Tocilizumab for Painful Chronic Pancreatitis (TOPAC)

Tocilizumab for Painful Chronic Pancreatitis: A Randomised, Placebo-Controlled, Double-blinded, Investigator Initiated Trial (TOPAC Trial)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Pancreatitis, Chronic
• Intervention / Treatment: Drug: Tocilizumab 20 MG/ML [Actemra]; Drug: Sodium Chloride 0.9% Inj

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 Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rasmus Hagn-Meincke, MD; Phone Number: 004597663520; Email: r.hagnmeincke@rn.dk

Study Locations

• Denmark
  • Nordjylland
    • Aalborg, Nordjylland, Denmark, 9000
      • Centre for Pancreatic Diseases and Mech-Sense research laboratory, Aalborg University Hospital
      • Contact: Rasmus Hagn-Meincke, MD; Phone Number: 004597663520; Email: r.hagnmeincke@rn.dk

Participation Criteria

Eligibility Criteria

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

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tocilizumab; 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 %)	Drug: Tocilizumab 20 MG/ML [Actemra]; Tocilizumab 8 mg/kg every four weeks for 24 weeks.; Other Names: RoActemra; Actemra
Placebo Comparator: Placebo; 100 ml sodium chloride 9 mg/mL (0.9 %).	Drug: Sodium Chloride 0.9% Inj; Placebo (Sodium chloride) every four weeks for 24 weeks.; Other Names: Natriumchloride 0.9 % Inj

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Questionnaire	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.	The intervention period is 24 weeks (assessed every 4 weeks from baseline to finalization)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Quality of Life Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Physical Functional Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Role Functional Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Cognitive Functional Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Emotional Functional Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Social Functional Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Symptom Burden Score (EORTC-QLQ-C30)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Pain severity Score (modified BPI)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Pain Interference Score (modified BPI)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Average Daily Pain Score (modified BPI)	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.	The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
Patient's Global Impression of Change (PGIC) Questionnaire	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.	The intervention period is 24 weeks (assessed at week 24)
CP Prognosis Score	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.	The intervention period is 24 weeks (assessed at weeks 0 and 24)
Number of patient using prescription opioids for pain control	Opioid use (yes, no, binary answer) continuously through the entire study	The intervention period is 24 weeks (continuously throughout the entire study)
Daily opioid dose for patients using prescription opiods	The between and within-group difference of opioid dose (continuous variable in mg of moprhine equivalent) in patients, from baseline at 24 weeks.	The intervention period is 24 weeks (continuously throughout the entire study)
Number of patient using weak analgesics for pain control	Weak analgesic use (yes, no, binary answer) continuously through the entire study	The intervention period is 24 weeks (continuously throughout the entire study)
Daily weak analgesics dose for patients	The between and within-group difference of weak analgesic dose (continuous variable in mg) in patients, from baseline at 24 weeks.	The intervention period is 24 weeks (continuously throughout the entire study)
Frequency of adverse events (Patient Diary)	The frequency of adverse events from baseline at 24 weeks.	The intervention period is 24 weeks (continuously throughout the entire study)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of soluble inflammation biomarker	The investigators plan to use an O-link multiplex platform to examine changes in soluble inflammatory biomarker levels, including several cytokines and chemokines.	The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
Levels of soluble fibrosis biomarker	The investigators plan to use an O-link multiplex platform to examine changes in soluble fibrosis biomarker levels, from baseline at 24 weeks.	The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
Levels of soluble Biomarker of Macrophage Activation	Macrophage activation biomarkers will be analyzed using enzyme-linked immunosorbent assays (ELISAs) levels, from baseline at 24 weeks.	The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
Levels of key Inflammatory Mediator	For the key inflammatory mediator, found in above mentioned analysis, the investigators will confirm the analyses using ELISAs levels from baseline at 24 weeks.	The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
Pancreatic inflammation (imaging)	The between and within-group difference of diffusion-weighted imaging for inflammation using multiparametric pancreatic MRI at baseline and after 24 weeks.	The intervention period is 24 weeks (conducted at weeks 0 and 24)
Pancreatic fibrosis (imaging)	The between and within-group difference of fibrosis detection using T1 mapping multiparametric pancreatic MRI parameters at baseline and after 24 weeks.	The intervention period is 24 weeks (conducted at weeks 0 and 24)
Pancreatic morphology (imaging)	The between and within-group difference of conventional anatomic imaging using multiparametric pancreatic MRI at baseline and after 24 weeks.	The intervention period is 24 weeks (conducted at weeks 0 and 24)
Pancreatic duct morphology (imaging)	The between and within-group difference of pancreatic duct morphology using Magnetic resonance cholangiopancreatography (MRCP) at baseline and after 24 weeks.	The intervention period is 24 weeks (conducted at weeks 0 and 24)
Biliary duct morphology (imaging)	The between and within-group difference of biliary duct morphology using MRCP at baseline and after 24 weeks.	The intervention period is 24 weeks (conducted at weeks 0 and 24)
P-QST: PinPrick (Temporal summation)	The pancreatic quantitative sensory testing (P-QST) is used to characterize pain processing and comprises different experimental pain stimuli: PinPrick test: A pinprick stimulator 256 mN (MRC Systems GmbH, Germany) will be used to perform the pinprick test. The patient is asked to rate the pain sensitisation using the VAS score after a single pinprick stimulus and after ten repetitive stimuli (applied with an interstimulus interval of 1 second). Two test areas are assessed: the dominant forearm and the anterior TH10 dermatome. The score is reported on a VAS score from 0 to 10. Higher scores indicate higher pain tolerance.	The intervention period is 24 weeks (performed at weeks 0 and 24)
P-QST: Pain Pressure thresholds	The P-QST is used to characterize pain processing and comprises different experimental pain stimuli: Pain pressure test: Pressure algometry is performed with a handheld pressure algometer (Type2, Somedic production AB, Sweden) and performed in four dermatomes and five locations: C5 (the clavicle), TH10 (the back and abdomen), L1 (the anterior superior iliac spine), and L4 (straight thigh). The probe has a surface area of 1cm2. Pressure will be increased at a rate of 30 kPa/sec until prespecified thresholds (i.e., pain detection threshold (PDT) and pain tolerance threshold (PTT)) are reached. The assessment parameters are the imposed pressure (kPa) at the PDT and PTT.	The intervention period is 24 weeks (performed at weeks 0 and 24)
P-QST: Cold Pressor	The P-QST is used to characterize pain processing and comprises different experimental pain stimuli: Cold pressor test: The patient's hand is immersed in cold water (approximately two degrees Celsius) for 120 seconds. At 40, 80, and 120 seconds, the patient is asked to rate the pain sensation using a VAS score. If the patient cannot keep their hand in the water for 120 seconds, the duration is noted, and the VAS score at the time they withdraw their hand is used as the maximum score. The assessment parameters are the cold pressor endurance time (seconds) and the evoked pain responses on a visual analog scale (VAS) score, 0 = no pain and 10 = worst pain imaginable. Lower values indicate higher pain tolerance.	The intervention period is 24 weeks (performed at weeks 0 and 24)
P-QST: Conditioned Pain Threshold	The P-QST is used to characterize pain processing and comprises different experimental pain stimuli: Conditioned pain modulation test is conducted using a pain pressure algometer, and the PTT is assessed at 15 cm above the patella in the L4 dermatome on the nondominant side before and after the cold pressor test is performed. The imposed pain pressure tolerance threshold is reported as kPa, with a minimum of 0, and no upper limit. Higher scores indicate higher pain tolerance.	The intervention period is 24 weeks (performed at weeks 0 and 24)
Electroencephalography (EEG) analysis	While performing the P-QST, the investigators measure EEG and ECG before and after the cold pressor test. A standard EEG electrode Cap Kit (EEG Electrode Cap Kit - OpenBCI Online Store) with ten electrodes is employed for these measurements.The Texas Instrument ADS1299 biopotential measurements system will be used for EEG and ECG recordings. This system is already being used in mobile brain-computer interfaces, and its signals are comparable to those of standard systems that can work in hospital settings. The EEG signals are transmitted wirelessly to an Android mobile telephone and stored for further processing. The results will be used to model connectivity between brain centres as well as the dominating centres of the brain. EEG power will be assessed in the Delta, Theta, Alpha, Beta, and Gamma bands between 1 and 70 Hertz. Finally, inverse modelling will be conducted to explore the dominating centres of brain activity.	The intervention period is 24 weeks (assessed at weeks 0 and 24)
Electrocardiographic (ECG) frequency domain	Four conventional ECG electrodes (Neurolink 700) is employed for these measurements. The ECG signals are transmitted wirelessly to an Android mobile telephone and stored for further processing. Frequency domains of heart variablity will be assessed using ECG,this involve Fast Fourier transformation of the Blackman Harris window included very low frequency (VLF), low frequency (LF), high frequency (HF), total power (TP), and the ratios LF/HF.	The intervention period is 24 weeks (assessed at weeks 0 and 24)
ECG time domain	Four conventional ECG electrodes (Neurolink 700) is employed for these measurements. The ECG signals are transmitted wirelessly to an Android mobile telephone and stored for further processing. Time domains of heart variablity will be assessed using ECG, this involve determining the mean RR interval, standard deviation of RR interval, heartbeat rate (HR), and root mean squared difference of successive normal RR intervals (RMSSD).	The intervention period is 24 weeks (assessed at weeks 0 and 24)

Collaborators and Investigators

• Sponsor: Soren Schou Olesen
• Collaborators: Aarhus University Hospital; University of Aarhus; Stanford University; Haukeland University Hospital; Viborg Regional Hospital
• Investigators: Principal Investigator: Søren S Olesen, MD, Ph.D., Mech-Sense, Department of Gastroenterology, Aalborg University Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: May 14, 2024
• First Submitted That Met QC Criteria: May 17, 2024
• First Posted (Actual): May 23, 2024

Study Record Updates

• Last Update Posted (Actual): May 23, 2024
• Last Update Submitted That Met QC Criteria: May 17, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Digestive System Diseases; Pancreatic diseases
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Disease Attributes; Pancreatic Diseases; Chronic Disease; Pancreatitis; Pancreatitis, Chronic
• Other Study ID Numbers: F2024-054; 2023-510084-35-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to the data is available upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No