Celiac Plexus Block for Chronic Pancreatitis RCT

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Brief Title

Celiac Plexus Block for Chronic Pancreatitis RCT

Official Title

Prospective Randomized Trial of EUS Guided Celiac Plexus Block for Chronic Pancreatitis

Brief Summary

      Rationale: Chronic pancreatitis is a chronic inflammatory disease of the pancreas which
      results in debilitating abdominal pain, decreased productivity and increased health care
      costs. Endoscopic ultrasound (EUS) guided celiac plexus block (CPB) is routinely used to
      treat pain related to chronic pancreatitis. While EUS guided neurolysis for pancreatic cancer
      has significant efficacy, the benefit of CPB for chronic pancreatitis pain is controversial
      and has not been studied in a rigorous manner.

      Objective: To assess whether EUS guided celiac plexus block decreases suffering,
      hospitalization, and opiate requirements related to chronic pancreatitis pain.

      Population: Patients undergoing EUS at Los Angeles County Hospital for painful chronic
      pancreatitis.

      Methods: Patients undergoing EUS to evaluate chronic pancreatitis with a typical visual
      analogue pain score >3, regular opiate use, and M ANNHEIM chronic pancreatitis score >6 will
      be eligible.

      Study Arms: Patients will be randomized to 1) diagnostic endoscopic ultrasound 2) endoscopic
      ultrasound with celiac plexus block

      Study Outcomes: The primary outcome will be a decrease in chronic pancreatitis pain assessed
      by the visual analogue scale and M ANNHEIM system at 24 weeks compared to immediately prior
      to the block. The ability to work and conduct normal activities, opiate medication
      requirements, and a Careprep symptom assessment at 24 weeks will also be compared prior to
      the block.

      Analytic Plan: The projected response rate to EUS guided CPB is 52%. Given known 30% placebo
      response in patients with pain related to chronic pancreatitis we anticipate that 83 patients
      will need to participate to demonstrate a difference. We aim to enroll 90 patients in this
      study.
    

Detailed Description

      1.0 Background and Hypothesis: Chronic pancreatitis is an inflammatory disease of the
      pancreas characterized by painful scarring and loss of glandular function.The prevalence of
      chronic pancreatitis in the United States is estimated to be 0.2 to 5% and results in 86,000
      hospitalizations. The majority of patients with chronic pancreatitis will develop significant
      abdominal pain which is debilitating and results in a significant burden on the health care
      system.

      Multiple approaches, including pancreatic enzymes, narcotic analgesia, celiac plexus block
      and surgical ganglionectomy have been used to treat pancreatic pain with variable success.
      Injection of local anesthesia agents and steroids into the celiac plexus for pain control has
      been used for many years via both surgical and percutaneous approaches. Topical therapy
      theoretically prevents the conduction of painful stimuli from the pancreas and addresses
      inflammatory changes in the afferent nerves themselves. Splanchnic nerves pass from the
      pancreas to the thoracic root ganglia via the celiac ganglia which are the target for
      intervention. Nerve changes in chronic pancreatitis including perineural inflammation,
      altered diameter, and upregulation of pain neuropeptides (including Substance P) are
      associated with increased sensitivity to stimuli from the pancreas (distension and
      inflammation) as well as pain independent of stimuli (neuropathic). Endoscopic ultrasound
      allows for close proximity, high resolution assessment of the gastrointestinal tract wall and
      adjacent anatomic structures. Physicians are able to perform EUS-guided celiac plexus
      injections in the outpatient setting under conscious sedation. The EUS guided approach offers
      better visualization of the celiac region and direct access to the celiac plexus. EUS guided
      celiac plexus block is a core part of the routine care of patients at Los Angeles County
      Hospital with chronic pancreatitis. Celiac plexus block is a recommendation for refractory
      chronic pancreatitis pain by the European Society of Gastrointestinal Endoscopy (ESGE).

      Several studies have shown that EUS-guided CPB has a beneficial role in treating pain caused
      by chronic pancreatitis. A randomized trial by Gress et al looked at the efficacy of
      EUS-guided versus CT-guided celiac plexus block for controlling abdominal pain of chronic
      pancreatitis in 18 patients. They found significant improvement in pain symptoms in patients
      randomized to EUS-guided celiac plexus block over a mean time period of 10 weeks. A study by
      the same group showed an improvement in overall pain score in 55% at 4 and 8 weeks of
      follow-up in 90 patients. Adverse events including diarrhea and infection occurred in 3%. A
      comprehensive review by Kaufman et al in 2010 evaluated the efficacy of EUS-guided celiac
      plexus block and celiac plexus neurolysis in alleviating chronic abdominal pain due to
      chronic pancreatitis and pancreatic cancer respectively. A total of 6 studies were included
      in their analysis, comprising 221 patients, and found that EUS-guided celiac plexus block was
      effective in 51.46% of patients with chronic pancreatitis. EUS-guided celiac plexus
      neurolysis (with alcohol) was effective in 72.54% of those with pancreas cancer.

      These modest improvement for celiac block for chronic pancreatitis (especially in comparison
      to celiac plexus neurolysis in pancreas cancer) have led some investigators to question
      whether EUS guided celiac plexus block is an effective treatment for chronic pancreatitis
      pain despite its routine use. Prospective randomized controlled studies examining the
      efficacy of endoscopic ultrasound guided celiac plexus block are lacking.

      2.0 Objectives and Purpose Our aim is to perform a pilot randomized trial to gauge the degree
      to which celiac plexus block performed under endoscopic ultrasound guidance will benefit
      patients with chronic pancreatitis. We will assess whether celiac plexus block significantly
      decreases pain scores, hospitalization, and pain medication requirements and increases the
      ability to return to normal activities.

      3.0 Study Design Patients presenting to the Los Angeles County Medical Center and
      Gastroenterology Clinic with chronic upper abdominal pain are the focus population of this
      study. Patients who are undergoing endoscopic ultrasound for standard clinical care to assess
      for chronic pancreatitis will be enrolled. They must have a M-ANNHEIM severity score of 6 or
      greater. Additionally, they must have at least intermittent if not chronic pain of intensity
      >3 on the visual analogue scale requiring opiate medication.

      The procedures will be performed by experienced endosonographers. The EUS-guided celiac
      plexus block will be performed under the guidance of linear array endosonography. A visual
      exam will first be performed with the EUS scope or a standard endoscope. Patients found to
      have a significant peptic ulcer or other mucosal abnormality will be excluded as the symptoms
      may be secondary to peptic disease. An EUS exam will then be performed to determine whether
      the patient has findings of chronic pancreatitis. The diagnosis of chronic pancreatitis will
      be confirmed based on EUS criteria (meeting four or more criteria of hyperechoic foci,
      hyperechoic strands, lobularity, cysts, stones, dilation of the main pancreatic duct,
      irregular pancreatic-duct margins, presence of side branches and hyperechoic pancreatic
      duct-margins).

      Those who are confirmed to have chronic pancreatitis will be randomized (1:1) during the
      procedure to celiac plexus block versus no injection treatment. Randomization will be
      performed using a computer program with concealed allocation. The research coordinator
      obtaining data for follow up visits and the patient will be blinded to randomization. The
      endosonographer will not be blinded. Ninety patients will be enrolled (see statistical
      considerations for sample size calculation).

      Those randomized to control will undergo EUS and confirmation of chronic pancreatitis but not
      celiac plexus block. Patients in the treatment group will receive celiac plexus block with
      10mL 0.25% bupivacaine and 2ml (40mg/cc) triamcinolone which are the standard doses. The 22
      gauge needle will be inserted into the base of the celiac plexus via the transgastric
      approach and a single injection will be performed. An intravenous antibiotic will be
      administered at the time of the block to those in the celiac plexus block group with the
      specific agent depending on the patient's allergy profile. The research coordinator obtaining
      data for follow up visits and the patient will be blinded to the details of the block (or
      lack thereof) procedure but it will be recorded.

      Following the procedure standard recovery room monitoring including assessment of blood
      pressure be performed for 2 hours for both groups. Periprocedural fluid and antibiotic use
      for celiac plexus block is not standardized and will be at the discretion of the endoscopist
      performing the cases.

      Patients will be assessed before the procedure, immediately afterward, and at 2 weeks, 6
      weeks, 3 months, and 6 months following the procedure. At the initial assessment and follow
      up visits Visual analogue pain scores will be recorded as well as an assessment of the
      ability to work and conduct activities of daily living. Pain medication requirements and
      whether symptoms are alleviated by analgesic or disrupt sleep will be noted. The M-ANNHEIM
      scoring system will be used to gauge symptoms as well.

      Additionally, patients will complete a focused version of the online CarePrep Program during
      each visit. The Online CarePrep (OCA) program is used to clinically evaluate patients with
      complex symptoms or conditions generally characterized significant physical symptoms,
      psychosocial issues, impaired quality-of-life and functional status, disability, and
      substance abuse. It has an online format that has been successfully used by outpatient with
      various gastrointestinal illness to report multifactorial symptoms. When performed prior to
      appointments it appears to facilitate efficient and productive medical visits.

      4.1 Side effects/Toxicities to be monitored:

      4.11 Three most common complications from celiac plexus block include hypotension, transient
      diarrhea, transient increase in pain. Extraordinarily rare/theoretical complications include
      paralysis, pneumothorax, loss of sphincter function, retroperitoneal bleeding, renal puncture
      and prolonged gastroparesis.

      4.12 Long term toxicities to be monitored after completion of the celiac block during the 6
      months the patients are followed.

      4.2 Dosage changed based on toxicity There will be no dosage adjustments as the procedure
      will be performed once during the study period.

      4.3 Adverse Event Reporting: 4.31 Type of event to be reported and timing of reports. If
      patients develop adverse events including hypotension, transient diarrhea, transient increase
      in pain, or less common complications of unilateral paresis or paraplegia, pneumothorax, loss
      of sphincter function, retroperitoneal bleeding, renal puncture, prolonged gastroparesis or
      infection, this will be reported to the principal investigators and will be reviewed by the
      study team as well as two staff physicians in the gastroenterology division who are not part
      of the study team. This will also be reported to the IRB.

      If patients experience any further events that are detected during follow up these will be
      coded as A) related to study or B) not related to study. Their severity and A) whether they
      were expected or B) not expected will also be recorded. These complications will also be
      reported to the principal investigators and will be reviewed by the study team as well as two
      staff physicians in the gastroenterology division who are not party of the study team. They
      will also be reported to the IRB.

      4.32 Places for submitting reports: Adverse events will be reported to the IRB and data
      safety monitoring committee.

      4.4 Data Monitoring Committee: The data safety monitoring committee will include the
      principal investigators from medicine/gastroenterology as well as the entire study team. Two
      outside senior physician from gastroenterology or surgery will also be asked to participate.
      Meetings will be convened if adverse events potentially related to the celiac block occur.

      5.0 Statistical Considerations Descriptive statistics will be performed for each group, and
      comparisons made to determine if the groups are balanced on the stratification factor of type
      of pancreatitis. Patient characteristics will be compared between groups as well to determine
      if there is imbalance of other possible covariates. We expect that there will be patients
      with chronic pancreatitis secondary to congenital abnormalities of the pancreatic duct,
      ethanol abuse, familial, and idiopathic etiologies.

      The sample size of 90 patients was chosen based on preliminary sample size calculations.
      Based on recent studies 30% of patients with pancreatitis type pain in the placebo arm will
      derive benefit.16 The predicted response rate of 51.5% for EUS guided celiac block was based
      on the large review by Kaufmann et al. For a 2 sided alpha of 0.05 and a power of 0.80, 83
      patients would be necessary to show a difference. Statistical analyses will be performed by
      biostatisticians at the Biostatistical and Bioinformatics Resource Group within the SC CTSI.
    


Study Type

Interventional


Primary Outcome

Long Term CHANGE in Pain Scores

Secondary Outcome

 Hospital re-admission

Condition

Pancreatitis, Chronic

Intervention

Celiac Block with triamcinolone and bupivicaine

Study Arms / Comparison Groups

 EUS with Celiac Block
Description:  Celiac Block with triamcinolone and bupivicaine Intra Plexus Triamcinolone and Bupivicaine Injection

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

1

Start Date

December 2014

Completion Date

February 12, 2018

Primary Completion Date

February 12, 2018

Eligibility Criteria

        Inclusion Criteria:

          -  Presentation with upper abdominal pain suggestive of pancreatitis who are undergoing
             EUS for evaluation

          -  M ANNHEIM severity index of 6 or greater to be included

          -  Intermittent episodes of pain>3 requiring opiate medication

        Exclusion Criteria:

          -  Patients who have allergic reactions to steroids or bupivacaine

          -  INR >1.6

          -  platelets <75

          -  decompensated cirrhosis

          -  incarcerated

          -  <18 years old

          -  unable to give informed consent

          -  peptic ulcer disease

          -  ongoing substance or alcohol use
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

James Buxbaum, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02399800

Organization ID

HS-14-00134


Responsible Party

Principal Investigator

Study Sponsor

University of Southern California


Study Sponsor

James Buxbaum, MD, Principal Investigator, Los Angels County Hospital


Verification Date

February 2018