Comparative Study to Evaluate Microbial Versus Porcine Pancreatic Enzyme Therapy in Chronic Pancreatitis (NP-PERT)

A Randomised, Double-Blind, Non-Inferiority Trial Comparing Microbial and Porcine Pancreatic Enzyme Replacement Therapy in Chronic Pancreatitis

Background: Chronic pancreatitis (CP) is a progressive inflammatory disorder causing irreversible pancreatic damage, eventually resulting in pancreatic exocrine insufficiency (PEI). This may lead to malabsorption, malnutrition, weight loss, and impaired quality of life. Pancreatic enzyme replacement therapy (PERT) is the standard treatment for PEI and is predominantly derived from porcine sources. However, religious, ethical, dietary, and supply-related concerns highlight the need for effective non-porcine alternatives. Microbial (fungal)-based pancreatic enzymes have shown promising safety and efficacy in preliminary studies, but evidence in CP remains limited.

Objective: To compare the efficacy and safety of non-porcine microbial (fungal)-based pancreatin with standard porcine-based pancreatin in patients with PEI secondary to CP.

Methods: This investigator-initiated, randomized, double-blind, single-center, non-inferiority trial will enroll 134 adults with CP-associated PEI (defined as having a fecal elastase <100 µg/g). After a two-week washout period, participants will be randomized 1:1 to receive either microbial-based or porcine-based pancreatin for 12 weeks. The primary outcome is the change from baseline in the Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) score at 12 weeks. Secondary outcomes include nutritional status, anthropometric measures, gastrointestinal symptoms, pain scores, stool consistency, glycaemic parameters, laboratory markers, and quality of life.

Discussion: This study aims to evaluate whether microbial-based pancreatin is non-inferior to porcine-based therapy and may provide a culturally acceptable and sustainable alternative for managing CP-related PEI.

Study Overview

• Status: Not yet recruiting
• Conditions: Pancreatitis, Chronic; Exocrine Pancreatic Insufficiency (EPI)
• Intervention / Treatment: Dietary supplement: Dietary Supplement: Pancreatic enzyme preparation from microbial (fungal) source that contains amylase (6650 DU), lipase (13000 FIP), and protease (7120 HUT, 15 SAPU, 3000 PC).; Other: Standard of care porcine pancreatic enzyme preparation: amylase (8000 U), lipase (25000 U), and protease (1000 U)

Detailed Description

Chronic pancreatitis (CP) is a complex inflammatory disorder of the pancreas. It is characterized by persistent inflammation that progressively damages the pancreatic tissue, leading to irreversible fibrotic changes. The dominant clinical manifestation of is abdominal pain and ongoing parenchymal injury leads to a gradual decline in both exocrine and endocrine function. However, the onset of pancreatic exocrine insufficiency (PEI) and diabetes is not universal, as a subset of individuals with CP retains sufficient exocrine reserve to avoid clinically significant malabsorption. When functional decline advances, however, patients may ultimately develop PEI and diabetes. In the absence of disease-modifying treatments, the current primary goal of management is early recognition and management of these complications. Treatment includes pain management, digestive support with pancreatic enzyme supplementation and nutrition, and endocrine management with oral antidiabetic medications and/or insulin.

In PEI, insufficient secretion of pancreatic enzymes leads to inadequate digestion and absorption of nutrients, resulting in weight loss, malnutrition, metabolic bone disease, and deficiencies of fat-soluble vitamins and minerals. PEI develops frequently in patients with CP, with a prevalence ranging from 30%-85% within 10-15 years after diagnosis.

Large cohort studies report an overall PEI prevalence of 50%-75%, particularly in patients with alcohol-related CP and longer disease duration. Management of PEI secondary to CP is important to improve nutritional status and quality of life. Pancreatic enzyme replacement therapy (PERT) is the mainstay of treatment for PEI. According to two meta-analyses, supportive treatment with pancreatic enzyme replacement showed significant improvement in the symptoms and consequences of PEI in patients with CP.

Currently available PERT preparations are primarily derived from porcine pancreas. Although clinically effective, porcine-derived PERT has certain limitations, including concerns related to its animal origin. Additionally, some patients may avoid such supplements due to lifestyle or ethical choices, such as vegetarians and vegans, while others, particularly followers of Islam and Judaism, may refrain from porcine-derived products due to religious dietary restrictions. Importantly, there is an increased lack of supplies due to the increasing prevalence of CP and other diseases associated with PEI. Therefore, new formulations of PERT are an unmet need.

Advances in biotechnology have led to the development of non-porcine microbial (fungal) based pancreatic enzymes that have been shown to have a good safety profile and efficacy in several conditions. Animal studies and human pilot studies have also shown benefit in CP. While the use of porcine PERT is well-established in CP, the utilization of non-porcine microbial-based PERT and its efficacy in CP is unclear.

HYPOTHESIS:

We hypothesize that non-porcine PERT will be as efficacious as the porcine based pancreatic enzymes in nutrient digestion. Hence, the aim of this study is to evaluate the clinical efficacy of non-porcine, microbial-based pancreatic enzymes compared with the current standard of care porcine enzymes, as a supportive therapy for patients with PEI secondary to CP.

REPORTING:

The study protocol will reported in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2025 guidelines.

MONITORING:

The conduct of the study will be monitored by a Data Safety Monitoring Board (DSMB).

STUDY DESIGN AND DURATION:

This is a multi-center, randomized, double-blind, parallel-group (1:1), placebo-controlled, non-inferior trial. The trial duration is 3 months (including enrolment and follow-up period). The study will be conducted in three independent branches of AIG hospitals, at Gachibowli, Somajiguda, and Banjara Hills, Hyderabad, India. The main branch at Gachibowli will be the coordinating center. Ethical approval has already been procured in the coordinating center (Asian Institute of Gastroenterology, Gachibowli).

FOLLOW-UP PLAN The patients will be provided with a structured diary wherein they will record their body weight every week using the same weighing machine for all measurements to ensure consistency. They will also record their medication intake, new symptoms, need for hospital visits, and any deviation in their diet regimen. A research coordinator will make a telephone call to each patient after weeks 4, 6, and 8 to collect any data that the patient recorded over the weeks. At the same time, the coordinator will also ensure and encourage compliance with the treatment. At the end of the study, the patient will visit the study centers where all the baseline measurements will be repeated. The patients will be directed to bring the study medicine containers, and a pill count will be done.

RANDOMIZATION, BLINDING, AND PERT ALLOCATION:

After obtaining written informed consent by the designated research coordinator, eligible participants who satisfy the inclusion criteria and complete the 2-week wash-out period will be randomized in a 1:1 ratio to either the non-porcine microbial (fungal)-based pancreatin group or the porcine-based standard-of-care pancreatin group. A block randomization method with a block size of 8 will be used to ensure equal allocation between the two groups. Randomization will be performed using a sealed envelope randomization software (https://www.sealedenvelope.com/power/continuous-noninferior/) by a statistician who is not involved in patient interaction, study interventions, or data analysis. Treatment allocation and blinding will be managed by an independent research coordinator not involved in the conduct of the study or patient care.

The principal investigator (PI), co-investigators, study staff, outcome assessors, and participants will remain blinded to treatment allocation throughout the study to ensure unbiased treatment administration and outcome assessment.

Unblinding will be permitted only in the event of a medical emergency or serious adverse event where knowledge of the assigned intervention is essential for clinical management. The PI will authorize unblinding and access the allocation code for the specific participant through the secure randomization system. The reason and date of unblinding will be documented, and the Institutional Ethics Committee will be notified as per regulatory requirements. Unblinding will be restricted to the affected participant and will not compromise the overall blinding of the trial.

STUDY AND ASSESSMENT METHOD:

Once the initial screening is completed by the PI and participant allocation is performed by an independent research coordinator, the designated co-investigators and research team from each center will systematically assess and record clinical, radiological (baseline), biochemical, and treatment-related details.

SAMPLE SIZE CALCULATION:

The study is designed as a non-inferiority trial comparing non-porcine microbial (fungal)based with porcine-based standard of care pancreatin on the primary continuous outcome measured by the PEI-Q total score (range 0-72). Non inferiority will be concluded if the upper bound of the one-sided 97.5% confidence interval for the mean difference does not exceed a pre-specified non-inferiority margin of 10 units, which is considered the minimal clinically important difference for the PEI-Q based on expert consensus. Sample size and power calculations for a range of non-inferiority margins (Δ = 5, 7.5, 10, 12.5, and 15 units), assuming a common standard deviation of 15 units and n = 60 participants per group, indicate that the study has approximately 94% power to demonstrate non-inferiority for a margin of 10 units, with higher power for larger margins and lower power for smaller margins. To adjust for 10% drop-outs, we will increase to sample size to 67 patients in each group adding up to a total of 134 patients.

STATISTICAL ANALYSIS A centralized database will be developed in RedCAP. Data will be uploaded from the three study centers and curated at the monitoring center in Aalborg, Denmark. All analyses will be conducted at the University of Aalborg, who will be blinded to treatment allocation and randomization.

Continuous variables will be expressed as mean with standard deviation (SD) or median with interquartile range (IQR), as appropriate. Categorical variables will be presented as frequencies and proportions.

A linear mixed-effects model will be used to assess changes in PEI-Q scores across all assessment time points. Summary statistics with corresponding 95% confidence intervals (CI) will be reported with the between group-difference at 12 weeks being the primary endpoint.

Continues secondary outcomes, including changes in nutritional parameters, SARC-F score, stool consistency, gastrointestinal symptom severity, quality of life, endocrine function, fecal elastase-1 levels, and body composition, will be analyzed using mixed-effects regression models for normally distributed variables and quantile regression models for non-normally distributed variables. Categorical outcomes will be analyzed using risk differences between groups with corresponding 95% confidence intervals.

Missing data will be handled using multiple imputation techniques. A two-tailed p-value of <0.05 will be considered statistically significant.

• Study Type: Interventional
• Enrollment (Estimated): 134
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rupjyoti Talukdar, MD; Phone Number: +917032804231; Email: rup_talukdar@yahoo.com
• Study Contact Backup: Name: Abdul Rasheed, PharmD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• CP fulfilling the M-ANNHEIM criteria 11 with documented PEI (defined as fecal elastase <100 µg/g stool on the background of morphological changes of CP).
• Willingness to undergo a 2-week wash-out period without pancreatic enzyme therapy before enrolment.
• Willing and able to provide written informed consent.

Exclusion Criteria:

• Major psychiatric illness impairing study participation.
• Systemic illness affecting digestion or study outcomes.
• Any condition deemed unsuitable for study participation by the investigator.
• Concurrent acute exacerbation of the CP at the time of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Non-porcine microbial (fungal) based pancreatic enzyme preparation; The non-porcine microbial enzyme preparation will contain amylase (6650 DU), lipase (13000 FIP), and protease (7120 HUT, 15 SAPU, 3000 PC)	Dietary supplement: Dietary Supplement: Pancreatic enzyme preparation from microbial (fungal) source that contains amylase (6650 DU), lipase (13000 FIP), and protease (7120 HUT, 15 SAPU, 3000 PC).; Dietary Supplement: Pancreatic enzyme preparation from microbial (fungal) source that contains amylase (6650 DU), lipase (13000 FIP), and protease (7120 HUT, 15 SAPU, 3000 PC).
Active Comparator: Standard of care porcine pancreatic enzyme; The standard of care porcine-based enzyme preparation will contain amylase (8000 U), lipase (25000 U), and protease (1000 U)	Other: Standard of care porcine pancreatic enzyme preparation: amylase (8000 U), lipase (25000 U), and protease (1000 U); Standard of care porcine pancreatic enzyme preparation: amylase (8000 U), lipase (25000 U), and protease (1000 U)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) score	The PEI-Q is a validated questionnaire that captures several symptoms related to exocrine pancreatic insufficiency and the result is presented as a composite score.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in quality of life	Quality of life will be assessed by the Short Form (SF)-36 tool. This is a standardised and validated questionnaire based scoring tool that contains 36 questions dealing with 8 domains of quality of life. The lowest score in this tool is 0 and the highest score is 100, a higher score indicating better quality of life.	3 months
Change in nutritional status: Anthropometry	Mid-upper arm muscle circumference (MAMC) in cm.	3 months
Change in nutritional status: Anthropomentry	Mid-arm muscle area (MAMA) in cm square.	3 months
Change in nutritional status: Biochemical assessment	Hemoglobin in gm/dL	3 months
Change in nutritional status: Biochemical assessment	Vitamin D	3 months
Change in nutritional status: Biochemical assessment	Vitamin B12	3 months
Change in body composition (Bioimpedence analysis): Body fat mass (kg)	Total body fat will be assessed using Bioimpedence analysis (BIA) This is a non-invasive method that operates by sending a low-level, imperceptible electrical current through the body. The normal range is 10-20kg.	3 months
Change in body composition (Bioimpedence analysis): Total body water (litres)	Total body water will be quantified using Bioimpedence analysis (BIA) This is a non-invasive method that operates by sending a low-level, imperceptible electrical current through the body.	3 months
Change in body composition (Bioimpedence analysis): Phase angle at 50kH (degrees)	Cell membrane integrity will be assessed using the phase angle function of Bioimpedence analysis (BIA) This is a non-invasive method that operates by sending a low-level, imperceptible electrical current through the body.	3 months
Change in body composition (Bioimpedence analysis): Visceral fat level (numerical unit; normal range (1-12).	Visceral fat level will be assessed using Bioimpedence analysis (BIA) This is a non-invasive method that operates by sending a low-level, imperceptible electrical current through the body. The normal range is from 1-12, a loser value indicating lower visceral fat and higher value indicates larger visceral fat.	3 months
Change in nutritional status: Subjective global assessment	Subjective global assessment (SGA) is a composite semi-quantitative tool that provides the degree of nutrition of an individual in three categories such as SGA A (Normal nutrition), SGA B (moderate malnutrition) and SGA C (Severe malnutrition).	3 months
Change in nutritional status: Body weight	Percent change in body weight (kg)	3 months
Change in nutritional status: Anthropometry	Mid-arm circumference (MAC) in cm.	3 months
Change in nutritional status: Anthropomentry	Triceps skin fold thickness (TSF) in cms.	3 months
Change in nutritional status: Biochemical assessment	Serum pre albumin (mg/dl)	3 months
Change in endocrine status	HbA1c	3 months
Change in endocrine function	Fasting blood glucose (mg/dl)	3 months
Change in endocrine function	C-peptide	3 months
Change in body composition (Bioimpedence analysis): Skeletal muscle mass (kg)	Skeletal muscle mass will be assessed using Bioimpedence analysis (BIA) This is a non-invasive method that operates by sending a low-level, imperceptible electrical current through the body	3 months
Stool consistency	Bristol stool scale [Type 1 (separate hard lumps, indicating constipation) to Type 7 (watery stool, indicating diarrhea].	3 months
Change in gastrointestinal symptoms	Patient Assessment of Upper Gastrointestinal Disorders - Symptom Severity Index (PAGI-SYM)	3 months
Change in sarcopenia score	SARC-F Questionnaire (Score of =/>4 is considered to have sarcopenia)	3 months
Change in patient's global impression of change (PGIC)	This will be evaluated using the Patient's Global Impression of Change (PGIC). The score ranges from 1-7, with a score of 1 indicating very much improved and 7 indicating very much worse	3 months
Change in quality of life (QOL)	QOL will be assessed using the EORTC-QLQ c30 with PAN-28.	3 months
Change in pain severity	Range of 0-10 in the Visual Analog Scale (VAS). A score of 0 indicates no pain, while 10 is maximum pain.	3 months.
Change in pain severity	Pain-related symptoms and characteristics will be assessed using the Short-form Comprehensive Pain Assessment Tool (COMPAT-SF).	3 months
Readmission during the study period	Number of admissions during the study period	3 months
Change in functional mobility during the study period.	This will be performed using the using the Timed Up and Go (TUG) test.	3 months.

Collaborators and Investigators

• Sponsor: Asian Institute of Gastroenterology, India
• Collaborators: Aalborg University
• Investigators: Principal Investigator: Rupjyoti Talukdar, MD, Asian Institute of Gastroenterology

Publications and helpful links

General Publications

• Conwell DL, Lee LS, Yadav D, Longnecker DS, Miller FH, Mortele KJ, Levy MJ, Kwon R, Lieb JG, Stevens T, Toskes PP, Gardner TB, Gelrud A, Wu BU, Forsmark CE, Vege SS. American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas. 2014 Nov;43(8):1143-62. doi: 10.1097/MPA.0000000000000237.
• Rentz AM, Kahrilas P, Stanghellini V, Tack J, Talley NJ, de la Loge C, Trudeau E, Dubois D, Revicki DA. Development and psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res. 2004 Dec;13(10):1737-49. doi: 10.1007/s11136-004-9567-x.
• Johnson CD, Arbuckle R, Bonner N, Connett G, Dominguez-Munoz E, Levy P, Staab D, Williamson N, Lerch MM. Qualitative Assessment of the Symptoms and Impact of Pancreatic Exocrine Insufficiency (PEI) to Inform the Development of a Patient-Reported Outcome (PRO) Instrument. Patient. 2017 Oct;10(5):615-628. doi: 10.1007/s40271-017-0233-0.
• Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2016 Oct;44(7):693-703. doi: 10.1111/apt.13746. Epub 2016 Aug 5.
• Rathnayake N, Abeygunasekara T, Liyanage G, Subasinghe S, De Zoysa W, Palangasinghe D, Lekamwasam S. SARC-F: an effective screening tool for detecting sarcopenia and predicting health-related quality of life in older women in Sri Lanka. BMC Geriatr. 2025 Feb 25;25(1):129. doi: 10.1186/s12877-025-05786-z.
• Detsky AS, McLaughlin JR, Baker JP, Johnston N, Whittaker S, Mendelson RA, Jeejeebhoy KN. What is subjective global assessment of nutritional status? 1987. Classical article. Nutr Hosp. 2008 Jul-Aug;23(4):400-7. No abstract available.
• Salhi A, Amara S, Mansuelle P, Puppo R, Lebrun R, Gontero B, Aloulou A, Carriere F. Characterization of all the lipolytic activities in pancreatin and comparison with porcine and human pancreatic juices. Biochimie. 2020 Feb;169:106-120. doi: 10.1016/j.biochi.2019.07.004. Epub 2019 Jul 6.
• Chan AW, Boutron I, Hopewell S, Moher D, Schulz KF, Collins GS, Tunn R, Aggarwal R, Berkwits M, Berlin JA, Bhandari N, Butcher NJ, Campbell MK, Chidebe RCW, Elbourne DR, Farmer AJ, Fergusson DA, Golub RM, Goodman SN, Hoffmann TC, Ioannidis JPA, Kahan BC, Knowles RL, Lamb SE, Lewis S, Loder E, Offringa M, Ravaud P, Richards DP, Rockhold FW, Schriger DL, Siegfried NL, Staniszewska S, Taylor RS, Thabane L, Torgerson DJ, Vohra S, White IR, Hrobjartsson A. SPIRIT 2025 Statement: Updated Guideline for Protocols of Randomized Trials. JAMA. 2025 Aug 5;334(5):435-443. doi: 10.1001/jama.2025.4486.
• Gan C, Chen YH, Liu L, Gao JH, Tong H, Tang CW, Liu R. Efficacy and safety of pancreatic enzyme replacement therapy on exocrine pancreatic insufficiency: a meta-analysis. Oncotarget. 2017 Oct 7;8(55):94920-94931. doi: 10.18632/oncotarget.21659. eCollection 2017 Nov 7.
• de la Iglesia-Garcia D, Huang W, Szatmary P, Baston-Rey I, Gonzalez-Lopez J, Prada-Ramallal G, Mukherjee R, Nunes QM, Dominguez-Munoz JE, Sutton R; NIHR Pancreas Biomedical Research Unit Patient Advisory Group. Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut. 2017 Aug;66(8):1354-1355. doi: 10.1136/gutjnl-2016-312529. Epub 2016 Dec 9.
• Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP. The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology. 1994 Nov;107(5):1481-7. doi: 10.1016/0016-5085(94)90553-3.
• Whitcomb DC, Frulloni L, Garg P, Greer JB, Schneider A, Yadav D, Shimosegawa T. Chronic pancreatitis: An international draft consensus proposal for a new mechanistic definition. Pancreatology. 2016 Mar-Apr;16(2):218-24. doi: 10.1016/j.pan.2016.02.001. Epub 2016 Feb 16.

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: July 5, 2026
• First Submitted That Met QC Criteria: July 5, 2026
• First Posted (Actual): July 13, 2026

Study Record Updates

• Last Update Posted (Actual): July 13, 2026
• Last Update Submitted That Met QC Criteria: July 5, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: chronic pancreatitis; exocrine pancreatic insufficiency; Pancreatic enzyme replacement therapy; porcine pancreatic enzyme; microbial (fungal) pancreatic enzyme
• Additional Relevant MeSH Terms: Pathologic Processes; Chronic Disease; Disease Attributes; Digestive System Diseases; Pancreatic Diseases; Pathological Conditions, Signs and Symptoms; Pancreatitis; Pancreatitis, Chronic; Exocrine Pancreatic Insufficiency; Hydrolases; Enzymes; Enzymes and Coenzymes; Carboxylic Ester Hydrolases; Esterases; Lipase; Peptide Hydrolases
• Other Study ID Numbers: NP-PERT 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No