Clinical trial NCT05042284: Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis
Official title: Effect of Non-enteric Coated Enzymes Substitution on Pain in Patients With Chronic Pancreatitis: a Double -Blinded Placebo Controlled Randomized Trial (NE-PERT Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Pancreatitis
Pain
Lead sponsor: Asian Institute of Gastroenterology, India
Sponsor class: OTHER
First posted: 2021-09-13
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in pain score 1
timeFrame: 3 months
measure: Change in pain score 2
timeFrame: 3 months
Secondary outcomes:
measure: Change in pain score 1
timeFrame: 6 months
measure: Change in pain score 2
timeFrame: 6 months
measure: Change in number of painful days
timeFrame: 3 months
measure: Change in number of painful days
timeFrame: 6 months
measure: Change in quality of life
timeFrame: 3 months
measure: Change in quality of life
timeFrame: 6 months
measure: Change in analgesic requirement
timeFrame: 3 months
measure: Change in analgesic requirement
timeFrame: 6 months
measure: Change in the number of hospitalization
timeFrame: 3 months
measure: Change in the number of hospitalization
timeFrame: 6 months
Other outcomes:
measure: Change in Quantitative sensory testing parameters (pin prick) [First follow-up]
timeFrame: 3 months
measure: Change in Quantitative sensory testing parameters (pin prick) [Second follow-up]
timeFrame: 6 months
measure: Change in Quantitative sensory testing parameters (cold tolerance) [First follow-up]
timeFrame: 3 months
measure: Change in Quantitative sensory testing parameters (cold tolerance) [Second follow-up]
timeFrame: 6 months
measure: Change in pain DETECT score [First follow-up]
timeFrame: 3 months
measure: Change in pain DETECT score [Second follow-up]
timeFrame: 6 months
Locations:
city: Hyderabad
country: India
facility: Asian Institute of Gastroenterology
state: Andhra Pradesh
Study officials:
affiliation: Asian Institute of Gastroenterology
name: Rupjyoti Talukdar, MD, AGAF
role: PRINCIPAL_INVESTIGATOR
References: