Condition category
Digestive System
Date applied
21/01/2020
Date assigned
23/01/2020
Last edited
16/06/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
No longer recruiting

Plain English Summary

Current plain English summary as of 10/06/2020:
Background and study aims
Acute necrotic collection (ANC) is one of the complications of acute pancreatitis, where death of pancreas cells which can develop into pus. In patients with persistent organ failure (POF), where the organ failure occurs for over 48 hours, the most severe type of pancreatitis, ANC is very common.

The current standard treatment for acute pancreatitis patients with ANC is to treat when the infection is suspected or confirmed and to postpone any invasive treatments for 4 weeks. However, the study team question if, in patients with POF, this delay may miss the opportunity to treat early infected ANC potentially leading to prolonged organ failure. The study team propose a novel early on-demand percutaneous drainage (PCD) approach using the persistent or worsening organ failure as an indication for drainage. PCD uses imaging guidance to place a needle or catheter through the skin into the ANC space to remove or drain the infected fluid.

The primary aim of this study is to assess the safety and outcomes of providing earlier PCD for patients with ANC and POF, based on the presence of persistent or worsening organ failure. This earlier approach will be compared to standard management. A secondary aim was to provide data for the design and power of a large-scale, multicenter, randomized, controlled trial

Who can participate?
Patients admitted to the center of severe acute pancreatitis (CSAP), Jinling Hospital during the study period were screened.

What does the study involve?
Patients are randomly allocated to either the early on-demand (EOD) catheter drainage group or the standard management group.

What are the possible benefits and risks of participating?
The current standard treatment for acute pancreatitis patients with ANC is to treat when the infection is suspected or confirmed and to postpone any invasive treatments for 4 weeks. However, the study team question if, in patients with POF, this delay may miss the opportunity to treat early infected ANC potentially leading to prolonged organ failure. Patients with acute necrotizing pancreatitis and early POF may benefit from earlier on-demand catheter drainage to reduce complications and duration of organ failure.

Where is the study run from?
Jinling Hospital affiliated to Nanjing University (China). Initiated by the Chinese Acute Pancreatitis Clinical Trials Group (CAPCTG).

When is the study starting and how long is it expected to run for?
From June 2016 to December 2020

Who is funding the study?
Jiangsu Province Key Research and Development Program (Social Development) Project (China)

Who is the main contact?
1. Dr Lu Ke
kkb9832@gmail.com; ctgkelu@nju.edu.cn
2. Dr Xiaowu Dong
dxw2333@163.com

Previous plain English summary:
Background and study aims
Acute necrotic collection (ANC) is one of the complications of acute pancreatitis. In patients with persistent organ failure (POF), namely, the most severe type of AP patients, ANC is very common and it is controversial that if early invasive intervention before confirming infection is beneficial in this entity. Based on the previous studies, most ANC could be well absorbed or demarcated naturally, and percutaneous drainage may lead to bacterial colonization or infection of pancreatic necrosis. So it was suggested to delay intervention in asymptomatic patients. However, considering the pathophysiology of SAP, despite the sterile nature, ANC always contains numerous enzymes and inflammatory mediators, which play important roles in the development of POF and SIRS. It is controversial whether a delayed strategy in patients showing clinical deterioration before clear signs or evidence of infection is beneficial or could even worsen the outcomes. The aim of this study is to compare the effect of organ function-directed and infection-directed intervention in patients with ANC combined with POF (more than a week).

Who can participate?
All adult patients admitted with a primary diagnosis of acute pancreatitis and persistent organ failure to the participating hospital of the Chinese Acute Pancreatitis Clinical Trials Group will be assessed for eligibility on a daily basis during their hospital stay.

What does the study involve?
Patients are randomly allocated to receive either organ function-directed or infection-directed intervention.

What are the possible benefits and risks of participating?
Participants may get some clinical benefit from the trial and some advice from doctors.

Where is the study run from?
Jinling Hospital affiliated to Nanjing University (China)

Who is funding the study?
Jiangsu Province Key Research and Development Program (Social Development) Project (China)

Who is the main contact?
1. Dr Dong Xiaowu
dxw2333@163.com
2. Dr Tong Zhihui
njzyantol@hotmail.com

Trial website

Contact information

Type

Scientific

Primary contact

Dr Lu Ke

ORCID ID

http://orcid.org/0000-0001-8093-5073

Contact details

305 Zhongshan Road East
Nanjing
210000
China
+86 (0)25-80860007
kkb9832@gmail.com

Type

Public

Additional contact

Dr Xiaowu Dong

ORCID ID

http://orcid.org/0000-0002-5717-5384

Contact details

305 Zhongshan Road East
Nanjing
210000
China
+86 (0)18512523817
dxw2333@163.com

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

2018NZKY-009-01

Study information

Scientific title

The timing and indications for drainage in acute pancreatitis patients with acute necrotic collections and persistent organ failure: a pilot randomized controlled trial comparing early on-demand drainage and standard management

Acronym

Study hypothesis

Current study hypothesis as of 10/06/2020:
For severe acute pancreatitis patients with acute necrotic collection and persistent organ failure in the early stages of disease, early on-demand percutaneous drainage could reduce mortality and major complications.

Previous study hypothesis as of 31/01/2020:
For severe acute pancreatitis patients complicated with acute necrotic collection and persistent organ failure in the early stages of disease, organ function-directed interventions may improve patient organ function and prognosis. This pilot study aimed to compare the effect of organ function-directed and infection-directed intervention.

Previous study hypothesis:
For severe acute pancreatitis patients complicated with acute necrotic collection and persistent organ failure in the early stages of disease, organ function-directed interventions may improve patient organ function and prognosis. This randomized, controlled, multi-center study aimed to compare the effect of organ function-directed and infection-directed intervention.

Ethics approval

Current ethics approval as of 10/06/2020:
Approved 16/04/2018, Clinical trial ethics committee of the Jinling Hospital (305 Zhongshan Road East, Nanjing, Jiangsu, China; +861 (0)25-80863234; wuqiong80863234@163.com), ref: 2018NZKY-009-01

Previous ethics approval:
Approved 16/04/2018, Clinical trial ethics committee of the General Hospital of the Eastern Theater (305 Zhongshan Road East, Nanjing, Jiangsu, China; +861 (0)25-80863234; wuqiong80863234@163.com), ref: 2018NZKY-009-01

Study design

Randomized controlled single-blinded pilot trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a participant information sheet

Condition

Acute pancreatitis

Intervention

Current interventions as of 16/06/2020:
All study subjects were randomized to either early on-demand (EOD) PCD group or the standard management group on Day 7 (The day of onset of abdominal pain was defined as Day 0).

Between randomization to Day 28 (intervention window, 21 days in total):
Patients who were randomized to the EOD group could receive PCD within the next 24 hours when one of the following criteria was met according to Modified Marshall Score:
1. Single or multiple organ systems failure (respiratory, renal and/or cardiovascular) unresolved for 7 days after randomization or;
2. New-onset organ failure arising after study Day 7 or;
3. Any worsening of any organ failure documented to be present on Day 7.

After placement, PCDs were audited by the investigators on a daily basis and were removed when the daily drainage volume was less than 50ml for three consecutive days and infection was not suspected or confirmed.

For the standard management group, interventions were postponed until 4 weeks after onset of abdominal pain whenever possible when infection was suspected or confirmed in line with current guidelines. PCD was also the primary choice of treatment in the standard management group

All the PCD procedures were performed by the same experienced team using 12F, 14F or 16F pig-tail catheters (UreSil, IL, US) in both groups, and the content drained from the site were cultured to determine whether it was sterile or infected. The size and numbers of drains placed was decided by the treating physicians.

Apart from timing and indication of drainage during the intervention window, all patients received standardized treatment according to the international guidelines including appropriate fluid resuscitation, early enteral nutrition, routine medical treatment like analgesics and proton-pump inhibitors if needed and organ support (e.g. mechanical ventilation, CRRT and vasoactive agent) as required. For infected pancreatic necrosis, once the diagnosis was made, all patients were managed with a step-up approach. Fine needle aspiration was not applied in this study and prophylactic antibiotics was avoided as well. Emergency surgery were indicated when active bleeding could not be controlled with arterial embolization, suspicion of bowel necrosis and gastrointestinal perforation leading to peritonitis occurred.


Previous interventions as of 31/01/2020:
Randomization will occur in a 1:1 fashion with computer-generated random numbers.

Organ function-directed group:
In addition to the standard treatment, ultrasound or CT guided percutaneous drainage would be applied once meeting one of the following conditions:
1. New-onset organ failure (no alleviation within 24 hours)
2. Unalleviated organ failure (either single or multiple, modified Marshall score ≥2) lasting for at least 7 days after randomization
3. Aggravation of organ failure from the baseline (either single or multiple) evidenced by increased modified Marshall score (no alleviation within 24 hours)

Infection-directed group:
Intervention including catheter drainage and necrosectomy would be delayed until suspicion or diagnosis of pancreatic infection and preferably after encapsulation of the necrotic collection (after 4 weeks mostly).

Previous interventions:
Randomization will occur in a 1:1 fashion for each center (sample size of each center was predefined based on its volume) with computer-generated random numbers.

Organ function-directed group:
In addition to the standard treatment, ultrasound or CT guided percutaneous drainage would be applied once meeting one of the following conditions:
1. New-onset organ failure (no alleviation within 24 hours)
2. Unalleviated organ failure (either single or multiple, modified Marshall score ≥2) lasting for at least 7 days after randomization
3. Aggravation of organ failure from the baseline (either single or multiple) evidenced by increased modified Marshall score (no alleviation within 24 hours)

Infection-directed group:
Intervention including catheter drainage and necrosectomy would be delayed until suspicion or diagnosis of pancreatic infection and preferably after encapsulation of the necrotic collection (after 4 weeks mostly).

Intervention type

Procedure/Surgery

Phase

Drug names

Primary outcome measure

Current primary outcome measure as of 16/06/2020:
Death and/or major complications within 90 days after randomization. Major complications refer to: new-onset organ failure that was not present 24h before randomization; bleeding requiring intervention; and gastrointestinal perforation or fistulas requiring intervention. THese will be assessed using medical records, the Revised Marshall Score, diagnosis based on CT, bacterial culture results, or the symptoms of the patients. Multiple events that happened in the same patient were considered as one incidence of major complications.

Previous primary outcome measure:
1. All-cause mortality in hospital according to the medical records at the time of discharge
2. Major complications, including organ failure measured using Revised Marshall Score at baseline and daily during observation, complications such as infected pancreatic necrosis, sepsis, abdominal bleeding and fistulas according to diagnosis based on CT, bacterial culture results or the symptoms of the patients

Secondary outcome measures

Current secondary outcome measures as of 16/06/2020:
1. Incidence of each of the individual components of death and the major complications listed in the primary outcome measure within 90 days after randomization
2. Incidence of infected pancreatic necrosis according to diagnosis based on CT, bacterial culture results, or the symptoms of the patient within 90 days after randomization
3. Incidence of sepsis according to SEPSIS 3.0 definition within 90 days after randomization
4. Incidence of external pancreatic fistula according to diagnosis based on CT, drainage, or the symptoms of the patient within 90 days after randomization
5. New receipt of organ support taken from the medical records at the time of discharge
6. The requirement for PCD, minimally invasive necrosectomy, open surgery, reoperation taken from the medical records at the time of discharge
7. Total number of PCD and minimally invasive necrosectomy procedures taken from the medical records at the time of discharge
8. The duration of organ failure and organ support between randomization and Day 28 (21 days in total) taken from the medical records at the time of discharge
9. Total expense taken from billing system at the time of discharge
10. Death by 180 days after randomization based on an additional follow-up

Previous secondary outcome measures:
1. Incidence and timing of infected pancreatic necrosis according to diagnosis based on CT, bacterial culture results or the symptoms of the patients
2. Incidence and timing of sepsis according to diagnosis based on CT, bacterial culture results or the symptoms of the patients
3. Incidence and timing of other common complications such as abdominal bleeding and fistulas according to diagnosis based on CT or the symptoms of the patients
4. Requirement of open surgery taken from the medical records at the time of discharge
5. ICU duration taken from the medical records at the time of discharge
6. Hospital duration taken from the medical records at the time of discharge
7. Total cost taken from billing system at the time of discharge

Overall trial start date

01/06/2016

Overall trial end date

31/12/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Current participant inclusion criteria as of 16/06/2020:
1. Symptoms and signs of acute pancreatitis based on abdominal pain suggestive of AP, serum amylase at least three times the upper limit of normal, and/or characteristic findings of AP on computed tomography
2. Admitted within 7 days from onset of abdominal pain
3. Confirmed persistent organ failure (respiratory, circulatory, renal) failure (revised Marshall score ≥ 2 points for at least 48 h) and still unresolved 7 days after onset
4. Age between 18 to 70 years old
5. Acute necrotic collection with available routes for ultrasound or CT guided percutaneous drainage

Previous participant inclusion criteria:
1. Symptoms and signs of acute pancreatitis based on abdominal pain suggestive of AP, serum amylase at least three times the upper limit of normal, and/or characteristic findings of AP on computed tomography
2. The duration of disease up to 1 week (starting with abdominal pain)
3. Confirmed persistent organ failure (respiratory, circulatory, renal) failure (revised Marshall score ≥ 2 points and the duration of up to 48 hours)
4. Age between 18 to 70 years old
5. Necrotic collection with available routes for ultrasound or CT guided percutaneous no matter sterile or infected

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

30

Total final enrolment

30

Participant exclusion criteria

Current participant exclusion criteria as of 16/06/2020:
1. Pregnancy
2. Chronic pancreatitis or pancreatic tumor-related pancreatitis
3. Percutaneous or transluminal drainage or surgery undertaken before admission
4. Previous history of cardio-pulmonary resuscitation during the present admission for AP
5. Expected to die within 48 h
6. Emergency surgery required due to active bleeding, bowel ischemia or necrosis, etc.
7. History of severe co-morbidities:
7.1. Greater than New York Heart Association class II heart failure
7.2. Active myocardial ischemia
7.3. History of cirrhosis
7.4 Chronic kidney disease with creatinine clearance <40 mL/min
7.5 Chronic obstructive pulmonary disease requiring home oxygen

Previous participant exclusion criteria:
1. Pregnant
2. Chronic pancreatitis, recurrent acute pancreatitis or pancreatic tumor-related pancreatitis
3. Percutaneous or transluminal drainage or surgery undertaken before admission
4. Previous history of cardio-pulmonary resuscitation
5. History of severe cardiovascular, respiratory, renal, hepatic, hematologic, or immunologic disease defined as:
5.1. Greater than New York Heart Association class II heart failure
5.2. Active myocardial ischemia
5.3. Cardiovascular intervention within the previous 60 days
5.4. History of cirrhosis
5.5 Chronic kidney disease with creatinine clearance< 40 mL/min
5.6 Chronic obstructive pulmonary disease with requirement for home oxygen

Recruitment start date

02/07/2018

Recruitment end date

12/08/2019

Locations

Countries of recruitment

China

Trial participating centre

Jinling Hospital affiliated to Nanjing University
305 Zhongshan Road East
Nanjing
210000
China

Sponsor information

Organisation

Jinling Hospital affiliated to Nanjing University

Sponsor details

305 Zhongshan Road East
Nanjing
210000
China
+86 (0)25-80860007
ctgkelu@nju.edu.cn

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

Jiangsu Province Key Research and Development Program (Social Development) Project (BE2016749)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Current publication and dissemination plan as of 16/06/2020:
Planned publication in a peer-reviewed journal.

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Previous publication and dissemination plan:
Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Intention to publish date

31/12/2020

Participant level data

Other

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

10/06/2020: The following changes have been made: 1. The study design has been changed from "Randomized controlled open-label pilot trial" to "Randomized controlled single-blinded pilot trial". 2. The sponsor contact details have been updated. 3. The interventions have been updated. 4. The primary outcome measure has been updated. 5. The secondary outcome measures have been updated. 6. The overall trial end date has been changed from 01/05/2020 to 31/12/2020 and the plain English summary has been updated accordingly. 7. The participant inclusion criteria have been updated. 8. The participant exclusion criteria have been updated. 9. The target number of participants and the total target enrolment have been changed from "100" to "30". 10. The publication and dissemination plan has been updated. 10/06/2020: The public title has been changed from "A comparison of different strategies for early severe acute pancreatitis" to "Early on-demand drainage versus standard management in acute necrotizing pancreatitis with early persistent organ failure". 10/06/2020: The following changes have been made: 1. The scientific title has been changed from "Infection-directed versus organ-function-directed intervention in acute necrotizing pancreatitis complicated with persistent organ failure: a pilot study" to "The timing and indications for drainage in acute pancreatitis patients with acute necrotic collections and persistent organ failure: a pilot randomized controlled trial comparing early on-demand drainage and standard management". 2. A scientific contact has been added. 3. The study hypothesis has been updated. 4. The ethics approval has been updated. 5. The plain English summary has been updated. 31/01/2020: This is a pilot study followed by the TIMING study (ISRCTN91106416). The following changes have been made: 1. The public title has been changed from "A multi-center randomized controlled study of interventions in severe acute pancreatitis patients complicated with acute necrotic collection and persistent organ failure" to "A comparison of different strategies for early severe acute pancreatitis". 2. The scientific title has been changed from "InfEction-directed Versus Organ-function-directed intervention for acute necrotic coLlection in severe acUte pancreaTitis complIcated with persistent OrgaN failure: a multi-center randomized trial (EVOLUTION trial)" to "Infection-directed versus organ-function-directed intervention in acute necrotizing pancreatitis complicated with persistent organ failure: a pilot study". 3. The acronym "EVOLUTION" has been removed. 4. The study design has been changed from "Multi-center randomized controlled open-label trial" to "Randomized controlled open-label pilot trial". 4. The intervention has been updated. 5. The study hypothesis has been updated. 6. The trial participating centre The First Affiliated Hospital of Nanchang University has been removed. 7. The trial participating centre Xiang Ya Hospital Zhongnan University has been removed. 8. The trial participating centre Sir Run Run Shaw Hospital affiliated with the Zhejiang University School of Medicine has been removed. 9. The trial participating centre Xijin Hospital of the Fourth Military Medical University has been removed. 10. The plain English summary has been updated to reflect these changes. 22/01/2020: Trial's existence confirmed by Clinical trial ethics committee of the General Hospital of the Eastern Theater.