Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000530820
Ethics application status
Approved
Date submitted
6/04/2021
Date registered
6/05/2021
Date last updated
17/09/2023
Date data sharing statement initially provided
6/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of pyridostigmine on the duration of post-operative ileus after colorectal surgery.
Scientific title
PyRICo-RCT – The effect of Pyridostigmine to Reduce the duration of post-operative Ileus after Colorectal Surgery in adults – a double-blinded Randomised Controlled Trial.
Secondary ID [1] 303879 0
Nil known
Universal Trial Number (UTN)
Trial acronym
PyRICo-RCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-operative ileus 321451 0
Post-operative complications 321454 0
Colorectal surgery 321455 0
Condition category
Condition code
Surgery 319217 319217 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study participants will be undergo standard peri-operative care as per our current enhanced recovery protocol (ERP). The ERP is standardised to the Royal Adelaide hospital, involving preoperatively educating patients, minimising the amount of bowel preparation, minimal fasting, carbohydrate and immunonutrition drinks. Intraoperatively this protocol aims for euvolemia, antibiotic prophylaxis as per guidelines, antiemetics, opioid sparing, multimodal analgesia and regional blocks where appropriate. Intraoperatively we also aim to avoid hypoxia and hypothermia along with achieving minimally invasive surgery if possible. Postoperatively oral intake, multimodal analgesia, mobilising, DVT prophylaxis, antiemetic therapy and IV therapy is guided by the protocol. In addition patients are randomised to receive either pyridostigmine or placebo.

Drug: Pyridostigmine bromide.

Dose: 60 mg twice daily.

Mode of administration: Oral tablet, blinded from patient and administrating staff by being encapsulated.

Duration: Administered from six hours following surgery, until passage of first stool.

Drug adherence: Pyridostigmine/placebo will be administered via blinded staff and recorded in the patients electronic medical records.
Intervention code [1] 320183 0
Prevention
Intervention code [2] 320184 0
Treatment: Drugs
Comparator / control treatment
The control arm will receive an oral microcrystalline cellulose placebo capsule, twice daily from 6 hours post-operatively until passage of first stool.
Control group
Placebo

Outcomes
Primary outcome [1] 327083 0
Duration of post-operative ileus (POI) measured using GI-2 composite score. This is a primary outcome calculated from the interval from surgery until first passage of stool AND tolerance of an oral diet.
Timepoint [1] 327083 0
Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and then reviewed once daily via telephone if they did not achieve their primary outcome at discharge.
Secondary outcome [1] 393709 0
Incidence of nasogastric tube re-insertion post-operatively.
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [1] 393709 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [2] 393710 0
Incidence of vomiting.
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [2] 393710 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [3] 393711 0
Time to first passage of flatus.
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [3] 393711 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [4] 393712 0
Time to first passage of stool.
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [4] 393712 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [5] 393713 0
Time to tolerance of solid diet.
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [5] 393713 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [6] 393714 0
Stool type (via Bristol stool chart).
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [6] 393714 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by clinical assessment.
Secondary outcome [7] 393715 0
Length of hospital stay.
(Obtained from audit of patient medical records)
Timepoint [7] 393715 0
From the date of surgery until discharge from hospital (in days).
Secondary outcome [8] 393716 0
Post-operative analgesics used.
(Obtained from audit of patient medical records)
Timepoint [8] 393716 0
From the date of surgery until discharge from hospital (in days). During this time, post-operative patients will be reviewed twice daily and the outcome will be determined by review of electronic medical records.
Secondary outcome [9] 393717 0
30-day post-operative complication rate (Clavien-Dindo graded).
(Obtained from twice daily clinical review and audit of patient medical records)
Timepoint [9] 393717 0
From the date of surgery, until 30 days postoperatively (in days). During this time, post-operative patients will be reviewed twice daily during hospital admission and the outcome will be determined by clinical assessment. Following discharge or day 30 of admission (whichever comes first) complications would be assessed via telephone.
Secondary outcome [10] 393718 0
Reported adverse events.
(Obtained from twice daily clinical review and audit of patient medical records and via study specific treatment questionnaire)
Timepoint [10] 393718 0
From the date of surgery, until 30 days postoperatively (in days). During this time, post-operative patients will be reviewed twice daily during hospital admission and the outcome will be determined by clinical assessment. Following discharge or day 30 of admission (whichever comes first) complications would be assessed via telephone.
Secondary outcome [11] 393719 0
Patient reported outcome (via the study specific treatment satisfaction questionnaire).
Timepoint [11] 393719 0
At baseline before the operation and day of discharge.
Secondary outcome [12] 394894 0
Direct hospital costs.
(Obtained from audit of hospital cost coding records)
Timepoint [12] 394894 0
From the date of surgery until discharge from hospital (in days) through data from cost-coding staff.

Eligibility
Key inclusion criteria
Inclusion criteria:
• Patients over 18 years of age
• Undergoing treatment from Central Adelaide Local Health Network
• Able to consent
• Undergoing elective large or small bowel resection for any indication or undergoing reversal of Hartmann’s or loop ileostomies or formation of stoma procedure will be invited to participate in this study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Under 18 years of age.
• Pregnancy
• ASA >=4 due to the higher likelihood or morbidity and mortality, which may confound resulting data.
• Residual active inflammatory bowel disease expected after surgery
• Prolonged QT syndrome (>0.43sec for males, >0.45 for females)
• Known adverse reaction to pyridostigmine
• Prescribing anticholinergic medications (e.g. Glycopyrrolate for drooling; amitriptyline for loose bowel actions);
• Asthma requiring regular medications (e.g. due to risk of exacerbation)
• Ischaemic heart disease or cardiac arrhythmias within the previous 12 months
• History of Epilepsy
• History of Parkinson’s disease
• History of Myasthenia gravis
• Uncontrolled Hyperthyroidism
• Active peptic ulcer disease
• Moderate to severe renal impairment Creatinine clearance of < 30 ml/min
• History of active disease affecting bowel transit (e.g. uncontrolled hypothyroidism, hypercalcaemia)
• Unable to give consent or participate due to dementia, cognitive impairment or language barrier.

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)
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 administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The a priori power calculation was carried out using G*Power 3.1 based on best available data (SIMULAX Trial) which showed mean duration of post-operative ileus (duration prior to first bowel motion) following elective colorectal surgery in the intervention arm 2 days (SD 1.85). (41) To be clinically significant we would expect a 1-day reduction with pyridostigmine intervention arm. Using the STIMULAX intervention arm as our control arm, we calculate a pooled Cohens d efficient or effect size was calculated at 0.54. We suggest comparing the duration of ileus in our RCT with this clinically significant reduction in POI.

Using a two-tailed independent-samples t-test for the difference between two unpaired means with an alpha-error of 0.05, beta-error of 0.2, and power of 0.8 and an effect size of 0.54 with an allocation ratio of 1:1 we calculated the need for 55 patients per treatment group. It was anticipated some participants may be excluded from analysis after administration of study medication or during the process of the study due to varied reasons and thus a recruitment target of 65 patients per arm was therefore set.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/06/2021
Actual
7/10/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
130
Accrual to date
130
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 19056 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 24300 0
St Andrew's Hospital Inc - Adelaide
Recruitment postcode(s) [1] 33606 0
5000 - Adelaide
Recruitment postcode(s) [2] 39847 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 308272 0
Hospital
Name [1] 308272 0
The Royal Adelaide Hospital
Country [1] 308272 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
30 Frome Rd, Adelaide
SOUTH AUSTRALIA, 5000 Australia
Country
Australia
Secondary sponsor category [1] 309068 0
None
Name [1] 309068 0
Address [1] 309068 0
Country [1] 309068 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308248 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 308248 0
Level 3, Roma Mitchell House
North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 308248 0
Australia
Date submitted for ethics approval [1] 308248 0
22/02/2021
Approval date [1] 308248 0
23/03/2021
Ethics approval number [1] 308248 0
2021/HRE00071

Summary
Brief summary
After abdominal surgery, the bowel can commonly be paralysed and slow to return to normal function. The resultant intolerance to food and liquids can result in severe bloating, inability to pass a bowel movement or gas, nausea, and vomiting. This complication of surgery is called post-operative ileus and is a source of discomfort for patients after surgery. In colorectal rectal surgery, this common complication results in the second most morbidity and mortality following an anastomotic leak and doubles the cost of an admission.

This study is a double blinded randomised controlled trial to determine if pyridostigmine can be included as part of an enhanced recovery protocol (ERP) to reduce the duration of post-operative ileus following colorectal surgery.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110066 0
Dr Luke Traeger
Address 110066 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide
SOUTH AUSTRALIA, 5000
Country 110066 0
Australia
Phone 110066 0
+61 8 7074 2164
Fax 110066 0
Email 110066 0
[email protected]
Contact person for public queries
Name 110067 0
Dr Luke Traeger
Address 110067 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide
SOUTH AUSTRALIA, 5000
Country 110067 0
Australia
Phone 110067 0
+61 8 7074 2164
Fax 110067 0
Email 110067 0
[email protected]
Contact person for scientific queries
Name 110068 0
Dr Luke Traeger
Address 110068 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide
SOUTH AUSTRALIA, 5000
Country 110068 0
Australia
Phone 110068 0
+61 8 7074 2164
Fax 110068 0
Email 110068 0
[email protected]

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 Supporting Document Provided



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.