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Trial registered on ANZCTR


Registration number
ACTRN12616001477415
Ethics application status
Approved
Date submitted
14/08/2016
Date registered
24/10/2016
Date last updated
5/05/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Topical Gabapentin Amitriptyline and Lignocaine (ToGA) ointment trial for post­haemorrhoidectomy analgesia
Scientific title
Compound topical Gabapentin, Amitriptyline, and Lignocaine ointment vs placebo for post­haemorrhoidectomy analgesia – a prospective double­blinded randomised controlled trial
Secondary ID [1] 289932 0
Nil known
Universal Trial Number (UTN)
U1111-1186-4627
Trial acronym
ToGA (Topical Gabapentin, Amitriptyline and Lignocaine) trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-haemorrhoidectomy pain 299906 0
Pain 299907 0
Haemorrhoid 299908 0
Condition category
Condition code
Oral and Gastrointestinal 299807 299807 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Anaesthesiology 300469 300469 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treating team or surgeon will perform initial assessment of patients with grade III or IV haemorrhoids referred from the community by their general practitioner or through the emergency department. They will then indicate the suitability of patients for a formal haemorrhoidectomy. Patients will receive a standard surgical treatment for management of grade III or IV haemorrhoids, after verbal and written informed consent performed by the consultant surgeon of the unit, or the treating surgical registrar after consultation with the on-call surgeon. On the day of surgery, patients will undergo standardised general anaesthesia by Monash Health anaesthetic unit prior to surgical procedure, along with associated standard monitoring. Patients will be placed in the lithotomy position to undergo formal Milligan-Morgan or Ferguson haemorrhoidectomy using diathermy.

Our routine immediate post-operative analgesia includes performing a bilateral pudendal nerve block. We use 20 ml of a 0.75% Ropivacaine solution for the pudendal block. This is infiltrated first superficially under the skin and then deeper along the submucosa and intramuscular spaces into all four quadrants. In the post-anaesthesia care unit (PACU), VAS (Numerical pain scoring system between 0 – 10) will be assessed by nursing staff, and recorded. Rescue opioid pro re nata will be provided.

Post-operative analgesic regimen will comprise of oral Paracetamol 1g every 6 hours, and opioid analgesia pro re nata will be provided for patients in the ward. All patients will also receive the conventional oral metronidazole 400mg thrice daily for five days, stool softeners, and smear of glyceryl trinitrate ointment thrice daily. Daily measurement of additional pro re nata opioid required will be recorded. Participants requiring opioid analgesia as inpatient, would also be discharged on oral opioid, and be required to document the number of tablets of oral opioid they require per day, in their pain diary.

A biostatistician will prepare a computer-generated randomisation schedule using random permuted blocks, in order to allocate the 166 study medications (and also study participants) to either Group A or B. The first group (A) — will receive the compound topical Gabapentin, Amitriptyline and Lignocaine ointment, and the second group (B)— will receive topical placebo ointment, made up of paraffin. The proposed topical ointment consists of: Gabapentin 6%, Amitriptyline 2%, and Lignocaine 5%. Both ointments will be produced by Department of Pharmacy, Monash Health. Both ointments will be labelled with the study number according to the randomisation allocation and dispensed by the Department of Pharmacy. Provision of labelled ointments by the pharmacy will ensure blinding of the patients and the treating team. Our ward pharmacist or member of the treating team will provide careful instructions on how to apply ointment, and monitoring of any side effects. The application of the ointment involves smearing a small amount of ointment onto patient's index finger and applying this directly onto the anus post-operative wound three times daily from day 1 post-operative for 2 weeks duration. Patients will be discharged from hospital once comfortable ambulating and showing no acute signs of urinary retention or faecal impaction as assessed by the treating team. Each patient will be provided with the Pain Diary post-op. Pain scoring will be performed and recorded by individual patients in the Pain Diary at post-operative day 1, 3, 7 and finally at 2 weeks outpatient follow-up.
Intervention code [1] 295613 0
Treatment: Drugs
Comparator / control treatment
Topical placebo ointment made up of white soft paraffin
Control group
Placebo

Outcomes
Primary outcome [1] 299283 0
The primary outcome measure will be the quality of post-haemorrhoidectomy pain control measured by using Visual Analogue Score (VAS: numerical pain scoring system between 0 to 10; 0: no pain and 10: worst imaginable), recorded in an individualised pain diary. VAS is a simple scoring system, and has been used in various studies to measure pain post-anorectal surgery. The baseline VAS score will be collected before or on the day of surgery and again at post-operative day 1,3, 7, and finally at 2 weeks outpatient follow-up.
Timepoint [1] 299283 0
Post-operative day 1,3, 7, and finally at 2 weeks outpatient follow-up.
Primary outcome [2] 299905 0
Oral morphine equivalents - outcome will be assessed by review of medical records. Early and late opioid consumption will be measured as oral morphine equivalents (OME), as OME is recommended by the Faculty of Pain Medicine, Australian New Zealand College of Anaesthetists. Early opioid within first 24 hours measured from time of admission will be used to compare with further daily OME measurement. This information will be retrieved from patient scanned medical records. Opioid consumption will be recorded as on-request IV fentanyl (mcg), oral immediate release oxycodone (mg) or intravenous morphine taken by the patients and the total converted to OME. The opioid conversions are as follows: for fentanyl, the conversion is a multiplication of a factor 0.3; for oxycodone, the conversion is a multiplication of a factor 1.5; for intravenous morphine, the conversion is a multiplication of a factor 3.
Timepoint [2] 299905 0
Post-operative day 1,3, 7, and finally at 2 weeks outpatient follow-up.
Secondary outcome [1] 326720 0
Urinary retention - which is defined as unable to void post-operatively, requiring insertion of an indwelling catheter in order to relieve discomfort.
Timepoint [1] 326720 0
7 post-operative days
Secondary outcome [2] 328476 0
Faecal impaction - which is defined as the inability to defaecate secondary to perianal pain, requiring readmission to hospital.
Timepoint [2] 328476 0
7 post-operative days

Eligibility
Key inclusion criteria
Adult patients of any sex between age 18-80 years old, with American Society of Anesthesiologists (ASA) physical status I to III, who is scheduled for elective formal haemorrhoidectomy for grade III or IV haemorrhoids under general anaesthesia.
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients with impaired decision-making ability, incapable to consent for procedure, perceived inability to complete pain diary, allergy to the Gabapentin, Amitriptyline, or Lignocaine, history of drug and alcohol abuse, opioid dependence, or do not have the capacity to weigh up potential risks and benefits of the trial will be excluded. Pregnant women, children or patients with disease states or terminal organ impairment will also be excluded from the study. Written and verbal informed consent will be obtained from all patients.

If during post-operative follow-up, patients were found to have surgical site infection, they will be excluded from the final analysis of pain control. These patients will still be included in the secondary comparative analysis between the two randomised groups.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Other design features
Phase
Type of endpoint/s
Efficacy
Statistical methods / analysis
The sample size calculation was made using Stata IC 12.1 (StataCorp, College Station, TX, USA) and using a statistical power of 90% at the 5% level of significance, a clinically significant average value of 4.3 and a standard deviation (SD) of 3.64, we calculate that 70 patients will be required in each group. To further account for possible loss of power due to non-parametric distribution and attrition, 166 patients will be required across the two treatment arms.

Group baseline characteristics will be examined for confounding factors. Continuous data will be presented as median (10th – 90th percentiles) or with mean and SD as appropriate. Categorical variables will be presented as frequency (percentage). Normally distributed data will be analysed with the Student t test. Skewed data will be analysed with the Mann-Whitney test for unpaired data. Categorical variables will be analysed using appropriate binomial or chi-square tests. Mixed-effect regression model will be used to test the difference in the rate of improvement in Visual Analogue Score between patients on the trial drug and placebo. This model can remove any possible between-patient variation, and focus on within-patient variation. Confidence intervals (CIs) will be computed throughout. All statistical analyses will be performed using Stata IC 12.1 (StataCorp, College Station, TX, USA). For all analyses, a p value < 0.05 will be considered statistically significant. An intention-to-treat analysis will be used.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/12/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
166
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6483 0
Dandenong Hospital - Dandenong
Recruitment hospital [2] 6484 0
Casey Hospital - Berwick
Recruitment postcode(s) [1] 14046 0
3175 - Dandenong
Recruitment postcode(s) [2] 14047 0
3806 - Berwick

Funding & Sponsors
Funding source category [1] 294305 0
Hospital
Name [1] 294305 0
Monash Health
Country [1] 294305 0
Australia
Primary sponsor type
Hospital
Name
Monash Health
Address
Department of Surgery
246 Clayton Road. Clayton. VIC 3168.
Country
Australia
Secondary sponsor category [1] 293145 0
None
Name [1] 293145 0
Address [1] 293145 0
Country [1] 293145 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295732 0
Monash Health Human Research Ethics Committee A (EC00382)
Ethics committee address [1] 295732 0
Research Support Services
Level 2, i Block,
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 295732 0
Australia
Date submitted for ethics approval [1] 295732 0
05/02/2016
Approval date [1] 295732 0
12/09/2016
Ethics approval number [1] 295732 0
HREC/16/MonH/14

Summary
Brief summary
Objectives: To examine the efficacy of compound topical Gabapentin, Amitriptyline, and Lignocaine ointment for the treatment of acute and intermediate pain post-haemorrhoidectomy surgery, when compared with placebo.

Design, setting, and participants: Prospective, double blinded, randomised, controlled, two-arm superiority trial conducted at a single Victorian site. Patient recruitment will be conducted between November 2016 and December 2017 of patients with grade III or IV haemorrhoids. The study will require 166 adult patients randomly allocated to have formal haemorrhoidectomy followed with either post-operative compound topical Gabapentin, Amitriptyline, and Lignocaine ointment (Group A), or placebo ointment (Group B). Patients, and treating team are blinded to group allocations.

Interventions: Both groups will be receiving formal haemorrhoidectomy under general anaesthesia, with the conventional intra­operative pudendal nerve block, and post­operative oral opioid pro re nata. Post-operatively patients will be randomised to either receive the compound topical Gabapentin, Amitriptyline, and Lignocaine ointment (Group A) or placebo ointment (Group B).

Main outcome measure: The quality of post-haemorrhoidectomy pain control by measuring Visual Analogue Score (VAS) recorded in an individualised pain diary, and also measuring the amount of additional pro re nata opioid consumption required for analgesia. Monitoring for the presence of urinary retention, or any faecal impaction will also be made, as a secondary measure of pain post-haemorrhoidectomy surgery.

Conclusion: Compound topical Gabapentin, Amitriptyline, and Lignocaine ointment is expected to produce better quality post-haemorrhoidectomy pain control, when compared with placebo ointment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 68250 0
Dr Thomas Suhardja
Address 68250 0
Dandenong Hospital
Department of Colorectal Surgery
135 David Street
Dandenong, VIC 3175
Country 68250 0
Australia
Phone 68250 0
+61 3 9554 1000
Fax 68250 0
Email 68250 0
[email protected]
Contact person for public queries
Name 68251 0
Thomas Suhardja
Address 68251 0
Dandenong Hospital
Department of Colorectal Surgery
135 David Street
Dandenong, VIC 3175
Country 68251 0
Australia
Phone 68251 0
+61 3 9554 1000
Fax 68251 0
Email 68251 0
[email protected]
Contact person for scientific queries
Name 68252 0
Thomas Suhardja
Address 68252 0
Dandenong Hospital
Department of Colorectal Surgery
135 David Street
Dandenong, VIC 3175
Country 68252 0
Australia
Phone 68252 0
+61 3 9554 1000
Fax 68252 0
Email 68252 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

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