Pinaverium Bromide in Post-cholecystectomy Sphincter of Oddi Dysfunction

Application of Pinaverium Bromide in the Treatment of Patients With Post-cholecystectomy Sphincter of Oddi Dysfunction (SOD): A Randomized, Controlled and Multicenter Clinical Study

Sphincter of Oddi dysfunction (SOD) refers to biliary kinetic abnormality of the sphincter of Oddi (SO), often accompanied by pain, hepatic and pancreatic enzyme elevation, common bile duct (CBD) dilation or onset of pancreatitis. Pain caused by SOD affects the quality of life (QoL).The primary objective of this trial is to evaluate the efficacy of relieving abdominal pain of Pinaverium Bromide in medication therapy for patients with post-cholecystectomy SOD.

Study Overview

• Status: Unknown
• Conditions: Sphincter of Oddi Dysfunction
• Intervention / Treatment: Drug: Pinaverium Bromide; Drug: Danshu Capsules

Detailed Description

1.1 Background (I)

1.1.1 10%~50% of the patients who previously underwent cholecystectomy experience recurrent abdominal pain with or without diarrhea, abdominal distention, enzymatic changes, etc., and sphincter of Oddi dysfunction (SOD) accounts for about 13% of such cases;

1.1.2 Sphincter of Oddi dysfunction (SOD):

• It refers to biliary kinetic abnormality of the sphincter of Oddi (SO), often accompanied by pain, hepatic and pancreatic enzyme elevation, common bile duct (CBD) dilation or onset of pancreatitis.
• Pain caused by SOD affects the quality of life (QoL).

1.1.3 The diagnosis of SOD is still being disputed, and there has been no optimal solution so far.

• The diagnosis of SOD is largely based on clinical judgment
• The gold standards ERCP and SOM are invasive diagnostic criteria

1.2 Background (II)

1.2.1 If biliary-type abdominal pain after cholecystectomy is considered as SOD, most of the patients are classified as SOD II and SOD III according to Rome III Criteria-modified.

Biliary SOD Type I: moderate or severe biliary-type abdominal pain; transient ALT / AST/ALP elevation > 2ULN; CBD dilation > 8mm as evidenced by ultrasound or other non-invasive examination Type II: biliary-type abdominal pain; One or two of above items Type III:only biliary-type abdominal pain

1.3 Background (III)

1.3.1 Treatment of SOD is being disputed: currently, the main method is to relax sphincter of Oddi (SO).

• Medications: antispasmodic drugs, nitrates, calcium ion antagonists, modulators of gastrointestinal (GI) motility
• EST(endoscopic sphincterotomy): postoperative complications and mortality

1.3.2 EST is not well effective in the treatment of SOD type II and type III, which are mostly caused by functional abnormalities

-ASGE guideline 2015 points out that EST is not recommended for patients with SOD type III. Endoscopic stents are not recommended, either.

1.3.3 Danshu Capsules: contains the active pharmaceutical ingredient (API) and has the effects of fighting infection, alleviating pain, promoting bile secretion and lifting muscle spasms; literature showed that Danshu Capsules effectively improved the symptoms of biliary disorders, such as pain, nausea and abdominal distension.

1.3.4 Pinaverium Bromide: able to improve the spasms of SO; literature showed that it treated biliary disorders effectively.·10%~50% of the patients who previously underwent cholecystectomy experience recurrent abdominal pain with or without diarrhea, abdominal distention, enzymatic changes, etc., and sphincter of Oddi dysfunction (SOD) accounts for about 13% of such cases.

• Study Type: Interventional
• Enrollment (Anticipated): 168
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Zhaohui Tang, MD,PhD; Phone Number: +86 021 25078999-7905; Email: tangzhaohui@yahoo.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200092
      • Recruiting
      • Zhang Yong
      • Principal Investigator: Xitai Sun, MD,PhD
      • Sub-Investigator: Xiaodong Shan, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Chief complaint of upper right abdominal pain following LC (within 2 weeks to 6 months) at a hospital visit, but not a pain caused by surgical incision, lasting 3 to 5 minutes each time, without a history of other biliary tract operation
• No presence of intestinal obstruction as evidenced by plain abdominal X-ray, with peptic ulcer and duodenal diverticulum ruled out through barium meal examination or gastroscopy
• No other obvious abnormalities as evidenced by abdominal ultrasound B and MRCP, except for bile duct dilation
• Patients with biliary-type sphincter of Oddi dysfunction (SOD) who are classified as SOD type II (biliary-type abdominal pain accompanied by hepatic enzyme elevation or common bile duct (CBD) dilation) and SOD type III (only biliary-type abdominal pain) according to Geenen-Hogan classification criteria

Exclusion Criteria:

• Postoperative biliary calculi, benign biliary stenosis, bile duct infection, overlong residual cystic duct (> 0.5cm), biliary tumors, etc.
• Peptic ulcer, duodenal diverticulum
• Pancreatitis, pancreatic-type SOD
• Adhesive intestinal obstruction
• Postoperative irritable bowel syndrome (IBS)
• A history of abdominal operation or other surgery
• Pregnant and lactating women
• Use of other drugs from one week after LC to enrollment, including antispasmodic drugs, analgesics, choleretic agents, calcium ion antagonists and GI motility drugs
• A history of allergy to Pinaverium Bromide / Danshu Tablets

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pinaverium Bromide group; Able to improve the spasms of SO; literature showed that it treated biliary disorders effectively.	Drug: Pinaverium Bromide; Pinaverium Bromide (100mg potid/day) for three months by oral; Other Names: Dicetel
Active Comparator: Danshu group; Contains the active pharmaceutical ingredient (API) and has the effects of fighting infection, alleviating pain, promoting bile secretion and lifting muscle spasms; literature showed that Danshu Capsules effectively improved the symptoms of biliary disorders, such as pain, nausea and abdominal distension.	Drug: Danshu Capsules; Danshu Capsules (0.9g potid/day) for three months by oral; Other Names: Danshu softgel Capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy Evaluation of Reduction in Abdominal Pain Scores，Change From Baseline to 3 Months After Medication	abdominal pain scores (baseline vs. 3 months after treatment); Abdominal pain score based on main symptom: Degree of pain in point（0 - no pain [0 point]；1~3 - mild pain [1 point]；4~6 moderate pain [2 point]]；7~10 - severe pain [3 point]）、Frequency in times/week (No episodes[0 point]；1 time/week[1 point]；2 times/week[2 point]; 3 times/week[3 point])、Duration in days/week(No episodes[0 point]；< 1 day/week[1 point]；1-2days/week[2 points]；≥ 3days/week[3 points]); The sum of the scores for the above three items is the total score for abdominal pain.; Efficacy evaluation: reduction in abdominal pain score, as compared with the baseline; = 100%: complete remission (CR)；60%~99%: significant remission (SR)；30% ~ 59%: partial remission (PR)；0% ~ 29%: no response (NR); Treatment response = CR + SR; Treatment response rate = (CR + SR) / the total number of patients	Change From Baseline to 3 Months After Medication

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the Common Bile Duct (CBD) Diameter Measured by Ultrasound B Once a Month	Changes in the CBD diameter measured by ultrasound B; Each patient is required to abstain from eating for 12 hours and then takes a measurement of the CBD diameter by ultrasound B the next morning; The measurement takes places once a month, four times totally (baseline / 4w after treatment / 8w after treatment / 12w after treatment)	Once a Month, Four Times Totally (baseline / 4w after treatment / 8w after treatment / 12w after treatment)
Efficacy of Lowering Liver Enzymes as Assessed by Laboratory Test Once a Month	Changes in hepatic enzyme levels (ALT, AST and ALP); The measurement takes place once a month, four times totally (baseline / 4w after treatment / 8w after treatment / 12w after treatment)	Once a Month, Four Times Totally (baseline / 4w after treatment / 8w after treatment / 12w after treatment)
Number of Participants With Treatment-Related Diarrhea,Change From Baseline to 3 Months After Medication	The number of patients presenting the symptoms of diarrhea will be calculated at the time of enrollment (baseline) and 3 months after treatment respectively.	From Baseline to 3 Months After Medication

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Related Adverse Events as Assessed by Researchers or Doctors Through Study Completion	Incidence of adverse events (throughout the treatment); The type and number of adverse events will be calculated at the baseline and each visit; Inquire about symptoms: rashes, pruritus, acid regurgitation, abdominal distention, diarrhea, etc.; Perform the following examinations at the last visit: blood / urine / stool test, liver / kidney function test, ECG	Through Study Completion, An Average of 1 Year

Collaborators and Investigators

• Sponsor: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Investigators: Principal Investigator: Zhaohui Tang, MD,PhD, Xinhua Hospital,School of Medicine,Shanghai Jiao Tong University; Study Chair: Zhiwei Quan, MD,PhD, Xinhua Hospital,School of Medicine,Shanghai Jiao Tong University

Publications and helpful links

General Publications

• Cotton PB, Durkalski V, Romagnuolo J, Pauls Q, Fogel E, Tarnasky P, Aliperti G, Freeman M, Kozarek R, Jamidar P, Wilcox M, Serrano J, Brawman-Mintzer O, Elta G, Mauldin P, Thornhill A, Hawes R, Wood-Williams A, Orrell K, Drossman D, Robuck P. Effect of endoscopic sphincterotomy for suspected sphincter of Oddi dysfunction on pain-related disability following cholecystectomy: the EPISOD randomized clinical trial. JAMA. 2014 May;311(20):2101-9. doi: 10.1001/jama.2014.5220.
• Vitton V, Ezzedine S, Gonzalez JM, Gasmi M, Grimaud JC, Barthet M. Medical treatment for sphincter of oddi dysfunction: can it replace endoscopic sphincterotomy? World J Gastroenterol. 2012 Apr 14;18(14):1610-5. doi: 10.3748/wjg.v18.i14.1610.
• Okoro N, Patel A, Goldstein M, Narahari N, Cai Q. Ursodeoxycholic acid treatment for patients with postcholecystectomy pain and bile microlithiasis. Gastrointest Endosc. 2008 Jul;68(1):69-74. doi: 10.1016/j.gie.2007.09.046.
• Kalaitzakis E, Ambrose T, Phillips-Hughes J, Collier J, Chapman RW. Management of patients with biliary sphincter of Oddi disorder without sphincter of Oddi manometry. BMC Gastroenterol. 2010 Oct 22;10:124. doi: 10.1186/1471-230X-10-124.
• Behar J, Corazziari E, Guelrud M, Hogan W, Sherman S, Toouli J. Functional gallbladder and sphincter of oddi disorders. Gastroenterology. 2006 Apr;130(5):1498-509. doi: 10.1053/j.gastro.2005.11.063.
• Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology. 2006 Apr;130(5):1377-90. doi: 10.1053/j.gastro.2006.03.008. No abstract available.
• Hernando N, Gisler SM, Reining SC, Deliot N, Capuano P, Biber J, Murer H. NaPi-IIa interacting proteins and regulation of renal reabsorption of phosphate. Urol Res. 2010 Aug;38(4):271-6. doi: 10.1007/s00240-010-0304-3. Epub 2010 Jul 28.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Anticipated): February 1, 2018
• Study Completion (Anticipated): February 1, 2018

Study Registration Dates

• First Submitted: July 4, 2016
• First Submitted That Met QC Criteria: July 11, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Estimate): July 14, 2016
• Last Update Submitted That Met QC Criteria: July 11, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Sphincter of Oddi Dysfunction; cholecystectomy; Pinaverium Bromide
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Postoperative Complications; Biliary Tract Diseases; Bile Duct Diseases; Biliary Dyskinesia; Common Bile Duct Diseases; Sphincter of Oddi Dysfunction; Postcholecystectomy Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Membrane Transport Modulators; Anticonvulsants; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Bromides; Pinaverium
• Other Study ID Numbers: XH-16-015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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