Clinical trial NCT06426160: Tocilizumab for Painful Chronic Pancreatitis
Official title: Tocilizumab for Painful Chronic Pancreatitis: A Randomised, Placebo-Controlled, Double-blinded, Investigator Initiated Trial (TOPAC Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pancreatitis, Chronic
Keywords: Inflammation
Pancreatic diseases
Digestive System Diseases
Lead sponsor: Aalborg University Hospital
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: University of Aarhus
name: Viborg Regional Hospital
name: Stanford University
name: Haukeland University Hospital
First posted: 2024-05-23
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomised, placebo-controlled, double-blinded investigator-initiated trial
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Questionnaire
timeFrame: The intervention period is 24 weeks (assessed every 4 weeks from baseline to finalization)
Secondary outcomes:
measure: Global Quality of Life Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Physical Functional Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Role Functional Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Cognitive Functional Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Emotional Functional Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Social Functional Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Symptom Burden Score (EORTC-QLQ-C30)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Pain severity Score (modified BPI)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Pain Interference Score (modified BPI)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Average Daily Pain Score (modified BPI)
timeFrame: The intervention period is 24 weeks (assessed at weeks 0, 12, and 24)
measure: Patient's Global Impression of Change (PGIC) Questionnaire
timeFrame: The intervention period is 24 weeks (assessed at week 24)
measure: CP Prognosis Score
timeFrame: The intervention period is 24 weeks (assessed at weeks 0 and 24)
measure: Number of patient using prescription opioids for pain control
timeFrame: The intervention period is 24 weeks (continuously throughout the entire study)
measure: Daily opioid dose for patients using prescription opiods
timeFrame: The intervention period is 24 weeks (continuously throughout the entire study)
measure: Number of patient using weak analgesics for pain control
timeFrame: The intervention period is 24 weeks (continuously throughout the entire study)
measure: Daily weak analgesics dose for patients
timeFrame: The intervention period is 24 weeks (continuously throughout the entire study)
measure: Frequency of adverse events (Patient Diary)
timeFrame: The intervention period is 24 weeks (continuously throughout the entire study)
Other outcomes:
measure: Levels of soluble inflammation biomarker
timeFrame: The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
measure: Levels of soluble fibrosis biomarker
timeFrame: The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
measure: Levels of soluble Biomarker of Macrophage Activation
timeFrame: The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
measure: Levels of key Inflammatory Mediator
timeFrame: The intervention period is 24 weeks (samples drawn at weeks 0, 4, 8, 16, and 24)
measure: Pancreatic inflammation (imaging)
timeFrame: The intervention period is 24 weeks (conducted at weeks 0 and 24)
measure: Pancreatic fibrosis (imaging)
timeFrame: The intervention period is 24 weeks (conducted at weeks 0 and 24)
measure: Pancreatic morphology (imaging)
timeFrame: The intervention period is 24 weeks (conducted at weeks 0 and 24)
measure: Pancreatic duct morphology (imaging)
timeFrame: The intervention period is 24 weeks (conducted at weeks 0 and 24)
measure: Biliary duct morphology (imaging)
timeFrame: The intervention period is 24 weeks (conducted at weeks 0 and 24)
measure: P-QST: PinPrick (Temporal summation)
timeFrame: The intervention period is 24 weeks (performed at weeks 0 and 24)
measure: P-QST: Pain Pressure thresholds
timeFrame: The intervention period is 24 weeks (performed at weeks 0 and 24)
measure: P-QST: Cold Pressor
timeFrame: The intervention period is 24 weeks (performed at weeks 0 and 24)
measure: P-QST: Conditioned Pain Threshold
timeFrame: The intervention period is 24 weeks (performed at weeks 0 and 24)
measure: Electroencephalography (EEG) analysis
timeFrame: The intervention period is 24 weeks (assessed at weeks 0 and 24)
measure: Electrocardiographic (ECG) frequency domain
timeFrame: The intervention period is 24 weeks (assessed at weeks 0 and 24)
measure: ECG time domain
timeFrame: The intervention period is 24 weeks (assessed at weeks 0 and 24)
Locations:
city: Aalborg
country: Denmark
facility: Centre for Pancreatic Diseases and Mech-Sense research laboratory, Aalborg University Hospital
state: Nordjylland
Study officials:
affiliation: Mech-Sense, Department of Gastroenterology, Aalborg University Hospital
name: Søren S Olesen, MD, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: