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The Role of Ursodeoxycholic Acid in Treatment of Gallstones in Hemolytic Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02472509
Recruitment Status : Terminated (Study not feasible - very low recruitment rate)
First Posted : June 16, 2015
Last Update Posted : October 10, 2017
Information provided by (Responsible Party):
Shaare Zedek Medical Center

Brief Summary:

It is well established that hemolytic diseases predispose patients to the development of pigment gallstones. Gallstones are noted in at least 5% of children under the age of 10 years, increasing to 40-50% in the second to fifth decades. The co-inheritance of Gilbert's syndrome increases the risk of cholelithiasis four to five-fold.

In patients with chronic hemolysis, total bile lipid concentration is decreased and the total bilirubin to total lipid ratio is increased. This suggests that the conjugating capacity of hepatocytes is surpassed by the excessive amount of bilirubin resulting from hemolysis. Increased bilirubin monoconjugate and unconjugated bilirubin can precipitate in bile and form complexes with inorganic ions, mostly calcium, and develop into stones.

Patients with hemolytic disorders can also develop biliary sludge, a suspension of precipitated particulate matter in bile dispersed in a viscous, mucin-rich liquid phase . The chemical composition of the precipitates correlates well with the composition of the associated stone and sludge often stands as a harbinger of future stone development.

There is strong data suggesting a benefit in treating cholelithiasis with UDCA and also in preventing gallstone development in various high risk scenarios.

There are several proposed mechanisms for the positive effect of UDCA in primary prevention of pigment stones. Mucoglycoproteins are present in significant amounts in black pigment stones and contribute to the matrix of gallstones. UDCA suppresses the secretion of protein and decreases the levels of various proteins in bile . It has also been suggested that increased colonic bile salt may solubilize unconjugated bilirubin and may prevent calcium complexing.

There is no published data at present on the role of UDCA in prevention and treatment of cholelithiasis in hemolytic diseases. The investigators hypothesise that UDCA can be of benefit to patients with hemolytic disorders in the primary prevention of pigment stones, possible resolution of biliary sludge and existent stones, and reduction of symptomatic episodes of cholelithiasis.

Condition or disease Intervention/treatment Phase
Hemolytic Disorders Gallstones Drug: Ursodeoxycholic Acid Phase 4

Detailed Description:

The research protocol extends for up to 12 months, during which the participant will attend 3 clinic visits at Shaare Zedek Medical Centre; one at study enrollment, one at 6 months and one at 12 months.

All patients identified will have their medical records reviewed for previous clinical, biochemical or sonographic evidence of gallstones.

Patients will undergo a baseline abdominal ultrasound to assess for biliary sludge, gallstones, or evidence of previous cholecystitis (eg. Thickened gallbladder wall).

All patients will also have blood tested for liver biochemistry, complete blood count, hemolytic screen and fasting lipids.

Participants will be commenced on UDCA 15mg/kg/day (maximum dose 900mg/day) in 2-3 divided doses for 12 months.

Patients who are unable to tolerate tablet medication will be started on UDCA syrup at the same dose.

Each of the in-house visits will include:

  1. An explicit history taking and review of patient's notes, including review of symptoms, blood tests and previous ultrasounds, other medical conditions and medications.
  2. Physical examination - including measuring splenic size, assessing for right upper quadrant abdominal tenderness
  3. Blood tests

    1. Hemoglobin, WBC
    2. Liver biochemistry: ALT, AST, GGT, ALP (Alkaline Phosphatase), Bilirubin (conjugated and unconjugated), Albumin
    3. Hemolytic screen: LDH, haptoglobin, reticulocytes
    4. Fasting lipids: LDL, HDL, Triglycerides

Repeat abdominal ultrasound will be performed at 12 months. The US will specifically relate to the following features in comparison to the baseline US:

  1. Presence of biliary sludge
  2. Presence of gallstone: i.Size ii.Number
  3. Presence of bile duct dilatation
  4. Presence of gall bladder wall thickening

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: The Role of Ursodeoxycholic Acid in Treatment of Gallstones in Hemolytic Disorders
Study Start Date : December 2014
Actual Primary Completion Date : September 10, 2017
Actual Study Completion Date : September 10, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Gallstones
Drug Information available for: Ursodiol

Arm Intervention/treatment
Experimental: Open Label
32 patients with hemolytic disorders meeting the inclusion and exclusion criteria will be commenced on Ursodeoxycholic acid (UDCA).
Drug: Ursodeoxycholic Acid

Patients will be commenced on UDCA 15mg/kg/day (maximum dose 900mg/day) in 2-3 divided doses for 12 months.

Patients who are unable to tolerate tablet medication will be started on UDCA syrup at the same dose.

Other Name: Ursolit

Primary Outcome Measures :
  1. Lack of sonographic, clinical or biochemical evidence of progression of cholelithiasis or biliary sludge. [ Time Frame: 12 months ]

Secondary Outcome Measures :
  1. Improvement in number and severity of episodes of symptomatic gallstones. [ Time Frame: 12 months ]
  2. Rate of surgical intervention for gallstones disease. [ Time Frame: 12 months ]
  3. Sonographic improvement (size and number of gallstones, presence of bile sludge, gallbladder wall thickness). [ Time Frame: 12 months ]
  4. Evaluate tolerability and adverse effects of UDCA therapy in hemolytic disorders. [ Time Frame: 12 months ]
    including non-specific abdominal discomfort, rash or nausea.

  5. Improved biochemical evidence of gallstone disease [ Time Frame: 12m ]
    reduced gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP).

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Diagnosis of a hemolytic disorder including spherocytosis, G6PD deficiency, thalassemia or sickle cell disease.
  2. Patients with cholelithiasis or bile sludge.
  3. Age greater than or equal to 4 years.
  4. Ability to consent to and participate in the study and follow study procedures.

Exclusion Criteria:

  1. Previous splenectomy (complete or partial)
  2. Evidence of hemolytic crisis at the time of research enrollment
  3. Patients with highly symptomatic gallstones who have planned surgical intervention
  4. Known allergy or intolerance to UDCA
  5. Existence of concurrent hepatic disease
  6. Any other laboratory or clinical condition that the investigator considers clinically significant that could impact the outcome of the study or the safety of the patient.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02472509

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Shaare Zedek Medical Center
Jerusalem, Israel, 91031
Sponsors and Collaborators
Shaare Zedek Medical Center
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Principal Investigator: Oren Ledder, MD Shaare Zedek Medical Center

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Responsible Party: Shaare Zedek Medical Center Identifier: NCT02472509    
Other Study ID Numbers: Ursolit_Hemolytic disorders
First Posted: June 16, 2015    Key Record Dates
Last Update Posted: October 10, 2017
Last Verified: October 2017
Keywords provided by Shaare Zedek Medical Center:
Ursodeoxycholic acid (UDCA)
White blood cells (WBC)
Alanine Transaminase (ALT)
Alkaline Phosphatase (ALP)
Aspartate Aminotransferase (AST)
Gamma-Glutamyl Transpeptidase (GGT)
Lactate dehydrogenase (LDH)
Low-Density Lipoprotein (LDL)
High-Density Lipoprotein (HDL)
Glucose-6-phosphate dehydrogenase (G6PD)
Ultrasound (US)
Additional relevant MeSH terms:
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Pathologic Processes
Biliary Tract Diseases
Digestive System Diseases
Gallbladder Diseases
Pathological Conditions, Anatomical
Ursodeoxycholic Acid
Cholagogues and Choleretics
Gastrointestinal Agents