Tocilizumab for Painful Chronic Pancreatitis: A Randomised, Placebo-Controlled, Double-blinded, Investigator Initiated Trial (TOPAC Trial)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Questionnaire
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Placebo
100 ml sodium chloride 9 mg/mL (0.9 %).
干预措施: Sodium Chloride 0.9% Inj (Drug)
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 %)
干预措施: Tocilizumab 20 MG/ML [Actemra] (Drug)
结局指标
主要结局
The Comprehensive Pain Assessment Tool Short Form (COMPAT-SF) Questionnaire
时间窗: 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.
次要结局
- Global Quality of Life Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Emotional Functional Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Daily weak analgesics dose for patients(The intervention period is 24 weeks (continuously throughout the entire study))
- Physical Functional Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Pain severity Score (modified BPI)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Pain Interference Score (modified BPI)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Daily opioid dose for patients using prescription opiods(The intervention period is 24 weeks (continuously throughout the entire study))
- Number of patient using weak analgesics for pain control(The intervention period is 24 weeks (continuously throughout the entire study))
- Cognitive Functional Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- CP Prognosis Score(The intervention period is 24 weeks (assessed at weeks 0 and 24))
- Frequency of adverse events (Patient Diary)(The intervention period is 24 weeks (continuously throughout the entire study))
- Role Functional Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Number of patient using prescription opioids for pain control(The intervention period is 24 weeks (continuously throughout the entire study))
- Social Functional Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Symptom Burden Score (EORTC-QLQ-C30)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Average Daily Pain Score (modified BPI)(The intervention period is 24 weeks (assessed at weeks 0, 12, and 24))
- Patient's Global Impression of Change (PGIC) Questionnaire(The intervention period is 24 weeks (assessed at week 24))
研究者
Soren Schou Olesen
Professor, MD, Ph.D.
Aalborg University Hospital