Article Text

Protocol
What should be measured and reported in clinical trials for the treatment of patients with acute pancreatitis? A study protocol for establishing a core outcome set
  1. Yuxin Shen1,
  2. Chen Hu1,
  3. Ling Li2,
  4. Zhiyao Chen1,
  5. Weiwei Chen3,
  6. Ziqi Lin1,
  7. Ping Zhu1,
  8. Qingyuan Tan1,
  9. Wei Huang1,
  10. Xin Sun2,
  11. Lihui Deng1,
  12. Qing Xia1
  1. 1West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
  2. 2Chinese Evidence-Based Medicine Centre, Cochrane China Centre and MAGIC China Centre, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  3. 3Department of Gastroenterology, Subei People’s Hospital, Yangzhou University, Yangzhou, Jiangsu, China
  1. Correspondence to Dr Qing Xia; xiaqing{at}medmail.com.cn; Dr Lihui Deng; denglihui{at}scu.edu.cn

Abstract

Introduction Acute pancreatitis (AP) is characterised by inflammation of the exocrine pancreas, which potentially leads to local complications and organ failure resulting in significant morbidity and mortality. A long-term follow-up by an experienced team is needed. Currently, a variety of outcome measures are used in clinical trials for patients with AP. However, due to heterogeneous and selective outcome reporting across trials of interventions, it is hard to combine or compare the trial results compromising systematic evaluations of effectiveness and safety. A core outcome set is demanded to standardise reporting for the management of AP in clinical trials, so as to conduct systematic reviews and to improve the quality of the existing evidence base on the management of AP. We designed a study to establish a core outcome set (COS) on what indicators should be measured and reported in clinical trials of patients with AP (COS-AP).

Methods and analysis This study protocol outlines the following five phases: Phase I will be a systematic review of randomised control trials and semistructured interviews with patients to initially establish a preliminary list of potential outcomes. Phase II will be the recruitment of key stakeholders’ groups comprising experts in pancreatic disease, clinical researchers, methodologists, journal editors and patients. Phase III will be two rounds of the Delphi surveys with key stakeholder groups. Phase IV will be a consensus on the outcomes that should be included in a final COS-AP. Phase V will be dissemination of COS-AP.

Ethics and dissemination Ethical approval for this study was obtained from the Biomedical Research Ethics Committee (BREC) of West China Hospital of Sichuan University (2020 No.691). The findings will be disseminated in peer-reviewed journals and meetings.

Trial registration This study was registered with Core Outcome Measures in Effectiveness Trials (COMET) database as study 2573.

  • Pancreatic disease
  • GASTROENTEROLOGY
  • Patient Reported Outcome Measures
  • Patient Participation
  • Surveys and Questionnaires
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This protocol, the first to focus on clinical outcomes of interventions applied in adult patients with AP, presents a planned approach for the development of a core outcome set (COS).

  • The study has been registered in the COMET database and will be implemented under COMET guidance.

  • This study will be supervised by a multidisciplinary advisory board of various stakeholders involving physicians, researchers, methodologists, journal editors and patients.

  • This study will clarify the outcomes that should be measured as part of COS but will not involve how the outcomes are measured, which will be carried out in the further development of the core outcome measure set for AP.

Introduction

Acute pancreatitis (AP) refers to an inflammatory disorder of the exocrine pancreas, which leads to an increasing incidence and hospitalisation.1 According to the revised Atlanta classification,2 AP is categorised as mild type in approximately 60% of patients, moderate severe in 20%–30% and severe in 5%–10%. Patients with severe AP, which is defined as persistent organ failure over 48 hours, suffer from a high mortality rate up to 50%.2 Despite the progress in basic and clinical researches in the past decades, this disease still substantially threatens patient quality of life and confers a significant socioeconomical burden.3 4

There is no specific licenced drug therapy that can change the course of the disease. According to published guidelines,5 6 initial interventions include intravenous fluid therapy, analgesia, nutritional supplementation and, when necessary, critical care and organ support, antibiotics, pancreatic exocrine and endocrine replacement therapy and endoscopic retrograde cholangiopancreatography. Accordingly, improving treatment options and prognosis for AP is a key challenge faced by researchers and clinicians.

Currently, high-quality clinical evidence for the treatment of AP remains lacking. Heterogeneous outcome measures and subjective efficacy indicators (such as ‘clinical efficacy’ or ‘total effective rate’) used in clinical trials not only lead to selective reporting bias7 but also waste research sample due to the results of similar studies cannot be combined or compared.8 A systematic review of clinical trials in AP from 1996 to 2014 identified traditional clinical outcome parameters (such as mortality, organ failure, systemic inflammatory response syndrome) and imaging-based assessments (necrotising pancreatitis, infected necrosis or acute fluid collections) partially meeting the clinical needs.9 It is suggested that the selection of study outcomes in clinical trials of AP should be determined by the proposed intervention. Traditional approaches, which focused on prevention or reduction of severe forms of illness such as persistent organ failure or mortality,9 are not optimal, particularly in trials with recruitment beyond 72 hours of admission. Outcomes of clinical trials in AP should also include the improvement in patient-reported outcomes related to pain, nutritional deficit and quality of life. However, these outcomes lack for objective golden standards. The inclusion of other severity parameters, such as C reactive protein, albumin and neutrophils, alongside severity scores might offer easier trial conduct and greater generalisability of results, but it requires validation.

To address these issues, the outcomes for clinical trials of the treatments and follow-up for AP must be standardised. A core outcome set (COS) is an agreed-upon, standardised minimum set of outcomes that should be measured and reported in all clinical trials in a specific area of health condition.7 10 Although the number of COS studies has increased in recent years, only one COS for one pathological type of AP, acute necrotising pancreatitis, could be searched in the Core Outcome Measures in Effectiveness Trials Initiative (COMET), which has not been published yet. Different from that COS on surgical intervention for acute necrotising pancreatitis, our study aims to determine a COS for pharmacological agents in AP (COS-AP) which will be measured and reported in clinical trials.

Scope

  1. Patients: adult (≥18 years old) patients with AP according to the revised Atlanta classification.2

  2. Interventions: all pharmacological agents applicable.

  3. Setting: gastroenterology department or pancreatitis Centre in large tertiary hospitals.

  4. Context of use: clinical trials.

Methods and analysis

This study has been registered in the COMET database as study 2573 (available at: https://comet-initiative.org/Studies/Details/2573). The protocol for generation of this COS is adapted from the COMET framework. This protocol of COS-AP is written following the Core Outcome Set Standardised Protocol (COS-STAP) guidelines.11 The completed checklist was added in online supplemental file 1.

Steering committee

A steering committee will consist of eight experts including two experts in pancreatic disease, two physicians, one clinical researcher, one methodologist, one COS developer and one journal editor. The steering committee is responsible for the design and quality of the study.

Design

This study will be conducted from January 2024 to December 2024 in accordance with the Core Outcome Set standards for development (COS-STAD).12 In the first step, preliminary outcomes will be generated based on a systematic review of effectiveness of clinical trials on AP and patient interviews. Second, key stakeholders’ groups comprising experts in pancreatic disease, clinical researchers, methodologists, journal editors and patients will be recruited. Third, two rounds of web-based Delphi surveys with various stakeholder groups will be conducted to prioritise the candidate outcomes. Next, a consensus meeting will be held to decide on the final COS. The final step is to disseminate COS-AP. The study flowchart is presented in figure 1.

Figure 1

Flowchart for developing a COS for AP. AP, acute pancreatitis; COS, core outcome set.

Phase I: identification of preliminary outcomes via a systemic review and semistructured interviews

Step 1: a systematic review of published studies to identify the existing knowledge

Search strategy

We plan to perform a comprehensive search of Chinese (CNKI, WanFang, VIP, CBM) and English databases (PubMed, MEDLINE, EMBASE, CENTRAL, AMED). We will also search the Chinese Clinical Trial Registry (chictr.org.cn) and Clinical Trial Registry (ClinicalTrials.gov). The retrieval period will range from 1 January 2012 to 31 June 2023. The search strategy for preliminary outcomes used for English databases is shown in online supplemental file 2.

Inclusion criteria and exclusion criteria

The adult patients with AP were diagnosed by Revised Atlanta Classification 2012.2 Study type will include randomised controlled trials (RCTs). Studies will be included with publications in Chinese or English.

The following studies will be excluded: (1) assessing the mechanisms or pharmacokinetics of interventions; (2) outcome measurement time, outcome definitions or measurement instruments cannot be extracted; (3) studies for which the full text cannot be obtained; (4) no information on ethical approval, funding or trial registration.

Data extraction

Articles retrieved from the search databases will be stored in an EndNote reference manager (V.X9.1). The reviewer (YS) will independently perform study selection and data extraction using a standardised form. The reviewer (CH) will cross-check the performance to avoid the mistake. Any disagreements will be resolved by discussion or consultation with a third investigator. Abstracts will be reviewed to determine their relevance, and full-text articles will be obtained for all studies with the potential to meet the eligibility criteria. Data extraction will include authors, year and journal of publication, research dates, region, sample size, sex, age, diagnosis, inclusion criteria, exclusion criteria, outcomes (including primary and secondary outcomes), outcome definitions, outcome measurement instruments and time points of measurement (intervention or follow-up time). Outcomes were extracted verbatim ‘word-for-word’ from the study abstract, methods or results sections of the included papers. The potential adverse events or reactions to specific interventions will be extracted and analysed. As there is no standard method for assessing the quality of outcome reporting, we will use methods described in previous researches.10 13

Step 2: semistructured patient interviews to obtain patients’ perspectives

Inclusion criteria and exclusion criteria

The adult patients who were diagnosed with AP by the revised Atlanta classification2 and signed the informed consent forms will be recruited. Those patients who had serious mental problems, communication difficulties or other factors that are not conducive to trial development will be excluded.

Sampling strategy

Based on a previous COS study involving semistructured interviews,14 we aim to recruit 30 patients. If there is a new point of view in the final interview, the sample size will be enlarged.

Recruitment process

Patients will be recruited from the inpatient and outpatient wards at the pancreatitis centre of West China Hospital, Sichuan University. Trained investigators will explain the purpose of the interview to patients. If the patients agree to participate, they will be required to sign the informed consent form and start a face-to-face conversation.

An outline of the interview content is as follows:

  1. When were you diagnosed with AP?

  2. How many episodes have you had?

  3. What troubles have you experienced after being diagnosed with AP?

  4. What degree of recovery do you hope to achieve through treatment?

  5. What are the outcomes you care about?

  6. What is the most important outcome for you?

This content will be piloted and updated as needed. The investigators will propose the questions and then assist the patients in completing the evaluation. The results of interview will be documented anonymously. The patients will also be informed that they can withdraw at any time.

Data analysis

All interviews will be transcribed verbatim, following which the transcriptions will be imported into qualitative analysis software. The framework methodology will be applied to construct thematic frameworks, develop thematic charts and interpret the results. Two investigators will cross-check each outcome, and those found to be new outcomes will be included in the outcome pool. Any discrepancies will be discussed to reach an agreement.

Step 3: merging of outcomes to form a checklist of preliminary outcomes

After completion of the systematic review and semistructured interviews, initial clinician-reported and patient-reported outcomes will be summarised and merged by two researchers. A checklist of preliminary outcomes will be formed:

  1. All outcomes will be imported into an Excel table and listed alphabetically to minimise potential bias. Composite outcomes will be extracted as individual outcomes.

  2. The duplicate outcomes will be removed.

  3. The verbatim outcomes will assign a standardised outcome term according to the definition of the outcomes to improve the consistency of naming, for instance, length of hospital stays, hospitalisation time and the number of days in hospital combined into ‘hospital stay’.15

Phase II: domain allocation and questionnaire design

According to a checklist of preliminary outcomes, items will be categorised:

  1. The integrated outcomes will be classified into different outcome domains according to the taxonomy proposed by the COMET initiative.16

  2. Subsequent discussion will be performed to determine the name of each domain.

  3. The final outcomes and attributed domains will be reviewed regarding clarity and appropriateness of outcome categorisation. The number of outcomes belonging to an outcome domain will be recorded.

  4. Finally, a survey questionnaire will be developed based on these domains. We will cooperate with a small group of representatives from both clinical and patient backgrounds to ensure each question is comprehensible to both stakeholder groups. Medical terms will be used with additional annotations in plain language or will be defined to avoid confusion by participants, especially patients without medical background.

  5. Scoring method as recommended by the COMET group for the development of COS: a 9-point Likert scale will be adopted to score candidate outcomes.17 Ratings of 1 to 3 will be considered to reflect ‘not important’, ratings of 4 to 6 will be considered to reflect ‘important but not critical’ and ratings of 7 to 9 will be considered to reflect ‘critical’.

Phase III: Delphi survey

Two rounds of Delphi surveys in electronic questionnaires will be conducted. Stakeholders will be invited to score the outcomes. The results will be used to reach a preliminary consensus on the COS for the treatment for AP.

Step 1: selection of Delphi stakeholder groups

Five stakeholder groups will be invited to participate in two rounds of the Delphi survey concerning COS-STAD: experts specialising in pancreatic disease, clinical researchers, methodologists in the field of evidence-based medicine, journal editors and patients.

Inclusion criteria for health professional stakeholders
  1. The involved stakeholders should have a bachelor’s degree or above.

  2. Clinicians should have work experience in tertiary hospitals.

  3. Clinicians should have at least 3 years of work experience.

  4. Researchers should have published at least one clinical article on AP.

Inclusion criteria for patient stakeholders
  1. Adult patients who had an episode of AP.

  2. There will be no restrictions based on sex.

  3. Patients involved should have the ability to read and write.

  4. Patients who have signed the informed consent forms.

Sampling strategy

According to previous studies, the sample size of stakeholders in the Delphi survey ranged from 12 to 174.18 We plan to initially select 100 participants, among which there are 20 stakeholders for each group. If needed, we will use the snowball sampling method to extend the sample size.

Step 2: round 1 Delphi survey

We will develop a questionnaire for core outcomes of AP according to the list of outcomes.

Implementation process

We will send an e-invitation letter to each potential stakeholder’s mailbox. In the email, we will present an overview of the study and a questionnaire, and invite them to complete the first round of Delphi survey voluntarily and anonymously at any time. All participants will be required to register with basic information, which will be generated independently based on the characteristics of each group. Given the specificity of the stakeholder of patients, if the patient has any incomprehension about the questionnaire, the researchers will answer by email or telephone. Participants must score every outcome on the Likert scale and can also add other outcomes. Participants will have 3 weeks to complete the questionnaire. The investigators will check the responses at the end of the second week and send an email to remind participants to complete the survey. If the response rate is less than 70%, the survey duration will be extended by 1 week.

Data analysis

After completing round 1 of the survey, the questionnaires will be collected by the investigators. Data analysis will include the response rates and the frequencies of the options for each outcome from each stakeholder group. The research group will review any new recommended outcomes. All saved outcomes will be presented in round 2 of Delphi survey.

Step 3: round 2 Delphi survey

In round 2 of the Delphi survey, the participants will receive their score from round 1 and the score distribution of each outcome in their own stakeholder group. If more than 10% of participants in at least one stakeholder group consider outcome to be important or critical (score ≥4), these items will be included in round 2 of the Delphi survey. If new outcomes are presented by the participants in round 1 of the Delphi survey, they will be assessed by the research experts and presented in round 2.

Implementation process

The participants who complete the outcomes in round 1 of Delphi survey will be invited to participate in the second round. Participants will be required to rescore the importance of outcomes using the same scoring criteria of round 1. If any participant’s score changes, they will be asked to provide reasons. They will have 3 weeks to complete the online survey. The investigators will check the responses at the end of the second week, and an email will be sent to remind participants to complete the survey. If the response rate is below 70%, the survey duration will be extended by 1 week.

Data analysis

Data analysis for round 2 of the Delphi survey will include response rates, the average score of each outcome, the frequencies of the response options for each outcome, the distribution of scores for each stakeholder group and the potential attrition bias. The average score of participants who complete or do not complete the two survey rounds will be used to compute the dropout bias. Changes in scores between the two rounds of Delphi surveys and the corresponding reasons will be examined. Statistically significant outcomes will be discussed at the consensus meeting. Previous COS research and COMET recommendations17 will be used to develop the consensus definition.

Phase IV: consensus meeting

In the final phase, a consensus meeting will be held to discuss and review the COS from the two rounds of the Delphi survey. Stakeholders who have completed both two rounds of the Delphi survey will be invited to participate. The overall number of attendees is expected to be 25, of which approximately 3 patients participated in the process. The consensus meeting will be held in Chengdu, China, and last 1 day. The meeting will be hosted by an experienced moderator without voting privileges.

Consensus meeting content

The investigators will report the findings from the two rounds of the Delphi survey. The ‘Consensus in’ outcomes by all stakeholder groups will be immediately included in the final COS, whereas the ‘Consensus out’ outcomes by all stakeholder groups will be excluded. Participants will vote anonymously on the ‘No consensus’ outcomes to determine whether the designation should be ‘Consensus in’ or ‘Consensus out’. If there is any conflict of view, the steering committee will resolve the results through the modified nominal group technique.19 The definitions of the consensus are shown in table 1.20 21

Table 1

Definitions of the consensus

Decisions on a final COS

We will develop a final COS-AP based on the results of the second round of the Delphi survey and meeting.

Phase V: dissemination of COS-AP

After the completion, multiple approaches will be adopted for the dissemination of COS-AP. The study will be reported according to the Core Outcome Set Standards for Reporting.22 The findings of our COS will be published in peer-reviewed journals and implemented in future guidelines and intervention trials. We will also present the findings at professional conferences in China and internationally. The participants will receive a copy of the report in the publication.

Patient and public involvement

The two rounds of Delphi surveys, the final consensus sessions and the semistructured interviews will include participation from patients and the general public.

Ethics and dissemination

Ethical approval for this study was obtained from the Biomedical Research Ethics Committee (BREC) of West China Hospital of Sichuan University (2020 No.691). The findings will be disseminated in peer-reviewed journals and at professional meetings.

Discussion

A COS is an agreed-upon, standardised minimum set of outcomes to resolve the issues on outcome reporting of published clinical studies. If researchers select the COS as the standard for outcome reporting in clinical trials, it can improve the consistency of outcome reporting, reduce the selective reporting bias and provide a higher level of evidence for clinical practice. Therefore, we aim to develop a COS for studies evaluating the treatment for AP. The COS will include the pooled outcomes for trials on the managements of AP and will also include efficacy and safety outcomes applicable in clinical trials.

Ethics statements

Patient consent for publication

References

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Footnotes

  • Contributors QX and LD contributed equally to this study as co-corresponding author. QX, LD and XS conceived the project. YS, LD and LL drafted the protocol and wrote the manuscript in English. YS, ZC, CH, WC, ZL, PZ, QT and WH contributed to the project implementation. YS, CH and QT contributed to the study of the systematic review. QX and XS revised the manuscript. QX is the principal investigator of the project. All authors have read, contributed to and approved the manuscript.

  • Funding This work was supported by the Project of Sichuan Provincial Administration of Traditional Chinese Medicine (Grant No. 2020ZD004), the National Key Research and Development Program of China (Grant No. 2020YFC2005604) and the National Natural Science Foundation of China (Grant No. 82074230). The funders have no role in the design of the study and collection, analysis and interpretation of data and in writing the manuscript.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods and analysis section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.