Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis (NE-PERT)

Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis: a Double -Blinded Placebo Controlled Randomized Trial (NE-PERT Trial)

Pain in CP entails several independent yet overlapping mechanisms including oxidative stress-mediated parenchymal inflammation, pancreatic and central neuropathy and neuroplasticity. Medical modalities for long-term pain management includes antioxidants and neuromodulators. Pancreatic enzymes are also invariably used for pain management. CP with ductal obstruction and pain is treated with either endotherapy or drainage surgery. However, it has been observed that a substantially increasing proportion of patients experience pain recurrence as the duration of follow-up after endotherapy or surgery gets longer.

Neural and dietary (proteins) stimuli activate CCK receptors in D1 & D2 which gives a positive feedback signal for pancreatic secretion. Once enzyme secretion starts, due to ductal and interstitial/tissue hypertension, nociception begins that results in pain. Blockade of the duodenal CCK receptors could inhibit the positive feedback loop, thereby reducing pancreatic secretion and resulting pain. Currently available enteric coated enzyme supplements are released throughout the small bowel and therefore may not be released sufficiently in the duodenum to effectively suppress the feedback loops. High doses of proteases (~25k-30k) would be required to block the receptors, while most of the currently available preparations have higher lipase but not proteases.

This led to the investigators' hypothesis that negative feedback of CCK by non enteric coated pancreatic enzymes could ameliorate pain in a more effective manner by NE-PERT.

Study Overview

• Status: Completed
• Conditions: Pain; Chronic Pancreatitis
• Intervention / Treatment: Drug: Non-enteric coated pancreatic enzyme preparation

Detailed Description

Chronic pancreatitis (CP) is a fibro-inflammatory disorder of the pancreas characterized by progressive and irreversible damage. It manifests with abdominal pain and/or exocrine or endocrine insufficiency. Recurrent abdominal pain is the dominant clinical hallmark that mandates aggressive management. Pain in CP entails several independent yet overlapping mechanisms including oxidative stress-mediated parenchymal inflammation, pancreatic and central neuropathy and neuroplasticity.

Medical modalities for long-term pain management includes antioxidants and neuromodulators. Pancreatic enzymes are also invariably used for pain management. CP with ductal obstruction and pain is treated with either endotherapy or drainage surgery. However, it has been observed that a substantially increasing proportion of patients experience pain recurrence as the duration of follow-up after endotherapy or surgery gets longer.

It has been postulated that neural and dietary (proteins) stimuli activate CCK receptors in D1 & D2 which gives a positive feedback signal for pancreatic secretion. Once enzyme secretion from the pancreas begins, due to ductal and interstitial/tissue hypertension, nociception is initiated that results in pain. On this premise, the investigators hypothesized that blocking the duodenal CCK receptors could inhibit the positive feedback loop, thereby reducing pancreatic secretion and resulting pain.

Earlier meta-analyses that evaluated the effect of pancreatic enzyme supplementation on pain reported that there were no overall benefits in pain management. All but two of those studies used enteric coated enzyme. Currently available enteric coated enzyme supplements are released throughout the small bowel and therefore may not be released sufficiently in the duodenum to effectively suppress the feedback loops. High doses of proteases (~25k-30k) would be required to block the receptors, while most of the currently available preparations have higher lipase but not proteases. However, on subgroup analyses in the aforementioned meta-analyses, pain reduction was observed in the two studies that used non-enteric coated preparations. These studies were done several years earlier, had a small sample size, and had a cross over design. This formed that rationale of the investigators' current study to test the hypothesis using a statistically valid design with a higher sample size that would allow subgroup analyses, adjust for alternative pain mechanisms, and achieve a better effect size.

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500082
      • Asian Institute of Gastroenterology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Chronic pancreatitis of at least 3 years
• At least 3 episodes of pain in the past 3 months
• Pain score of at least 3 on VAS (0-10)
• Age 18-60yrs
• Both genders

Exclusion Criteria:

• Acute pancreatitis episode at the time of enrolment.
• Pancreatic cancer.
• Other chronic painful conditions.
• Active substance use (alcohol, smoking, smokeless tobacco, illicit drugs).
• Pregnancy and lactation.
• Inability to give informed consent.

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: NE PERT; Non-enteric coated pancreatic enzyme capsules containing 30,000U of protease will be provided three times a day along with food (breakfast, lunch and dinner)	Drug: Non-enteric coated pancreatic enzyme preparation; The patients will be given a non-enteric coated pancreatic enzyme capsule containing 30000 U of protease thrice daily along with meals for 3 months.; Other Names: Placebo
Placebo Comparator: Placebo; Similar appearing glucose capsules will be provided three times a day along with food (breakfast, lunch and dinner)	Drug: Non-enteric coated pancreatic enzyme preparation; The patients will be given a non-enteric coated pancreatic enzyme capsule containing 30000 U of protease thrice daily along with meals for 3 months.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain score 1	Visual analogue score will be used. Score ranges from 0-10, 10 indicating most severe.	3 months
Change in pain score 2	Izbicki pain score will be used. Score ranges from 0-100, 100 indicating most severe.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in number of painful days	Number of days when the patient experienced pain	3 months
Change in number of painful days	Number of days when the patient experienced pain	6 months
Change in quality of life	Will be measured using the EORTC QLQ c30 with PAN28 tool. Score ranges from 0 to 100. 0 indicates worst for function scales, while 100 indicates worst for symptom scales.	3 months
Change in quality of life	Will be measured using the EORTC QLQ c30 with PAN28 tool. Score ranges from 0 to 100. 0 indicates worst for function scales, while 100 indicates worst for symptom scales.	6 months
Change in analgesic requirement	Number of analgesic tablets required will be recorded	3 months
Change in analgesic requirement	Number of analgesic tablets required will be recorded	6 months
Change in the number of hospitalization	Number of hospital admissions and days in hospital will be recorded	3 months
Change in the number of hospitalization	Number of hospital admissions and days in hospital will be recorded	6 months
Change in pain score 1	Visual analogue score will be used. Score ranges from 0-10, 10 indicating most severe.	6 months
Change in pain score 2	Izbicki pain score will be used. Score ranges from 0-100, 100 indicating most severe.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Quantitative sensory testing parameters (pin prick) [First follow-up]	Pin prick sensation (0-10; 10 indicates maximum)	3 months
Change in Quantitative sensory testing parameters (pin prick) [Second follow-up]	Pin prick sensation (0-10; 10 indicates maximum);	6 months
Change in Quantitative sensory testing parameters (cold tolerance) [First follow-up]	Cold tolerance (0-10 VAS every 10secs for 2 mins.; 10 indicates severe)	3 months
Change in Quantitative sensory testing parameters (cold tolerance) [Second follow-up]	Cold tolerance (0-10 VAS every 10secs for 2 mins.; 10 indicates severe)	6 months
Change in pain DETECT score [First follow-up]	The painDETECT questionnaire will be used. Range is 0-38, 38 indicates most severe neuropathic pain.	3 months
Change in pain DETECT score [Second follow-up]	The painDETECT questionnaire will be used. Range is 0-38, 38 indicates most severe neuropathic pain.	6 months

Collaborators and Investigators

• Sponsor: Asian Institute of Gastroenterology, India
• Investigators: Principal Investigator: Rupjyoti Talukdar, MD, AGAF, Asian Institute of Gastroenterology

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2021
• Primary Completion (Actual): July 30, 2024
• Study Completion (Actual): July 30, 2024

Study Registration Dates

• First Submitted: August 20, 2021
• First Submitted That Met QC Criteria: September 2, 2021
• First Posted (Actual): September 13, 2021

Study Record Updates

• Last Update Posted (Actual): September 4, 2024
• Last Update Submitted That Met QC Criteria: September 2, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Pancreatic Diseases; Chronic Disease; Pancreatitis; Pancreatitis, Chronic
• Other Study ID Numbers: NE PERT 1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: After 6 months of data publication, on reasonable request.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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