Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001262998
Ethics application status
Approved
Date submitted
3/09/2020
Date registered
24/11/2020
Date last updated
24/11/2020
Date data sharing statement initially provided
24/11/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Pyridostigmine to reduce the duration of postoperative Ileus in patients undergoing colorectal surgery
Scientific title
PyRICo-P – Pyridostigmine to Reduce the duration of postoperative Ileus after Colorectal Surgery – a Phase II study.
Secondary ID [1] 302170 0
None
Universal Trial Number (UTN)
U1111-1257-5947
Trial acronym
PyRICo-P
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postoperative Ileus
 318824 0
Postoperative Complications
 318825 0
Colorectal Surgery 318826 0
Condition category
Condition code
Surgery 316835 316835 0 0
Other surgery
Oral and Gastrointestinal 316836 316836 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Study participants will receive standard peri-operative care as per our current Enhanced recovery protocol (ERP) but with the addition of

Name: Pyridostigmine bromide

Dose: 60 mg twice a day

Duration: From the day of surgery, six hours after the operation until the passage of stool

Mode of administration: Oral tablet

Adherence to the intervention would be monitored by routine checking of medication administration charts
Intervention code [1] 318470 0
Prevention
Intervention code [2] 318471 0
Treatment: Drugs
Comparator / control treatment
No Control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324954 0


30-day postoperative complication rate (Clavien-Dindo graded)

Timepoint [1] 324954 0
From the date of surgery until 30 days postoperatively (in days)
Primary outcome [2] 324955 0
Duration of Post-operative ileus (POI) measured using a validated composite outcome measure GI-2: the interval from surgery until the first passage of stool AND tolerance of an oral diet
Timepoint [2] 324955 0
Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and then reviewed once daily telephonically if they did not achieve their primary outcome at discharge
Primary outcome [3] 325334 0
Reported adverse events
Timepoint [3] 325334 0
From the date of surgery until 30 days postoperatively (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed by clinical assessment of participants post-surgery. Examples of adverse events - severe allergic rash due to the medication, exacerbated side-effects of the medication.
Secondary outcome [1] 386306 0
Incidence of nasogastric tube re-insertion post-operatively
Timepoint [1] 386306 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed by clinical assessment of participants post-surgery.
Secondary outcome [2] 386307 0
Incidence of vomiting
Timepoint [2] 386307 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed by clinical assessment of participants post-surgery.
Secondary outcome [3] 386308 0
Time to first passage of flatus

Timepoint [3] 386308 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed by clinical assessment of participants post-surgery.
Secondary outcome [4] 386309 0
Time to tolerance of solid diet

Timepoint [4] 386309 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed by clinical assessment of participants post-surgery.
Secondary outcome [5] 386310 0
Length of hospital stay

Timepoint [5] 386310 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed as a routine during daily ward rounds.
Secondary outcome [6] 386311 0
Post-operative analgesics used

Timepoint [6] 386311 0
From the date of surgery until discharge from hospital (in days). Patients will be reviewed twice per day from the date of surgery until discharge from hospital (in days) and this outcome would be assessed through electronic medical records.
Secondary outcome [7] 386312 0
Patient-reported outcome (via surgical recovery score) will be used to assess patient functional recovery.

Timepoint [7] 386312 0
At baseline before the operation, day of discharge and 30day from the day of surgery
Secondary outcome [8] 386313 0
Direct hospital costs.
Timepoint [8] 386313 0
From the date of surgery until discharge from hospital (in days) through data from cost-coding staff.

Eligibility
Key inclusion criteria
- Adult patients (aged 18 or older) from Central Adelaide Local Health Network catchment area

- Undergoing elective colorectal surgery (including large or small bowel resections for any indication or undergoing reversal of Hartmann's or loop-ileostomy closure or formation of a stoma

- Able to give informed consent
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

Previous adverse reaction to pyridostigmine

ASA >=4 due to the higher likelihood or morbidity and mortality, which may confound resulting data.

Active inflammatory bowel disease

Prolonged QT syndrome (greater than 0.43sec for males, 0.45 for females)

Medications that are prescribed directly for their anti-cholinergic effects (e.g. Glycopyrrolate for drooling; amitriptyline for loose bowel actions);

Asthma requiring regular medications

Ischaemic heart disease or cardiac arrhythmias within the previous 12 months

History of epilepsy

History of Parkinson’s disease

Hyperthyroidism

Peptic ulcer disease

Diagnosed pelvic disorders that may be a cause of constipation

Moderate to severe renal impairment Creatinine clearance of < 30 ml/min

CrCl ml/min = [140-age(years)] x bodyweight (kg) / R x serum creatinine (micromol/L)

R = 0.815 for males, 0.85 for females

History of bowel obstructions, strictures or history of any diseases affecting bowel transit (e.g. uncontrolled hypothyroidism, hypercalcaemia), irritable bowel syndrome (IBS), history of faecal incontinence)

Inability to give consent or participate in post-operative assessments due to dementia, cognitive impairment and/or language barrier.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
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 published data (ALCCaS Trial) which showed mean duration of POI (duration prior to first bowel motion) following elective colorectal surgery to be 4.65 days (SD 2.15). (Hewett PJ, Allardyce RA, Bagshaw PF, Frampton CM, Frizelle FA, Rieger NA, et al. Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional open surgical treatments for colon cancer: the ALCCaS trial. Ann Surg. 2008;248(5):728-38.) It was estimated that if therapeutically active, oral pyridostigmine may be reasonably expected to reduce the mean duration of POI by one day to 3.65 days. A reduction from 4.65 to 3.65 days would also represent a shift which would be clinically significant in practice. We suggest comparing the duration of ileus in our Phase II study cohort with this historical baseline ileus duration.

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 it was determined that to detect a 22% difference (which is equivalent to a reduction of a day) in duration of POI between groups with an allocation ratio of 1:1, estimated stepped rules of thumb for required pilot trial sample size per treatment arm with a NCT approach is 10 patients per treatment group. (Whitehead AL, Julious SA, Cooper CL, Campbell MJ. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat Methods Med Res. 2016;25(3):1057-73.) 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 15 patients was therefore set.


Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
17/09/2020
Date of last participant enrolment
Anticipated
5/02/2021
Actual
Date of last data collection
Anticipated
5/03/2021
Actual
Sample size
Target
15
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 17369 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 31098 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 306594 0
Hospital
Name [1] 306594 0
The Royal Adelaide Hospital
Country [1] 306594 0
Australia
Primary sponsor type
Hospital
Name
The Royal Adelaide Hospital
Address
Port Road, Adelaide 5000
South Australia, Australia
Country
Australia
Secondary sponsor category [1] 307204 0
None
Name [1] 307204 0
Address [1] 307204 0
Country [1] 307204 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306779 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 306779 0
Level 3, Roma Mitchell House
North terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 306779 0
Australia
Date submitted for ethics approval [1] 306779 0
16/03/2020
Approval date [1] 306779 0
26/08/2020
Ethics approval number [1] 306779 0
CALHN Reference Number: 13049

Summary
Brief summary
Post-operative ileus (POI) is characterized by impairment of bowel motility and is a common complication after major abdominal surgery in general, and after colorectal surgery in particular. The principal features of POI include nausea and vomiting, inability to tolerate diet, significant abdominal distension and delayed passage of flatus and stool. POI as a complication has the largest overall effect on length of postoperative hospitalization.

The purpose of this phase II trial is to determine the safety and effectiveness of oral pyridostigmine after elective colorectal surgery.

We hypothesise that, within an optimised Enhanced Recovery Protocols (ERPs) setting, giving oral pyridostigmine to patients post-operatively will result in a reduction in the duration of postoperative Ileus.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 104990 0
Dr Nagendra N Dudi-Venkata
Address 104990 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 104990 0
Australia
Phone 104990 0
+61 430759215
Fax 104990 0
Email 104990 0
[email protected]
Contact person for public queries
Name 104991 0
Dr Nagendra N Dudi-Venkata
Address 104991 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 104991 0
Australia
Phone 104991 0
+61 430759215
Fax 104991 0
Email 104991 0
[email protected]
Contact person for scientific queries
Name 104992 0
Dr Nagendra N Dudi-Venkata
Address 104992 0
Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 104992 0
Australia
Phone 104992 0
+61 430759215
Fax 104992 0
Email 104992 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.