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

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.