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Trial registered on ANZCTR


Registration number
ACTRN12616000895482
Ethics application status
Approved
Date submitted
4/07/2016
Date registered
7/07/2016
Date last updated
10/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of continuous antiplatelet therapy versus temporary interruption of antiplatelet therapy on the occurrence of bleeding during colonoscopic polypectomy
Scientific title
Impact of continuous antiplatelet therapy versus temporary interruption of antiplatelet therapy on immediate and clinically significant delayed bleeding after colonoscopic polypectomy: a randomised controlled trial
Secondary ID [1] 289622 0
Nil
Universal Trial Number (UTN)
Trial acronym
EPOC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
colonic adenomas 299387 0
Condition category
Condition code
Oral and Gastrointestinal 299371 299371 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Cardiovascular 299372 299372 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Standard care arm
Temporary interruption of antiplatelet therapy (clopidogrel or prasugrel or ticagelor):
Cessation 7 days prior to colonoscopy and recommencement 2 days after colonoscopy.
If a patient is not usually on aspirin, low dose aspirin (75mg - 100mg) orally daily will be commenced to bridge the period the patient is off antiplatelet medication.
If a patient is on antiplatelet therapy plus aspirin, patient’s usual dose of aspirin is continued
If there are any concerns about temporary interruption of antiplatelet therapy, the endoscopist can liaise with cardiology/neurology to decide whether it is appropriate to temporarily interrupt antiplatelet therapy, or the patient can be excluded from the trial.

Polypectomy:
Cold snare polypectomy
Polyps less than or equal to 10mm
Up to 10 polyps during a single colonoscopy
Observe polypectomy site
If there is any bleeding observe for 2 minutes.
At the end of 2 minutes if haemostasis has not occurred, adjunctive therapy in the form of mechanical clips will be used.
If polyps larger than 10mm are encountered, management is up to the discretion of the endoscopist with options including a) piecemeal cold snare, b) endoscopic mucosal resection, c) reschedule patient.

Intervention arm
Continue antiplatelet therapy (clopidogrel or prasugrel or ticagrelor).

Polypectomy:
Cold snare polypectomy
Polyps less than or equal to 10mm
Up to 10 polyps during a single colonoscopy
Observe polypectomy site
If there is any bleeding observe for 2 minutes.
At the end of 2 minutes if haemostasis has not occurred, adjunctive therapy in the form of mechanical clips will be used.
If polyps larger than 10mm are encountered, management is up to the discretion of the endoscopist with options including a) piecemeal cold snare, b) endoscopic mucosal resection, c) reschedule patient.
Intervention code [1] 295214 0
Treatment: Other
Intervention code [2] 295232 0
Prevention
Intervention code [3] 295233 0
Treatment: Drugs
Comparator / control treatment
Standard care arm - Temporary interruption of antiplatelet therapy (clopidogrel or prasugrel or ticagelor):
* Cessation 7 days prior to colonoscopy and recommencement 2 days after colonoscopy.
* If a patient is not usually on aspirin, low dose aspirin (75mg - 100mg which will be decided at the discretion of the endoscopist) orally daily will be commenced to bridge the period the patient is off antiplatelet medication.
* If a patient is on antiplatelet therapy plus aspirin, patient’s usual dose of aspirin is continued
Intervention arm - Continue antiplatelet therapy (clopidogrel or prasugrel or ticagrelor).

Adherence will be by asking the patient about their compliance and there are fields for this information to be recorded on the case record forms.
Control group
Active

Outcomes
Primary outcome [1] 298834 0
Primary outcome
The primary aim of the study is to investigate in patients, who are already receiving antiplatelet therapy and are undergoing elective colonoscopy, whether or not “continuation of antiplatelet therapy” differs, in terms of occurrence of bleeds, to “temporary interruption of antiplatelet therapy”. A composite primary end point will be used. This will include:
* Use of rescue endoscopic clips post-polypectomy to control immediate intra-procedural bleeding
OR
* A major bleed, which must be symptomatically or clinically overt and is associated with an unplanned admission or re-admission to hospital for rectal bleeding
OR
* Bleeding that directly contributes to death

At 30 days post-procedure, a phone call will be made to the patient and all outcomes will be recorded on the case record forms.
Timepoint [1] 298834 0
30 day follow up.
Secondary outcome [1] 325372 0
Non-major bleeding defined as any sign or symptom of PR bleeding that does not fit the above criteria but does meet at least one of the following:
* Requiring medical intervention by a healthcare professional
* Leading to increased level of care
* Prompting a face to face evaluation
* PR bleeding not requiring medical attention
* Need for further intervention for bleeding such as endoscopic, surgical or radiological intervention
* Requirement for red blood cell transfusion
Timepoint [1] 325372 0
30 day follow up phone call
Secondary outcome [2] 325439 0
Transient ischaemic attack
* Brief neurological deficit caused by focal brain ischaemia; with clinical symptoms lasting for <1 hour and not for >24 hours
OR
Stroke
- Any new, focal neurologic deficit that persists for >24 hours
- Any new, focal neurologic deficit of any duration and evidence of acute infarction on CT or MRI of the brain
Timepoint [2] 325439 0
30 day follow up phone call
It should be noted that such an event would potentially be a serious adverse event and would need to be notified to the chief investigator by the principle investigator from the site involved
Secondary outcome [3] 325440 0
Myocardial infarction
* Detection of a rise and/or fall of cardiac biomarker values with at least one value above the 99th percentile of the upper reference limit with at least one of the following:
- Symptoms of ischaemia.
- New or presumed new significant ST- segment-T wave (ST-T) changes or new left bundle branch block.
- Development of pathological Q waves in the ECG.
- Imaging evidence of new loss of viable myocardium with new regional wall motion abnormality.
- Identification of an intracoronary thrombus by angiography
Timepoint [3] 325440 0
30 day follow up phone call
It should be noted that such an event would potentially be a serious adverse event and would need to be notified to the chief investigator by the principle investigator from the site involved
Secondary outcome [4] 325441 0
Stent thrombosis
* Angiographic confirmation of thrombosis in the stent or within 5mm proximal or distal to the stent, with or without occlusion, which is associated with at least one of the following:
* Acute onset of ischaemic symptoms at rest
* ECG signs of acute ischaemia
Timepoint [4] 325441 0
30 day follow up phone call
It should be noted that such an event would potentially be a serious adverse event and would need to be notified to the chief investigator by the principle investigator from the site involved

Eligibility
Key inclusion criteria
*Any patient aged >18 years scheduled for routine colonoscopy who is
* On single agent antiplatelet therapy: clopidogrel or prasugrel or ticagrelor
OR
* On dual antiplatelet agent: aspirin and clopidogrel or prasugrel or ticagrelor
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
One or more of the following criteria precludes trial eligibility
Liver cirrhosis
* Chronic renal impairment (eGFR less than or equal to 30)
* History of a bleeding diathesis
* Thrombocytopenia of any cause (Platelet count less than or equal to 90)
* Other concurrent anticoagulation/antiplatelet agents
* Percutaneous coronary intervention
- with bare metal stent within the last 30 days
- with drug eluding stent within the last 12 months
*Acute coronary syndrome within the last 90 days
* Any other concern by treating physician(s)
* Inability to provide informed consent

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)
Patients will be screened for eligibility from their referrals to the endoscopy service or identified in gastroenterology clinic and mailed the Participant Information and Consent Forms together with a letter of invitation and reply-paid envelope. Eligibility will be confirmed by a member of the research team at a follow up phone call approximately one week after patients have received the PICF. Patients who are willing to participate will be asked to return the signed PICF. On receiving the signed consent form, the research nurse will randomise participants according to a computer-generated randomisation sequence which will be placed in opaque sealed envelopes. Patients will then be notified by telephone call of their randomisation. Endoscopists will remain blinded to allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
SPSS statistical package will be used to generate a random sequence generation of numbers 1 and 2. Number 1 will be allocated to standard of care and number 2 will be allocated to continuing clopidogrel/prasugrel/tigacrelor
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?

The people administering the treatment/s

Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety
Statistical methods / analysis
1. Analysis sets
Full Analysis Set 1 (FAS1): All patients who were randomized to a treatment arm. In accordance with the intention to treat principle, these patients will be analysed according to the treatment arm to which they were randomized regardless of subsequent treatment actually received.

Full Analysis Set 2 (FAS2): The set of randomized patients, a subset of FAS1, who subsequently had a polypectomy. In accordance with the intention to treat principle, these patients will be analysed according to the treatment arm to which they were randomized.

Per-Protocol Set 1 (PPS1): The subset of patients in FAS1 who did not have a major protocol deviation. Major protocol deviations include, but are not limited to: Actual study treatment different from the treatment assigned by randomization, and, documentation that key exclusion criteria were met at the time of randomization, namely, liver cirrhosis, chronic renal impairment (eGFR less than or equal to 30), history of a bleeding diathesis, thrombocytopenia of any cause (Platelet count less than or equal to 90), other concurrent anticoagulation/antiplatelet agents, percutaneous coronary intervention with bare metal stent within the last 30 days or with drug eluding stent within the last 12 months, or, acute coronary syndrome within the last 90 days. Other major protocol deviations leading to exclusion from PPS1 will be identified and documented prior to the locking of the database for the final analysis.

Per-Protocol Set 2 (PPS2): The subset of patients in FAS2 who did not have a major protocol deviation. Major protocol deviations include, but are not limited to, those listed for PPS1. Other major protocol deviations leading to exclusion from PPS2 will be identified and documented prior to the locking of the database for the final analysis.

Safety Set 1 (SS1): All patients in FAS1 who subsequently have a colonoscopy. Randomized patients who withdraw or who are deemed lost-to-follow-up prior to their scheduled colonoscopy will be excluded from SS1.

Safety Set 2 (SS2): All patients in FAS2.

2. Primary endpoint
Occurrence of a bleed defined as (i) the use of rescue endoscopic clips post-polypectomy to control immediate intra-procedural bleeding or (ii) the occurrence of a symptomatically or clinically overt major post-polypectomy bleed. This endpoint is measurable only in randomized patients who subsequently have a polypectomy (FAS2).

3. Statistical hypothesis, model and method of analysis
We wish to compare the occurrence of bleeds with the intervention (continuous antiplatelet therapy) to the standard practice or control (temporary interruption of antiplatelet therapy, defined as cessation 7 days prior to colonoscopy and recommencement at least 2 days after colonoscopy). The proportion of patients in a treatment arm who experience a bleed will be calculated using the number in that treatment arm who are in the analysis set as the denominator. We will investigate if one treatment arm is inferior (greater occurrence of bleeds) to the other.

4. Handling of missing values, censoring and discontinuation
Patients in FAS2, the set of randomized patients who subsequently had a polypectomy, who for any reason have a missing assessment of the primary endpoint will be deemed to have met the primary endpoint (i.e. a “bleed” event).

5. Supportive analyses
Two supportive analyses of the primary endpoint are anticipated. In the first supportive analysis, the two-sided binomial test will be repeated on PPS2 (the subset of patients in FAS2 who did not have a major protocol deviation). In the second supportive analysis, limited to patients in FAS2, a logistic regression analysis of the occurrence of a bleed event will be conducted with covariates that include, but are not limited to, type (if any) of anti-coagulants, gender and age. The adjusted odds-ratio, and its associated 95% confidence interval, for a bleed event in the intervention arm versus the control arm will be reported, one-by-one for each covariate and for a best fitting model involving some or all of the nominated covariates. The set of candidate covariates will be pre-specified in a Statistical Analysis Plan (SAP) that will be finalized prior to the first interim analysis.

6. Secondary objectives, endpoints and analyses
Analyses of all binary secondary endpoints will be restricted to FAS2 and will be of two types – two-sided binomial tests and logistic regression analyses in the manner of the supportive analysis of the primary endpoint. Details will be pre-specified in the SAP.

7. Safety objectives, endpoints and analyses
Summary tables of adverse events of any grade, occurring up to 30 days post colonoscopy, will be reported by type and treatment arm for both SS1 and SS2.

8. Interim analyses
We are aiming for a target of 992 patients in FAS2 and we expect that this will require up to 2730 patients to be registered on the study and randomized (1:1) to the two treatment arms. Up to two interim analyses of the primary endpoint, occurrence of a bleed event (after polypectomy), are planned to occur when approximately one third and two thirds of the patients in the FAS2 have been randomized on the study and have had their polypectomies and associated assessments. These interim analyses will be based on the two-sided test comparing the rates of bleeding in each arm and are intended to provide a trigger for modification or stopping of the trial if one arm is evidently inferior to the other. The Lan-DeMets (O’Brien-Fleming-like) alpha-spending function will be used to set the significance level (alpha) at the time of each interim analysis. If the interim analyses occur precisely after n=331 and n=661 patients have been assessed then the respective alphas are 0.0002 and 0.0120, and, for the final analysis, a=0.0463 (in this way the cumulative alpha at the final analysis is 0.05).

9. Sample size calculation
For the primary endpoint, we conjecture that pc = 0.10 and we will test the null hypothesis that the two treatment arms have the same rates (H0: pt = pc) with a two-sided binomial test conducted at the 5% significance level (a=0.05). Under the specific alternative that one treatment arm is inferior to the other, either, pt – pc > 0.06 or pt – pc < -0.06 we require at least 980 evaluable patients (490 in each treatment arm) in order for the two-sided test to have 80% power. With provision for two interim analyses, roughly equally spaced in terms of the number of accrued and evaluable patients, we require 992 evaluable patients (496 per arm). We estimate that should the trial continue to a final analysis of 992 evaluable patients, we will need to make provision for the registration and randomization of up to 2730 patients.
If the trial does not stop early, and the null hypothesis is not rejected at the final analysis, the probability that the 90% CI for the difference in the rates lies entirely within the equivalence limits of +/- 0.055 is greater than 77% when the true rate is 0.10 in both treatment arms.

Recruitment
Recruitment status
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)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 6091 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [2] 6093 0
Footscray Hospital - Footscray
Recruitment hospital [3] 6094 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 6095 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 6096 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 6097 0
Frankston Hospital - Frankston
Recruitment hospital [7] 6098 0
Westmead Hospital - Westmead
Recruitment hospital [8] 6099 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [9] 6100 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [10] 6101 0
Queen Elizabeth II Jubilee Hospital - Coopers Plains
Recruitment hospital [11] 6102 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [12] 6103 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [13] 6104 0
The Alfred - Prahran
Recruitment hospital [14] 8327 0
Sunshine Hospital - St Albans
Recruitment hospital [15] 8328 0
Sunbury Day Hospital - Sunbury
Recruitment hospital [16] 8329 0
The Northern Hospital - Epping
Recruitment hospital [17] 8330 0
Epworth Richmond - Richmond
Recruitment hospital [18] 8331 0
The Bays Hospital - Mornington - Mornington
Recruitment hospital [19] 8332 0
Dandenong Hospital - Dandenong
Recruitment hospital [20] 8333 0
Calvary North Adelaide Hospital - North Adelaide
Recruitment hospital [21] 10878 0
Box Hill Hospital - Box Hill
Recruitment postcode(s) [1] 16395 0
3021 - St Albans
Recruitment postcode(s) [2] 16397 0
3076 - Epping
Recruitment postcode(s) [3] 16398 0
3121 - Richmond
Recruitment postcode(s) [4] 22632 0
3128 - Box Hill
Recruitment postcode(s) [5] 16400 0
3175 - Dandenong
Recruitment postcode(s) [6] 16396 0
3429 - Sunbury
Recruitment postcode(s) [7] 16399 0
3931 - Mornington
Recruitment postcode(s) [8] 16401 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 293988 0
Self funded/Unfunded
Name [1] 293988 0
None
Address [1] 293988 0
None
Country [1] 293988 0
Primary sponsor type
Hospital
Name
The Alfred
Address
55 Commercial Rd, Melbourne VIC 3004
Country
Australia
Secondary sponsor category [1] 292805 0
None
Name [1] 292805 0
None
Address [1] 292805 0
None
Country [1] 292805 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295404 0
The Alfred Ethics Committee
Ethics committee address [1] 295404 0
55 Commercial Rd, Melbourne VIC 3004
Ethics committee country [1] 295404 0
Australia
Date submitted for ethics approval [1] 295404 0
Approval date [1] 295404 0
25/05/2016
Ethics approval number [1] 295404 0
168/16

Summary
Brief summary
Colonoscopic polypectomy reduces morbidity and mortality from colorectal cancer. A proportion of patients undergoing colonoscopic polypectomy are on antiplatelet agents such as clopidogrel/prasugrel and ticagrelor. Current recommendations about peri-endoscopic management of these medications is individualized with guidelines generally recommending temporary interruption although the evidence behind this is poor. This randomized controlled trial aims to determined whether these antiplatelet agents can be continued for screening colonoscopy, mitigating the cardiovascular risk of temporary interruption of clopidogrel/prasurgrel or ticagrelor.
Trial website
Nil
Trial related presentations / publications
Nil
Public notes

Contacts
Principal investigator
Name 67178 0
A/Prof Gregor Brown
Address 67178 0
The Alfred
55 Commercial Rd, Melbourne VIC 3004
Country 67178 0
Australia
Phone 67178 0
+61 3 9076 2223
Fax 67178 0
Email 67178 0
g.brown@alfred.org.au
Contact person for public queries
Name 67179 0
Dr Shara Ket
Address 67179 0
The Alfred
55 Commercial Rd, Melbourne VIC 3004
Country 67179 0
Australia
Phone 67179 0
+61 3 99030130
Fax 67179 0
Email 67179 0
skket1@student.monash.edu
Contact person for scientific queries
Name 67180 0
Dr Shara Ket
Address 67180 0
The Alfred
55 Commercial Rd, Melbourne VIC 3004
Country 67180 0
Australia
Phone 67180 0
+61 3 99030130
Fax 67180 0
Email 67180 0
skket1@student.monash.edu

No information has been provided regarding IPD availability
Summary results
No Results