Efficacy and safety of intensive triglyceride-lowering therapy on reducing recurrence of hypertriglyceridemia-associated pancreatitis (REDUCE): protocol for a multicentre, randomised controlled trial

Abstract

Introduction

Recurrence of hypertriglyceridaemia-associated acute pancreatitis (HTG-AP) is common. Uncontrolled HTG after hospital discharge is an important risk factor for recurrence. However, the optimal triglyceride (TG) goal of lipid-lowering therapy for outpatients remains unclear. The efficacy and safety of intensive TG-lowering therapy on reducing recurrence of HTG-AP trial aims to determine whether intensive TG-lowering therapy (with a TG goal of <150 mg/dL (equal to 1.7 mmol/L)), compared with usual care (with a TG goal of <500 mg/dL (equal to 5.65 mmol/L)), can reduce recurrence in patients after a first episode of HTG-AP.

Methods and analysis

This is an investigator-initiated, multicentre, open-label, parallel, superiority, randomised, controlled trial. Adult patients who have been successfully treated and discharged from their index episode of HTG-AP will be screened for eligibility after a 4-week to 3-month run-in period in the outpatient setting, and then patients with the fasting serum TG levels ≥150 mg/dL at baseline are eligible. During the study period, a total of 256 study participants will be randomised to receive either intensive TG-lowering therapy or usual care. In the intensive TG-lowering therapy group, the goal of TG levels is lower than 150 mg/dL, which will be monitored at 1 month, 3 months, 6 months, 12 months and 18 months after randomisation. In the usual care group, the goal of TG levels is lower than 500 mg/dL according to the current guidelines. Lifestyle suggestions and TG-lowering agents are the main strategies to manage the lipid level. The primary endpoint is the incidence of recurrent episodes of HTG-AP at 18 months after randomisation.

Ethics and dissemination

This study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (No. 2023101–3). Ethics approval of each participating centre is required before initiation of enrolment. The results of this study will be published in peer-reviewed journals and reported at international conferences.

Trial registration number

ChiCTR2300073483 (Chinese Clinical Trial Registry)

Protocol version

V.4.0 (2024).

Correspondence to Dr Yin Zhu; [email protected] ; Dr Lu Ke; [email protected]

STRENGTHS AND LIMITATIONS OF THIS STUDY

• Centralised randomisation minimised selection bias by ensuring allocation concealment across all participating sites.

• The trial has a pragmatic design with the interventions in both two groups being part of common clinical treatment to ensure patient safety.

• The lack of blinding methods may introduce bias, and the efficacy of the intensive intervention may be partly impacted by patients’ compliance.

• The 18-month follow-up period limits the ability to assess clinical outcomes beyond this timeframe.

Introduction

Acute pancreatitis (AP) is a common gastrointestinal disease with diverse causes, including gallstones, alcohol consumption and hypertriglyceridaemia (HTG).¹ HTG has emerged as the third most common cause, accounting for approximately 4.7% of all cases globally with an increasing trend.^{2 3} In China, HTG has escalated to become the second leading cause of AP with an increasing trend, now accounting for over 25% of cases.^4–6 Recurrence of HTG-associated acute pancreatitis (HTG-AP) is frequent.⁷ Recurrent AP (RAP) contributes significantly to the overall disease burden by necessitating repeated hospitalisations, negatively affecting the quality of life and increasing the risk of developing chronic pancreatitis and pancreatic cancer.^8–10

Basolaterally secreted or leaked pancreatic lipase-mediated triglyceride (TG) lipolysis may play a pivotal role in the initiation and progression of HTG-AP.¹¹ The presence of HTG provides more substrate for lipase and therefore is expected to produce more toxic free fatty acid accumulation, which can cause cytotoxic injury to the pancreas and other organs.^12–17 Previous studies repeated showed that uncontrolled serum HTG post discharge is an important risk factor for recurrence.^{18 19} However, the optimal TG goal for lipid-lowering therapy post discharge is unknown, and current guidelines do not have uniform recommendations on this topic. The recommended TG levels for intervention range from 500 mg/dL (equal to 5.65 mmol/L) to 1000 mg/dL (equal to 11.3 mmol/L),^20–24 which means mild increased serum TG can be left untreated. However, there is increasing evidence indicating that even mildly to moderately elevated TG levels are associated with an increased risk of AP.^{25 26} A prospective study involving 116 550 participants over 6.7 years revealed that the adjusted HR for AP was 1.17 for every 1 mmol/L increase in TG levels.²⁵ Furthermore, elevated TG levels (≥150 mg/dL) in the outpatient setting have been identified as a risk factor for the recurrence of HTG-AP.²⁶ We have therefore framed a hypothesis that intensive TG-lowering therapy (with a TG goal of <150 mg/dL) can reduce the recurrent attacks in patients with index episode of HTG-AP. This hypothesis will be tested in a multicentre, randomised controlled trial comparing intensive TG-lowering therapy to usual care.

Methods and analysis

Study design

This REDUCE (efficacy and safety of intensive tRiglyceride-lowering thErapy on reDucing recUrrence of hypertriglyCeridemia-associated pancrEatitis) trial is an investigator-initiated, multicentre, open-label, parallel, superiority, randomised, controlled trial. The overall flowchart of the study is shown in figure 1.

Figure 1. The overall flowchart of the REDUCE study. HTG-AP, hypertriglyceridaemia-induced acute pancreatitis; REDUCE, efficacy and safety of intensive triglyceride-lowering therapy on reducing recurrence of hypertriglyceridaemia-associated pancreatitis; TG, triglyceride.

This trial protocol was written in accordance with the Standard Protocol Items: Recommendation for Intervention Trial guideline.²⁷

Study population

Adult patients who have been successfully treated and discharged following their index episode of HTG-AP will be screened for eligibility after a run-in period (lasting 4 weeks to 3 months) in the outpatient setting. The 4-week to 3-month run-in period allows observation of baseline TG levels, which reflect the postrecovery metabolic state unaffected by acute-phase fluctuations. This timeframe aligns with guidelines prioritising lifestyle interventions for initial TG management and limits the run-in period to 3 months post-discharge, thereby enhancing enrolment practicality. Patients who were referred to other hospitals seeking additional treatment were excluded. After signing informed consent (shown in online supplemental materials), study participants meeting all the eligibility criteria will be randomised.

Eligibility criteria

The inclusion criteria are:

• Patients with an index episode of HTG-AP, and HTG is the exclusive cause for AP (HTG-AP was diagnosed when patients had AP with serum TG >1000 mg/dL or a serum TG level of 500–1000 mg/dL accompanied by chylous serum absent of other causes for AP).^{28 29}

• Age ≥18 years old.

• Time from discharge to randomisation ≥4 weeks (no more than 3 months, and the day of discharge will not be counted), and patients without AP onset-related symptoms between discharge and randomisation.

• Fasting serum TG levels at baseline ≥150 mg/dL.

• Expression of good compliance and willingness to maintain current lifestyle during the study period.

The exclusion criteria are:

• Usage of any medications that may affect serum TG levels 4 weeks before randomisation.

• With active liver disease, including primary biliary cirrhosis and persistent abnormal liver function of unknown cause or active peptic ulcer.

• Pregnant or lactating women or women with a pregnancy plan within 18 months.

• History of hypothyroidism, nephrotic syndrome, Cushing's syndrome or AIDS.

• History of chronic pancreatitis or pancreatic cancer.

• History of severe cardiovascular disease and organ dysfunction, such as malignancy, heart failure, coronary heart disease, chronic obstructive pulmonary disease, liver failure or kidney failure.

• No signed informed consent.

Intervention and follow-up

Eligible participants will be randomised in a 1:1 fashion into one of the two treatment strategies.

Intensive TG-lowering therapy group

In the intensive TG-lowering therapy group, the goal of TG levels is set at below 150 mg/dL. Specifically, fasting serum TG levels will be monitored at 1 month, 3 months, 6 months, 12 months and 18 months after randomisation, and TG-lowering agents will be prescribed if fasting serum TG levels are ≥150 mg/dL and discontinued when fasting serum TG <150 mg/dL at two consecutive follow-up visits. The choice of TG-lowering agents will be at the discretion of the physician, with fibrates (such as fenofibrate or bezafibrate) being recommended as the primary choice. If a patient’s TG levels remain ≥150 mg/dL at 6 months after randomisation, supplemental therapy (such as a combination of fibrates and n-3 fatty acids or a combination of fibrates and niacin) will be suggested. Intensive TG-lowering therapy is a goal-oriented strategy, and the final decision on prescription will be influenced by patients’ compliance.

Usual care group

In the usual care group, the goal of TG levels is set at below 500 mg/dL, which is the lowest value for TG-lowering agents recommended by the current guidelines.^20–24 Specifically, TG-lowering agents will be initiated if fasting serum TG levels ≥500 mg/dL and discontinued when fasting serum TG <500 mg/dL at two consecutive follow-up visits. The choice of TG-lowering agents will also be at the discretion of the physician, with fibrates being recommended. If a patient’s TG levels remain ≥500 mg/dL at 6 months after randomisation, combination therapy will be suggested.

General outpatient management

The participants in both treatment strategies will receive health education on lifestyle at discharge and during follow-up according to the 2023 Chinese guideline for lipid management.²² Lifestyle interventions serve as the foundation for lipid management, encompassing elements such as adopting a balanced diet, incorporating moderate physical activity, managing weight, quitting smoking and limiting alcohol consumption. Participants will be encouraged to proactively make lifestyle changes according to their preferences, with an emphasis on sustaining these changes during the study period. For patients with comorbid diseases like diabetes mellitus, treatment is recommended in both treatment strategies.

Endpoints

Primary endpoint

The primary endpoint is the incidence of recurrent episodes of HTG-AP within 18 months after randomisation. In detail, the diagnosis of recurrent episodes of HTG-AP is defined as at least two episodes of AP separated by more than 1 month, with complete resolution of symptoms between each episode and without manifestations of chronic pancreatitis. When a patient relapses, if the level of TGs does not meet the diagnostic criteria for HTG-AP but there are no other causes of recurrence, this is also considered an endpoint event.

Secondary endpoints

The secondary endpoints assessed at 1 month, 3 months, 6 months, 12 months and 18 months after randomisation are as follows:

• Patient-reported outcomes measured by PAN-PROMISE score (a 7-item patient-reported scale for symptoms including pain, abdominal distension, eating difficulty, bowel movements difficulty, nausea/vomiting, thirst, and fatigue) based on an international, prospective cohort study (The details of the PAN-PROMISE score are shown in online supplemental materials)³⁰;

• Fasting serum TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels;

• Fasting serum glucose (GLU) level and the value of haemoglobin A1c;

• Weight, body mass index (BMI) and waist circumference³¹;

• The status of smoking and drinking.

The secondary endpoints about clinical outcomes assessed at 18 months after randomisation are as follows:

• The incidence of complications including stress hyperglycaemia,⁹ post-AP diabetes mellitus,⁹ abdominal obesity,³² pancreatic exocrine insufficiency³³ and chronic pancreatitis.³⁴

• Quality of life assessed by the EuroQol five-dimensional five-level health scale (EQ-5D-5L) questionnaire. (The details of the EQ-5D-5L questionnaire are shown in online supplemental materials).³⁵

• Unplanned readmission rate.³⁶

• All-cause mortality rate.

The definitions of secondary endpoints are depicted in table 1.

Table 1

The definitions of the secondary endpoints

Secondary endpoints	Definitions
Waist circumference31	The circumference of the midpoint between the lower edge of the lowest rib and the upper edge of the ilium
Stress hyperglycaemia11	HbA1c <6.5% and FPG ≥7.0 mmol/L during and/or within 3 months after diagnosis of AP
Post-acute pancreatitis diabetes mellitus11	HbA1c ≥6.5% and/or FPG ≥7.0 mmol/L 3 months after diagnosis of AP
Abdominal obesity32	Waist circumference ≥90 cm for men, and ≥85 cm for women
Pancreatic exocrine insufficiency33	Faecal elastase <200 µg/g or pancreatic enzyme supplementation for more than 3 months with related symptoms such as steatorrhoea and wasting
Chronic pancreatitis34	Meet one of the major diagnostic criteria or at least two minor diagnostic criteria. The major diagnostic criteria are: (1) definite imaging findings and (2) definite pathological findings; the minor diagnostic criteria are: (1) repeated upper abdominal pain; (2) abnormal blood amylase; (3) pancreatic exocrine insufficiency; (4) pancreatic endocrine insufficiency; (5) pathogenic mutations and (6) history of heavy drinking (an alcohol intake of ≥80 g/d for a male or 60 g/d for a female for at least 2 years, excluding other causes).
Unplanned readmission36	An admission to the inpatient unit following discharge from the index hospitalisation for persistent symptoms related to the pancreatitis episode, complications of pancreatitis or therapy or recurrent pancreatitis

AP, acute pancreatitis; FPG, fasting plasma glucose; HbA1c, haemoglobin A1c.

The primary and secondary endpoints will be assessed by site investigators using standardised criteria. As this is an open-label trial, endpoint assessors are not masked to treatment allocation. However, the primary endpoint (recurrence of HTG-AP) is an objective event defined by strict diagnostic criteria. Secondary endpoints (eg, TG levels, hospital readmissions) are also objectively measured via laboratory reports and medical records. While investigators are aware of treatment allocation, the objective nature of these endpoints reduces the risk of assessment bias.

Trial committees

This is collaborative research among the Chinese Acute Pancreatitis Clinical Trials Group, investigator-initiated by YZ from the First Affiliated Hospital of Nanchang University. A trial management committee (TMC) was established, consisting of members from each participating site. The TMC will be responsible for the day-to-day running, coordinating and management of the trial. An independent data and safety monitoring committee (IDSMC) is responsible for overseeing the safety and quality of the data. The committee is independent and has no competing interests with the research. The IDSMC will consider protocol adherence, trial withdrawal and safety monitoring and provide recommendations for the continuation of the trial. A trial steering committee is responsible for overseeing the trial and considering the commendations from the data monitoring committee.

Randomisation and blinding methods

Permuted block randomisation with variable block size (4, 6 and 8) stratified by the participating sites will be performed through the use of a central randomisation website (capctg.medbit.cn) that is secure, encrypted and password protected. Participants and investigators will not be blinded to the study. However, the trial statistician will be blinded to patient allocation.

Sample size calculation and recruitment

This study is a superiority trial, and the sample size is estimated based on findings from our previous study.³⁷ The 18-month recurrence rate was 22% in patients with HTG-AP with usual care. We estimated that a sample size of 254 participants could provide 80% power at a two-sided alpha level of 0.05 to detect a 60% reduction in recurrence considering a 10% loss to follow-up. Considering that the sample size should be a multiple of four, which is the smallest randomisation block size, we finally plan to randomise 256 patients in total (128 per group). The sample was calculated by using the PASS software (PASS V.11, NCSS software, Kaysville, Utah, USA).

To date, we have recruited nine centres as follows: First Affiliated Hospital of Nanchang University, Ganzhou People’s Hospital, Hebei General Hospital, Nanjing Jinling Hospital, Jingdezhen First People’s Hospital, Jinjiang Hospital of Traditional Chinese Medicine, Peking Union Medical College Hospital, West China Hospital and Yichun People’s Hospital. The trial will use competitive enrolment, defined as a recruitment strategy where participating centres enrol eligible participants based on their capacity (eg, patient volume, staffing, resources) without predefined quotas. Given the estimated volume of eligible cases, enrolment is projected to require 18–24 months.

Data collection and management

A Web-based electrical database (Unimed Scientific, Wuxi, China) will be used for the data collection and storage. All data will be input by the nominated investigators (one or two in each participating centre), who will be trained for data entry conducted by the leading site (First Affiliated Hospital of Nanchang University). An independent administrator from the leading site will inspect the quality of data and follow-up through the electronic data capturing system on a weekly basis, providing feedback in a timely manner to ensure the accuracy, completeness and legibility of data. To maintain patient confidentiality, all data stored in the electronic database will be de-identified. Prior to statistical analysis, all data will be securely locked. The study consists of two periods: the run-in period before randomisation and the follow-up period after randomisation. The schedule of enrolment, interventions and assessments is shown in figure 2.

Figure 2. The schedule for participants’ enrolment, interventions and assessments.

Statistical analysis

Primary analyses will be based on the modified intention-to-treat (ITT) population, and secondary supportive analyses will be done on the ITT population. Missing data will be handled by multiple imputations to evaluate the robustness of the primary endpoint analyses. The populations are defined as follows:

• ITT population: this population consists of all randomised participants.

• Modified ITT population: this population is a subset of the ITT population, excluding participants who are ineligible, have no follow-up data or withdraw consent.

• Safety population: this population consists of all randomised participants.

Continuous variables will be reported as means and SD or as median with 25^th–75^th percentile. Categorical variables will be presented as frequencies and percentages. HRs and 95% CIs will be calculated using a Cox proportional-hazards model to compare group differences. Kaplan-Meier curves will be used to compare the cumulative incidence of recurrence tested by log-rank test. The generalised equation estimation model will be employed to estimate the effect of treatment on the percentage change in lipid levels.

Predefined subgroup analysis will be conducted based on sex (male vs female), age (<40 years old vs ≥40 years old), BMI (<25.0 kg/m² vs ≥25.0 kg/m²), baseline glucose levels (fasting serum GLU <7.0 mmol/L vs fasting serum GLU ≥7.0 mmol/L or fasting serum GLU <7.0 mmol/L with hypoglycaemic therapy) or baseline TG levels (< 500 mg/dL vs ≥500 mg/dL) without adjustment for multiple comparisons. Statistical tests will be two-sided, and p values <0.05 will be deemed as significant. A detailed process for the trial analysis will be described in the statistical analysis plan.

Adverse events

Adverse events (AEs) are graded on a scale of 1–3 (mild, moderate or severe) according to the Study Data Tabulation Model of Clinical Data Interchange Standards Consortium, as any untoward medical occurrence in a patient or clinical investigation subject administered an investigational intervention and which does not necessarily have to have a causal relationship with this treatment. The causal relationship between AEs and treatment should be evaluated.

All randomised patients will be monitored and evaluated for any AEs throughout the study period via inquiries, physical examinations and other diagnostic methods as needed. Blood laboratory tests will be examined before treatment and within 6 weeks whenever there are changes in the classes or doses of TG-lowering drugs. Serious AEs must be promptly reported to the ethics committee within 24 hours.

Trial status

The REDUCE trial was registered on 12 July 2023 in the Chinese Clinical Trial Registry (ChiCTR2300073483). The first patient was randomised on 2 August 2023. As on 20 August 2024, 165 of the 256 patients have been randomised and the recruitment of patients is on schedule.

Consent and confidentiality

Informed consent signed by the patient himself is required for each participant of this study. All data stored in the electronic database are de-identified to guarantee patients’ privacy.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Ethics and dissemination

This study has been approved by the Ethics Committee of the First Affiliated Hospital of Nanchang University (No. 2023101–3). Ethics approval of each participating centre is required before initiation of enrolment. The results of this study will be published in peer-reviewed journals and reported at international conferences. All the investigators will have full access to the data after the end of the study. Anyone who wants to do a post hoc analysis needs to submit a formal writing proposal to the TMC. Only approved authors can have access to the database.

Discussion

HTG is a common cause of AP, and the risk of recurrent AP increases with elevated serum TG levels.^{3 25 38} This provides a rationale for TG-lowering therapy to prevent recurrent pancreatitis. However, the optimal TG goal for HTG-AP patients remains uncertain.^{39 40} Although a lower TG goal may correlate with reduced recurrent rates, it also exposes patients to AEs associated with TG-lowering drugs and increased financial burden. Thus, it is vital to investigate the optimal TG goal after discharge for patients with HTG-AP. The findings of the REDUCE trial will answer the clinical question: whether intensive TG-lowering therapy is superior to usual care in reducing the recurrence of HTG-AP patients with acceptable safety.

This trial is a treat-to-target trial, which is a concept used in designing therapeutic strategies, with treatment modalities oriented towards achieving a well-defined, clinically relevant end-target. The principle of treat-to-target is founded on an important management approach used against some of the most prevalent diseases like diabetes mellitus, hypertension and coronary heart disease.⁴¹ In the REDUCE trial, the chosen TG target in the intensive TG-lowering therapy group is based on available evidence. Several large cohort studies suggested that mild-to-moderate HTG is associated with a higher risk of AP.^{25 42 43} Wu et al²⁶ suggested that maintaining serum TG levels below 150 mg/dL is important for preventing recurrence. Our prospective cohort study indicated that duration of TG lowering drugs post index attack for more than 12 months decreased the cumulative incidence of recurrence by 75% compared with the treatment duration of less than 1 month.³⁷ These findings are promising and have motivated us to initiate the multicentre, randomised controlled trial to gather more robust clinical evidence.

One important limitation of the REDUCE trial is the exclusion of patients with alcoholic pancreatitis, which may limit generalisability to individuals with mixed-aetiology populations. Second, the variable run-in period (4 weeks–3 months) may introduce bias in baseline TG levels. Third, the trial only measured standard lipid panel (TG, TC, LDL-C and HDL-C) for pragmatic feasibility across centres, while omitting the advanced biomarkers such as very low-density lipoprotein, chylomicrons and apolipoprotein B that could provide deeper insights into lipid metabolism. These limitations highlight trade-offs between internal validity and clinical feasibility, with future studies planned to address unresolved questions.

This work was supported by the Key Laboratory Project of Digestive Diseases in Jiangxi Province (2024SSY06101) and Jiangxi Clinical Research Center for Gastroenterology (20223BCG74011). We would like to acknowledge all the patients and clinical staff who participated in the REDUCE study.

Data availability statement

No data are available.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

This study involves human participants and was approved by ethics committee of the First Affiliated Hospital of Nanchang University (No. 2023101-3). Participants gave informed consent to participate in the study before taking part.

Footnote

XX and LD contributed equally.

Collaborators On behalf of the Chinese Acute Pancreatitis Clinical Trials Group (CAPCTG): Yin Zhu, Ling Ding, Xin Xu, Xin Huang, Yupeng Lei, Yao Wu, Huajing Ke, Jianhua Wan, Wenhua He, Liang Xia, Lingyu Luo, Huifang Xiong, Nonghua Lu, Tao Chen, Weiqin Li, Lu Ke, Lanting Wang, Gaifang Liu, Na Liu, Lihui Deng, Shihang Zhang, Jinyi Sheng, Zhihua Tang, Chunping Zhu, Youshun Liu, Jianwen Sheng, Guan Gui, Yingjie Chen, Hongwei Zhang, Dong Wu, Jianing Li, Yinyu Pan and Duan wang.

Contributors All authors contributed to the design and development of the study protocol and have reviewed the manuscript. YZ and LK conceived and instructed the study. LDi and XX designed the study. TC provided statistical expertise. WH, LX, LL, HX and NL made contributions to the concept and design of the study. GL, LDe, JinS, CZ, JianS, HZ, DW, LK and YZ are responsible for the day-to-day running, coordinating and management of the study. XX and LDi drafted the manuscript. YZ, LK and TC critically reviewed and revised the manuscript. YZ acts as guarantor.

Funding This study was supported by grants from Science and Technology Innovation Team Cultivation Project of the First Affiliated Hospital of Nanchang University (YFYKCTDPY202202).

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

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.

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