Tocilizumab for Painful Chronic Pancreatitis

Phase 2

Recruiting

• Conditions: Pancreatitis, Chronic
• Interventions: Drug: Tocilizumab 20 MG/ML [Actemra]; Drug: Sodium Chloride 0.9% Inj

• Registration Number: NCT06426160
• Lead Sponsor: Soren Schou Olesen

Brief Summary

This placebo-controlled study will investigate the effect of tocilizumab (an anti-interleukin-6 receptor antibody) on symptom burden, physical functioning, and quality of life in patients with chronic pancreatitis.

Detailed Description

Recent independent research has emphasized the crucial role of immune cell infiltration and its interaction with pancreatic stellate cells in driving the inflammatory process and fibrogenesis in chronic pancreatitis (CP). The cytokine Interleukin 6 (IL-6) has been identified as a key mediator in this process, and preclinical studies have indicated that inhibiting IL-6 signaling can lead to favorable therapeutic outcomes. Consequently, targeting IL-6 signaling therapeutically holds great promise as a disease-modifying treatment for CP.

Until now, there have been no placebo-controlled trials in humans to test immune-modulating treatments for CP. However, there have been some promising results in preclinical studies. For example, administering an anti-IL-6 receptor antibody to an animal model of CP reduced pancreatitis-related pain, indicating a potential therapeutic effect. Blocking IL-6 signaling in an in-silico model of CP was also shown to have disease-modifying effects. Recent anecdotal evidence indicates that using tocilizumab to treat patients with COVID-19 and concomitant pancreatitis can decrease inflammation and pain in the pancreas. Additionally, blocking IL-6 signaling has been demonstrated to have anti-fibrotic effects in patients with systemic sclerosis. Taken together, these findings suggest that targeting IL-6 signaling could be a promising approach for reducing inflammation and fibrogenesis in CP. Tocilizumab (RoActemra) is an anti-IL-6 receptor antibody currently used to treat several inflammatory diseases.

Objectives:

The investigators hypothesize that treatment with tocilizumab, compared with a placebo, will reduce symptom burden (CP-related pain) and improve physical functioning and quality of life in patients with CP. In addition, the investigators hypothesize that the clinical effects will be linked to a decrease in pancreatic inflammation and fibrosis as well as systemic inflammation. The investigators also hypothesize that the pain-relieving effect of tocilizumab will lead to the normalization of pain processing in CP patients. To test these hypotheses, the project is organized into four sub-studies.

Sub-study 1 (main study - randomized placebo-controlled trial): The objective of sub-study 1 is to conduct an investigator-initiated phase 2b double-blinded, placebo-controlled, randomized clinical trial to investigate the clinical effect of tocilizumab on patient-reported outcomes.

Sub-study 2 (inflammatory biomarkers): The objective of sub-study 2 is to investigate the effects of tocilizumab on systemic inflammation using blood-based immune and fibrosis markers.

Sub-study 3 (quantitative imaging biomarkers): The objective of sub-study 3 is to investigate the effect of tocilizumab on pancreatic inflammation and fibrosis using Magnetic Resonance Imaging (MRI) of the pancreas.

Sub-study 4 (pain processing): The objective of sub-study 4 is to investigate the effect of tocilizumab on pain processing using Pancreatic Quantitative Sensory Testing (P-QST) and electrophysiological methods (EEG and ECG).

Study Timeline

• Study First Submitted: 2024-05-14
• Study First Submitted QC: 2024-05-17
• Study Start: 2024-05-21
• Study First Posted: 2024-05-23
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-24
• Last Update Posted: 2024-06-25
• Primary Completion: 2026-06
• Study Completion: 2026-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

• Signed informed consent.
• Probable or definitive diagnosis of CP according to the M-ANNHEIM criteria. This entails a typical clinical history of CP, including recurrent pancreatitis or abdominal pain in combination with the following additional criteria:
• A definitive diagnosis of CP is established by one or more of the following additional criteria:
• i) Pancreatic calcification
• ii) Moderate or marked ductal lesions (according to the Cambridge classification)
• iii) Exocrine pancreatic insufficiency, defined as pancreatic steatorrhea markedly reduced by enzyme supplementation
• iv) Histological verification of CP
• A probable diagnosis of CP is established by one or more of the following additional criteria:
• i) Mild ductal alterations (according to the Cambridge classification)
• ii) Recurrent or persistent pseudocysts
• iii) Pathological test of pancreatic exocrine function (such as faecal elastase-1 test, secretin test, secretin-pancreozymin test)
• iv) Diabetes mellitus
• Abdominal pain of presumed pancreatic origin (i.e., upper abdominal pain radiating to the back).
• Evidence of ongoing pancreatic inflammatory activity, with an inflammatory pancreatic flare occurring one or more times within the past six months. An inflammatory pancreatic flare is defined as an exacerbation of pancreatic pain in combination with one or more of the following criteria:
• i) Plasma amylase levels elevated 2-fold or more than the participant's usual amylase level.
• ii) Elevated plasma levels of CRP 2-fold the upper normal level without suspicion of other sources such as infection.
• iii) Signs of pancreatic inflammation on cross-sectional imaging.
• ≥ 18 years of age
• The participant must be able to read and understand the informed consent forms.
• The participant is willing and able to comply with the scheduled visits, treatment plan, and other trial procedures.

Exclusion Criteria

• End-stage CP indicated by severe pancreatic atrophy defined as segmented pancreas volume <20 ml on the latest available cross-sectional imaging examination (Computed Tomography (CT) or MRI).
• Pancreatic duct obstruction by a stricture and/or stone amendable to endoscopic or surgical treatment. Patients with previous pancreatic duct decompression procedures are allowed to participate.
• Ongoing alcohol or substance abuse. The patient must document abstinence from alcohol and substance abuse for the preceding six months prior to study enrolment. Recreational alcohol consumption within the safety limits recommended by the National Danish Health Authorities (i.e., max. ten units of alcohol per week) is allowed.
• Active or recurrent infections.
• Untreated ulcers in the gastrointestinal tract (however, those who have undergone proper treatment and one month has elapsed with no recurrence of symptoms will not be excluded).
• Known hypersensitivity to Tocilizumab.
• Positive test for Tuberculosis during screening
• Positive test for Hepatitis during screening
• Severe liver disease, indicated by ALT with >5 upper normal limits.
• Thrombocytopenia (platelet count < 50 x 109/L).
• Neutropenia (neutrophil count <2 x 109/L).
• Pregnancy and no contraception use, fertile women (<55 years) must provide a urine sample for pregnancy test upon inclusion.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tocilizumab	Tocilizumab 20 MG/ML [Actemra]	8 mg / kg Tocilizumab will be diluted to a final volume of 100 mL with sterile, non-pyrogenic sodium chloride 9 mg/mL (0.9 %)
Placebo	Sodium Chloride 0.9% Inj	100 ml sodium chloride 9 mg/mL (0.9 %).

Primary Outcome Measures

Name	Time	Method
The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Questionnaire	The intervention period is 24 weeks (assessed every 4 weeks from baseline to finalization)	The between-group difference (tocilizumab vs. placebo) of the change from baseline in the COMPAT-SF score at 24 weeks. The COMPAT-SF score is noramlized on a 0-100 score. Higher scores indicate a higher degree of pain.

Secondary Outcome Measures

Name	Time	Method
Emotional Functional Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Emotional Functional Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The emotional functional score ranges from 0 to 100. A high score on the functional scales represents a high level of daily functioning.
Daily weak analgesics dose for patients	The intervention period is 24 weeks (continuously throughout the entire study)	The between and within-group difference of weak analgesic dose (continuous variable in mg) in patients, from baseline at 24 weeks.
Global Quality of Life Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in the Global Quality of Life Score from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC-QLQ-C30) questionnaire at 24 weeks. The global quality of life score range from 0 to 100. A high score on the Global Quality of Life score represents a high level of life quality.
Physical Functional Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Physical Functional Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The physical functional score ranges from 0 to 100. A high score on the functional scales represents a high level of daily functioning.
Pain severity Score (modified BPI)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Pain severity score from baseline in the modified Brief Pain Inventory at 24 weeks. The pain severity score is rated on a visual analogue scale (VAS), 0 = no pain, 10 = worst pain imaginable), based on four pain severity items. Higher scores reflect more severe pain.
Pain Interference Score (modified BPI)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Pain Interference score from baseline in the modified Brief Pain Inventory at 24 weeks. The pain interference score is rated on a VAS, 0 = no pain, 10 = worst pain imaginable, based on seven pain interference items. Higher scores reflect more pain interference with daily life.
Daily opioid dose for patients using prescription opiods	The intervention period is 24 weeks (continuously throughout the entire study)	The between and within-group difference of opioid dose (continuous variable in mg of moprhine equivalent) in patients, from baseline at 24 weeks.
Number of patient using weak analgesics for pain control	The intervention period is 24 weeks (continuously throughout the entire study)	Weak analgesic use (yes, no, binary answer) continuously through the entire study
Cognitive Functional Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Cognitive Functional Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The cognitive functional score ranges from 0 to 100. A high score on the functional scales represents a high level of daily functioning.
CP Prognosis Score	The intervention period is 24 weeks (assessed at weeks 0 and 24)	The between-group difference in the CP prognosis score from baseline at 24 weeks. The CP prognosis score ranges from 5-15 points. Higher scores indicates higher risk of readmission to hospital.
Frequency of adverse events (Patient Diary)	The intervention period is 24 weeks (continuously throughout the entire study)	The frequency of adverse events from baseline at 24 weeks.
Role Functional Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Role Functional Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The role functional score ranges from 0 to 100 A high score on the functional scales represents a high level of daily functioning.
Number of patient using prescription opioids for pain control	The intervention period is 24 weeks (continuously throughout the entire study)	Opioid use (yes, no, binary answer) continuously through the entire study
Social Functional Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Social Functional Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The social functional score ranges from 0 to 100. A high score on the functional scales represents a high level of daily functioning.
Symptom Burden Score (EORTC-QLQ-C30)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Symptom Score from baseline in the EORTC-QLQ-C30 questionnaire at 24 weeks. The symptom burden score ranges from 0 to 100. A high score for the symptom items represents a high level of symptomatology.
Average Daily Pain Score (modified BPI)	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)	The between-group difference in Average Daily Pain score from baseline in the modified Brief Pain Inventory at 24 weeks. The average daily pain score ranges is rated on a VAS-scale, 0-10, 0 = no pain, and 10 = worst pain imaginable.
Patient's Global Impression of Change (PGIC) Questionnaire	The intervention period is 24 weeks (assessed at week 24)	The between-group difference in the PGIC questionnaire, a self-reporting seven-point rating scale (points from 1-7) on how the participant experiences treatment change from baseline at 24 weeks. Higher score corresponds to improvement.

Trial Locations

Locations (1)

Centre for Pancreatic Diseases and Mech-Sense research laboratory, Aalborg University Hospital; 🇩🇰 Aalborg, Nordjylland, Denmark