:

Premedication:
Sedative medication if required for anxiety.
Ranitidine if required for reflux.
No analgesic premedication unless assigned to the intervention group.

Induction:
Midazolam at the discretion of the attending anaesthetist
Propofol-titrated to effect
Neuromuscular blockade-rocuronium or vecuronium at the discretion of the attending anaesthetist
Opioid: Fentanyl 1-5 mcg/kg (dose as per attending anaesthetist)

Maintenance:
Volatile anaesthesia (desflurane or sevoflurane) or propofol at the discretion of the attending anaesthetist.
Further neuromuscular blockade as per the attending anaesthetist.
NSAID: All participants will receive intra-operative parecoxib (40 mg intravenous)
Opioid: further fentanyl boluses at the discretion of the attending anaesthetist

Emergence:
Sugammadex for reversal of neuromuscular blockade (no neostigmine)

Post operative
Post operative nausea and vomiting: all participants will receive dexamethasone 4 mg and ondansetron 4 mg. For women considered at very high risk of Post Operative Nausea and Vomiting needing triple prophylaxis then a third agent may be added at the discretion of the attending anaesthetist.
All patients will receive a fentanyl Patient Controlled Intravenous Analgesia (20 mcg/ml, 20 mcg bolus, 5 minute lockout) for at least the first overnight stay post operatively. Further management will then be as per the King Edward Hospital Pain Service.
All patients will be commenced on celecoxib (200 mg twice per day) for 5 days, to commence on the morning after surgery.
Paracetamol 1g 4 times per day for 5 days
PRN Tramadol 50-100 mg 2 hrly Intravenous or orally to a maximum of 400 mg per 24 hours
Once the Patient controlled Intravenous Anagesia has been taken down, further breakthrough pain will be managed with: Buprenorphine 200-400 mcg sub lingual as required 2 hourly to a maximum of 1800 mcg/24 hours or oxycodone 5-10 mg 2 hourly to a maximum of 40 mg/24 hours

Protocol for control treatment group:
This group will receive a standardised anaesthetic and post-operative analgesia as per the above instructions, as well as the following:

Pre-operative:
Placebo
(‘Pregabalin 75-150 mg orally’)
Placebo (‘Paracetamol 1g orally’)

Intra-operative:
Nil additional

Post operative:
Placebo (‘Pregabalin 75 mg twice per day for 5 days’)
Control group
Placebo

Outcomes
Primary outcome [1] 307675 0
Visual Analogue Scale (VAS) pain scores (0-10) dysmenorrhoea, non-menstrual pain, dyspareunia, dyschezia: AT REST (Composite outcome)
Timepoint [1] 307675 0
3 and 6 months
Primary outcome [2] 307678 0
QOL assessments (EQ-5D/health scale 0-100 + SF-12) (Composite outcome)
Timepoint [2] 307678 0
3 and 6 months
Primary outcome [3] 307708 0
Visual Analogue Scale (VAS) pain scores (0-10) dysmenorrhoea, non-menstrual pain, dyspareunia, dyschezia: ON MOVEMENT (Composite outcome)
Timepoint [3] 307708 0
3 and 6 months
Secondary outcome [1] 352550 0
Post-operative analgesia requirements (medication chart review)
Timepoint [1] 352550 0
6 hours, 12 hours and 24 hours post-operatively
Secondary outcome [2] 352551 0
Post-operative sedation (Sedation score: 0 = awake, 10 = asleep)
Timepoint [2] 352551 0
In recovery - assessed at 10 minute intervals post-operatively for thirty minutes
Secondary outcome [3] 352557 0
Post-operative nausea and vomiting. (Composite outcome)
Nausea (Y/N); if yes 0-10 Nausea Scale for nausea
Vomiting (Y/N); if yes number of episodes
Timepoint [3] 352557 0
6 hours, 12 hours and 24 hours post-operatively
Secondary outcome [4] 352558 0
Discharge time - length of hospital stay assessed from day of surgery until hospital discharge (from hospital records)
Timepoint [4] 352558 0
At discharge
Secondary outcome [5] 353273 0
Visual Analogue Scale (VAS) pain scores (0-10) dysmenorrhoea, non-menstrual pain, dyspareunia, dyschezia: AT REST (Composite outcome)
Timepoint [5] 353273 0
6 hours, 12 hours, 24 hours, 6 weeks, 12 months post-operatively
Secondary outcome [6] 353274 0
QOL assessments (EQ-5D/health scale 0-100 + SF-12) (Composite outcome)
Timepoint [6] 353274 0
6 hours, 12 hours, 24 hours, 6 weeks, 12 months post-operatively
Secondary outcome [7] 353275 0
Visual Analogue Scale (VAS) pain scores (0-10) dysmenorrhoea, non-menstrual pain, dyspareunia, dyschezia: ON MOVEMENT (Composite outcome)
Timepoint [7] 353275 0
6 hours, 12 hours, 24 hours, 6 weeks, 12 months post-operatively

Eligibility
Key inclusion criteria
• Women between 18 and 40 years of age who complain of regular significant dysmenorrhea and / or pelvic pain that has persisted for more than 1 year AND
• Who have undergone a staging laparoscopy according to the AFS endometriosis score by a gynaecologist and are documented to have an American Fertility Society Score of 2 or 3.
o OR have a tertiary level pelvic ultrasound documenting an AFS of 2 or 3
• AND
• Planned surgery for treatment of endometriosis
Minimum age
18 Years
Maximum age
40 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
• Contraindication to any of the medications being used in either Group One or Group Two
• Surgical procedure other than laparoscopic treatment of endometriosis, check of tubal patency and minor hysteroscopic procedure OR
• Active or relapsing pelvic inflammatory disease OR
• Poor communication of written and spoken English for informed consent purposes
• Less than 18 or more than 40 years of age

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Investigator and patient blinded. Computer generated randomisation in blocks of 2 will be performed at the time of surgery and concealment will be achieved by a sealed opaque envelope technique. Members of the surgical team and other investigators involved with data collection will be blinded to the group allocation. As the anaesthetist will be involved with setting up and administering the study medications they will not be blinded to the group allocation, however they will not be involved with the data collection or follow up. The patients and anaesthetists will be blinded to the administration of pre-operative paracetamol and pregabalin, and post-operative pregbalin, as funding for a placebo has been sourced.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be recruited at the endoscopy clinic at King Edward Memorial Hospital. Consent and information sheets will be provided in the clinic. Patient will undergo formal informed consent when reviewed by the medical staff. Computer generated randomisation in blocks of 2 will be performed at the time of surgery and concealment will be achieved by a sealed opaque envelope technique.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
N/A
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Statistical analysis will be performed by a dedicated biostatistician with the Women’s and Infants Research Foundation. Data will be assessed for normality of distribution and analysed accordingly. Normally distributed data will be assessed with the independent t test and rank sum tests for non parametric comparisons. Proportions will be analysed using the Chi square tests or Fishers exact test as appropriate. Results will be reported as means with standard deviations for normally distributed variables, medians and interquartile ranges for non-normally distributed variables and frequency and percentages for categorical variables. A two sided p value of <0.05 will be considered statistically significant.

Recruitment
Recruitment status
Not yet 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)
WA
Recruitment hospital [1] 12107 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 24269 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 300852 0
Charities/Societies/Foundations
Name [1] 300852 0
Australasian Gynaecological Endoscopy & Surgery Society
Address [1] 300852 0
PO Box 717 Indooroopilly
QLD 4068 AUSTRALIA
Country [1] 300852 0
Australia
Primary sponsor type
Individual
Name
Jennifer Pontre
Address
King Edward Memorial Hospital, 374 Bagot Rd, Subiaco, WA 6008
Country
Australia
Secondary sponsor category [1] 300404 0
None
Name [1] 300404 0
N/A
Address [1] 300404 0
N/A
Country [1] 300404 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301627 0
King Edward hospital HREC
Ethics committee address [1] 301627 0
374 Bagot Rd, Subiaco, WA, 6008
Ethics committee country [1] 301627 0
Australia
Date submitted for ethics approval [1] 301627 0
17/04/2018
Approval date [1] 301627 0
15/06/2018
Ethics approval number [1] 301627 0
Ethics committee name [2] 301631 0
Women and Newborn Health Service Ethics Committee
Ethics committee address [2] 301631 0
374 Bagot Rd
Subiaco
WA 6008
Ethics committee country [2] 301631 0
Australia
Date submitted for ethics approval [2] 301631 0
17/04/2018
Approval date [2] 301631 0
15/06/2018
Ethics approval number [2] 301631 0
19029

Summary
Brief summary

This is a double blinded prospective randomised pilot study to investigate whether the use of a combination of analgesic medications (ketamine, lignocaine and pregabalin), when combined with conventional general anaesthesia, influences the incidence of chronic pelvic pain in women undergoing surgical management of moderate to severe endometriosis. Chronic pelvic pain (CPP) is common in women with endometriosis, and can develop despite surgical treatment of the disease. CPP is defined as the presence of non-cyclic daily pain of 6 months duration or longer that localizes to the anatomic pelvis and is severe enough to cause functional disability and require medical or surgical treatment. Endometriosis causes pain through a variety of mechanisms including direct compression/infiltration of nerves by the lesions, inflammation, and damage to pelvic nerves during surgery and may lead to changes in the central nervous system which propagate chronic pain. The medications being investigated in this study have potentially beneficial effects in preventing the central nervous system changes which may lead to chronic pelvic pain.

Patients will be recruited from the endoscopy and pre-admission clinics and the day of surgery admission unit at King Edward Memorial Hospital. They will be eligible for the study if they have an American Fertility Society Score of 2 or 3 on previous laparoscopy and are scheduled for laparoscopic treatment on endometriosis.

At recruitment patients will undergo a visual analogue scale (VAS) assessment for pain and will complete a quality of life (QOL) assessment. Patients will be randomised to either a standard care group who will be managed with a conventional general anaesthesia approach or to the intervention group, who will receive pre-medication with paracetamol and pregabalin, followed by an IV bolus and infusion of lignocaine and ketamine intra-operatively, with regular pregabalin in the post-operative period. The standard care group will receive oral placebos to replace pre-operative paracetamol and pregabalin, and post-operative pregabalin. Repeat pain scores will be recorded on day 1, and repeat pain scores and QOL scores at 6 weeks, 3 months, 6 months and 12 months post-operatively.
Trial website
N/A
Trial related presentations / publications
N/A
Public notes
N/A

Contacts
Principal investigator
Name 87582 0
A/Prof Nolan McDonnell
Address 87582 0
King Edward Memorial Hospital
374 Bagot Rd
Subiaco WA
6008
Country 87582 0
Australia
Phone 87582 0
+61 864582222
Fax 87582 0
Email 87582 0
nolan.mcdonnell@health.wa.gov.au
Contact person for public queries
Name 87583 0
Dr Jennifer Pontre
Address 87583 0
King Edward Memorial Hospital
374 Bagot Rd
Subiaco WA
6008
Country 87583 0
Australia
Phone 87583 0
+61 420576078
Fax 87583 0
Email 87583 0
jennifer.pontre@health.wa.gov.au
Contact person for scientific queries
Name 87584 0
Dr Jennifer Pontre
Address 87584 0
King Edward Memorial Hospital
374 Bagot Rd
Subiaco WA
6008
Country 87584 0
Australia
Phone 87584 0
+61 420576078
Fax 87584 0
Email 87584 0
jennifer.pontre@health.wa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This decision has not yet been made by the team. If made available, all data will be de-identified.
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable