ANZCTR - Registration

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]

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

Postoperative Complications

Colorectal Surgery

Condition category

Condition code

Surgery

Other surgery

Oral and Gastrointestinal

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]

Prevention

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

No Control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

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

Timepoint [1]

From the date of surgery until 30 days postoperatively (in days)

Primary outcome [2]

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]

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]

Reported adverse events

Timepoint [3]

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]

Incidence of nasogastric tube re-insertion post-operatively

Timepoint [1]

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]

Incidence of vomiting

Timepoint [2]

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]

Time to first passage of flatus

Timepoint [3]

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]

Time to tolerance of solid diet

Timepoint [4]

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]

Length of hospital stay

Timepoint [5]

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]

Post-operative analgesics used

Timepoint [6]

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]

Patient-reported outcome (via surgical recovery score) will be used to assess patient functional recovery.

Timepoint [7]

At baseline before the operation, day of discharge and 30day from the day of surgery

Secondary outcome [8]

Direct hospital costs.

Timepoint [8]

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

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]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

The Royal Adelaide Hospital

Country [1]

Australia

Primary sponsor type

Hospital

Name

The Royal Adelaide Hospital

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Central Adelaide Local Health Network Human Research Ethics Committee

Ethics committee address [1]

Level 3, Roma Mitchell House
North terrace
Adelaide, South Australia, 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/03/2020

Approval date [1]

26/08/2020

Ethics approval number [1]

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

Public notes

Contacts

Principal investigator

Name

Dr Nagendra N Dudi-Venkata

Address

Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000

Country

Australia

Phone

+61 430759215

Email

[email protected]

Contact person for public queries

Name

Nagendra N Dudi-Venkata

Address

Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000

Country

Australia

Phone

+61 430759215

Email

[email protected]

Contact person for scientific queries

Name

Nagendra N Dudi-Venkata

Address

Wayfinding 5E 330 -A, Desk -1,
Colorectal Unit, Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000

Country

Australia

Phone

+61 430759215

Email

[email protected]

Trial Review

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