Extracorporeal Shock Wave Lithotripsy and Endotherapy for Pain in Chronic Pancreatitis

Study Overview
=================
Brief Summary
-----------------
Pain is a common symptom of chronic pancreatitis and remains a significant therapeutic challenge. In patients with pathological changes of the pancreatic duct, including stones and strictures, endoscopic procedures with or without preceding extracorporeal shock wave lithotripsy (ESWL) have been used with varying success to treat pain, but high quality evidence is lacking so support this practice. The main objective of this study is to investigate the pain-relieving effects of combined ESWL and endotherapy in patients with painful CP in comparison with sham treatment.

Detailed Description
-----------------
Pain is the predominant symptom in patients with chronic pancreatitis (CP) and remains a considerable therapeutic challenge. In patients with pathological changes of the pancreatic duct, including stones and strictures, endoscopic procedures with or without preceding extracorporeal shock wave lithotripsy (ESWL) and surgery have been used with varying success to treat pain. The rationale for endoscopic therapy or surgical drainage procedures is based on the hypothesis that obstruction of the pancreatic duct leads to ductal hypertension and pain. However, clinical pain symptoms correlate poorly with pancreatic ductal morphology and the response to endoscopic or surgical treatment is unpredictable, with long term response rates ranging from 30-60%. The evidence for these treatments are, however, based on case-series and comparison between different procedures, while no prospective sham controlled trials have evaluated the effectiveness of invasive treatments for pain in CP. In addition, a marked placebo effect has been observed in most trials of painful CP and this, together with the natural history of disease, needs consideration when treatment effects are evaluated. Therefore, the rationale behind invasive treatments for pain in CP treatments can be questioned. Recent meta-analyses have documented that the non-specific effects of surgery and other invasive procedures are generally large; particularly in the field of pain-related conditions. For example, arthroscopic meniscectomy for degenerative meniscal lesions has for many years been considered the state of the art treatment for this common condition. However, a high quality randomized controlled trial (RCT) and meta-analysis have not shown any differences in pain relieving effects between surgery and sham procedures for degenerative meniscal lesions. These findings challenge conventional wisdom and underline the necessity of properly conducted RCTs including a sham procedure, when the effectiveness of invasive procedures is evaluated. Albeit endoscopic therapy or surgery are widely used for pain in CP these treatments are only effective in a subset of patients. An improved understanding of the mechanisms underlying pain in CP suggest that the pain etiology in most patients is multifactorial and, in addition to the proposed mechanical mechanisms for pain (ductal obstruction/hypertension), a large body of evidence support a ´neuropathic pain phenotype´ with abnormal processing in the peripheral and central neural pathways. This likely explains the variable response to endoscopic and surgical treatments and underline an unmet need for biomarkers to identify responders to the different treatment modalities. Quantitative sensory testing (QST) can be used to investigate the state of the pain system; the technique is based on the rationale that different neural pathways and networks can be explored using standardized stimulation with simultaneous recording of the evoked pain response by psychophysical and/or objective methods. Due to spinal convergence between visceral afferents from the pancreas and somatic afferents from the Th10 skin dermatome, somatic QST can be reliable used to assess if the pain system is locally sensitized by nociceptive input from the pancreas (segmental sensitization). However, in many patients with chronic pain the pain system has become dysfunctional and has undergone a more universal sensitization. In such cases the QST profile of testing in several dermatomes together with specific test paradigms (temporal summation and assessment of descending inhibition) can be used to determine whether patients have abnormal central pain processing. The hypothesis of the present study is that combined ESWL and endotherapy induce short term (3 months) and mid-term (6 months) pain relief in patients with CP compared to a sham procedure. In addition, the investigators hypothesize that QST can be used to predict the outcome of combined ESWL and endoscopic therapy. Hence, patients with evidence of abnormal pain processing are hypothesized to have a worse outcome to treatment compared to patients with segmental or no evidence of sensitization.

Official Title
-----------------
A Randomized, Single-blinded, Single-center, Parallel-group, Sham-controlled, Prospective Trial of Combined Extracorporeal Shock Wave Lithotripsy and Endotherapy for Pain in Chronic Pancreatitis

Conditions
-----------------
Chronic Pancreatitis, Chronic Pain

Intervention / Treatment
-----------------
* Procedure: ESWL
* Procedure: ERCP
* Procedure: Sham ESWL
* Procedure: Sham ERCP


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients from the ages of 18 with a diagnosis of chronic calcific pancreatitis diagnosed using the Mayo Clinic diagnostic criteria. Both diabetic and non-diabetic patients will be allowed to enter the study. The patients must suffer from chronic abdominal pain characteristic for CP with a pain intensity >3 VAS on a 0-10 VAS and meet the criteria for chronic pain (pain ≥ 3 days per week in at least 3 months). Obstruction of the pancreatic duct due to intraductal stones with dilatation of the duct proximal to the obstruction, as determined by magnetic resonance cholangiopancreatography, abdominal computed tomography, or both. The patients must be able to read and understand the provided informed consent. Patients must personally sign and date informed consent document indicating that he/she has been informed of all pertinent aspects of the trial. Patients should be willing to comply with the scheduled visits, clinical and experimental assessment plan, and other trial procedures. Exclusion Criteria: Patients with any clinically significant laboratory abnormalities that in the opinion of the investigator may increase the risk associated with trial participation or may interfere with the interpretation of the trial results. Previous history of pancreatic surgery, ESWL or ERCP. Patients with a pancreatic stricture on cross-sectional imaging prior to study enrolment Active alcohol or illegal drug dependencies. Patients with evidence or history of medical or surgical disease of importance for this study as judged by investigator. Patients must not suffer from painful conditions other than CP that make them unable to distinguish the pain associated with CP from chronic pain of other origin. Presence of pancreatic head mass, multiple strictures, large ascites, large fluid collections.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ESWL followed by ERCP<br>Patients enrolled in the active treatment group will be subjected to ESWL followed by ERCP and pancreatic duct stenting. | Procedure: ESWL<br>* ESWL will be conducted under epidural anesthesia. For epidural anesthesia, bupivacaine will be used to block the T6-T12 spinal segments. The patient's eyes will be lightly covered all along the procedure. Once epidural anesthesia is achieved, the patient will be given a light sedation and ESWL will be performed using a Dornier dual focus lithotripsy system providing a maximum of 5000 at the rate of 90 shocks per minute in over 1-2 days.<br>Procedure: ERCP<br>* Once ESWL is over, an endoscopic pancreatic sphincterotomy will be performed and complete stone removal will be attempted with subsequent stenting of the pancreatic duct in the presence of a pancreatic stricture (not detected on MRCP prior to enrolment) or in case of incomplete stone removal<br>|
| Sham Comparator: Sham ESWL followed by sham ERCP<br>Patients enrolled in the sham treatment group will be subjected to sham ESWL followed by sham ERCP with no pancreatic duct intervention. | Procedure: Sham ESWL<br>* In the sham/control group, patients will be given a transient superficial pin-prick sensation to give the feel of epidural anesthesia. After that the lithotripsy machine the will be switched on, without establishing any form of contact with the patients body.<br>Procedure: Sham ERCP<br>* Following sham ESWL patientswill be subjected to sham ERCP to examine the papillary area, but no pancreatic ductal intervention will be performed.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline pain score at 3 months | The primary clinical endpoint is pain relief. Average and maximal daily clinical pain intensity scores will be recorded in a patient pain diary based on a 0-10 visual analogy scale (VAS), with registration of the baseline pain intensity scores the week prior to intervention and weekly recordings continued for a 3 months period after intervention. Mean values of pain scores will be calculated over 1 week to adjust for day-to-day variability in pain intensity. The difference in pain scores between patients receiving active treatment (ESWL and ERCP) and sham treatment are compared, with the primary comparison of average pain scores 3 months after intervention. Weekly telephone interviews from a study co-ordinator will be undertaken to facilitate accurate registration and compliance pain score). | 3 months after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of responders versus non-responders | The ratio of responders versus non-responders defined by a decrease in the average clinical pain score (VAS) of 30% after 3 and 6 months compared to baseline. | 3 and 6 months after intervention | 
| Change in analgesic consumption | Change in analgesic consumption (if used) after 3 and 6 months compared to baseline | 3 and 6 months after intervention | 
| Hospitalization | Total number of hospitalizations during the study period after 3 and 6 months | 3 and 6 months after intervention | 
| Change in quality of life (EORTC-QLQ C 30) | Change in quality of life using the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30) after 3 and 6 months compared to baseline | 3 and 6 months after intervention | 
| Changes in pain and physical functioning composite scores (BPI-sf) | Changes in pain and physical functioning composite scores of the modified brief pain inventory-short form (mBPI-sf) after 3 and 6 months compared to baseline | 3 and 6 months after intervention | 
| Patient Global Impression of Change | Patient Global Impression of Change (PGIC) after 3 and 6 months | 3 and 6 months after intervention | 
| Complications | Assessment of complications to interventions after 3 and 6 months | 3 and 6 months after intervention | 
| Change from baseline pain score at 6 months | This will be evaluated as described for the primary end-point | 6 months after intervention | 
| Pain free days after intervention | Difference in number of pain free days between groups after 3 and 6 months. | 3 and 6 months after intervention | 
| Change in anxiety and depression after intervention | • Difference in depression and anxiety scores of the Hospital Anxiety and Depression scale between groups after 3 and 6 | 3 and 6 months after intervention |