Hemolytic DisordersPhase 4NCT02472509
The Role of Ursodeoxycholic Acid in Treatment of Gallstones in Hemolytic Disorders
A Phase 4 study testing Ursodeoxycholic Acid in people with Hemolytic Disorders and Gallstones, run by Shaare Zedek Medical Center at 1 site in Israel.
Trial 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. Read more about this study
- Who is it for?
- Ages 4 years and older
- Conditions the study is for
- Hemolytic Disorders, Gallstones
- What is being tested?
- Ursodeoxycholic Acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteIsrael
- Study dates
- Dec 2014to 10 Sep 2017
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 4 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Diagnosis of a hemolytic disorder including spherocytosis, G6PD deficiency, thalassemia or sickle cell disease.
- Patients with cholelithiasis or bile sludge.
- Age greater than or equal to 4 years.
- Ability to consent to and participate in the study and follow study procedures.
Who cannot join
- Previous splenectomy (complete or partial)
- Evidence of hemolytic crisis at the time of research enrollment
- Patients with highly symptomatic gallstones who have planned surgical intervention
- Known allergy or intolerance to UDCA
- Existence of concurrent hepatic disease
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read more
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.
Read the 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:
- An explicit history taking and review of patient's notes, including review of symptoms, blood tests and previous ultrasounds, other medical conditions and medications.
- Physical examination - including measuring splenic size, assessing for right upper quadrant abdominal tenderness
- Blood tests
- Hemoglobin, WBC
- Liver biochemistry: ALT, AST, GGT, ALP (Alkaline Phosphatase), Bilirubin (conjugated and unconjugated), Albumin
- Hemolytic screen: LDH, haptoglobin, reticulocytes
- 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:
- Presence of biliary sludge
- Presence of gallstone: i.Size ii.Number
- Presence of bile duct dilatation
- Presence of gall bladder wall thickening
- Conditions
- Hemolytic Disorders, Gallstones
- Being tested
- Ursodeoxycholic Acid
- Keywords
- 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)
- Medical subject headings
- Gallstones
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ursodeoxycholic AcidDrug
Also called Ursolit
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.
| Study group | Role | What they receive |
|---|---|---|
| Open Label | Experimental | 32 patients with hemolytic disorders meeting the inclusion and exclusion criteria will be commenced on Ursodeoxycholic acid (UDCA). Receives: Drug: Ursodeoxycholic Acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
Lack of sonographic, clinical or biochemical evidence of progression of cholelithiasis or biliary sludge.
Measured: 12 months
Secondary outcomes (5)
Improvement in number and severity of episodes of symptomatic gallstones.
Measured: 12 months
Rate of surgical intervention for gallstones disease.
Measured: 12 months
Sonographic improvement (size and number of gallstones, presence of bile sludge, gallbladder wall thickness).
Measured: 12 months
Evaluate tolerability and adverse effects of UDCA therapy in hemolytic disorders.
including non-specific abdominal discomfort, rash or nausea.
Measured: 12 months
Improved biochemical evidence of gallstone disease
reduced gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP).
Measured: 12m
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jun 2015 (estimated)
- Study startDec 2014
- Primary completion10 Sep 2017
- Study completion10 Sep 2017
Why it stopped: Study not feasible - very low recruitment rate
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hemolytic DisordersStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Shaare Zedek Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Oren Ledder, MD, Principal investigator, Shaare Zedek Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02472509
- Sponsor's protocol ID
- Ursolit_Hemolytic disorders
- Status last verified
- Oct 2017
- First submitted
- 4 Feb 2015
- Last updated
- 10 Oct 2017
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of Ursodeoxycholic Acid in Treatment of Gallstones in Hemolytic Disorders
- ClinicalTrials.gov ID
- NCT02472509
- Acronym / sponsor ID
- Ursolit_Hemolytic disorders
- Conditions
- Hemolytic Disorders, Gallstones
- Keywords
- 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)
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study not feasible - very low recruitment rate
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Shaare Zedek Medical CenterUniversity, hospital or other
- Study start
- Dec 2014
- Primary completion
- 10 Sep 2017 (actual)
- Study completion
- 10 Sep 2017 (actual)
- First posted
- 16 Jun 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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:
- An explicit history taking and review of patient's notes, including review of symptoms, blood tests and previous ultrasounds, other medical conditions and medications.
- Physical examination - including measuring splenic size, assessing for right upper quadrant abdominal tenderness
- Blood tests
- Hemoglobin, WBC
- Liver biochemistry: ALT, AST, GGT, ALP (Alkaline Phosphatase), Bilirubin (conjugated and unconjugated), Albumin
- Hemolytic screen: LDH, haptoglobin, reticulocytes
- 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:
- Presence of biliary sludge
- Presence of gallstone: i.Size ii.Number
- Presence of bile duct dilatation
- Presence of gall bladder wall thickening
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open Label | Experimental | Drug: Ursodeoxycholic Acid32 patients with hemolytic disorders meeting the inclusion and exclusion criteria will be commenced on Ursodeoxycholic acid (UDCA). |
Who may qualify
- Ages
- 4 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (4 listed)
- Diagnosis of a hemolytic disorder including spherocytosis, G6PD deficiency, thalassemia or sickle cell disease.
- Patients with cholelithiasis or bile sludge.
- Age greater than or equal to 4 years.
- Ability to consent to and participate in the study and follow study procedures.
Key exclusion criteria (6 listed)
- Previous splenectomy (complete or partial)
- Evidence of hemolytic crisis at the time of research enrollment
- Patients with highly symptomatic gallstones who have planned surgical intervention
- Known allergy or intolerance to UDCA
- Existence of concurrent hepatic disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Ursodeoxycholic AcidAlso: UrsolitPatients 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. | Drug | Open Label |
Primary outcome
Lack of sonographic, clinical or biochemical evidence of progression of cholelithiasis or biliary sludge.
Time frame: 12 months
5 secondary outcomes
Improvement in number and severity of episodes of symptomatic gallstones.
Time frame: 12 months
Rate of surgical intervention for gallstones disease.
Time frame: 12 months
Sonographic improvement (size and number of gallstones, presence of bile sludge, gallbladder wall thickness).
Time frame: 12 months
Evaluate tolerability and adverse effects of UDCA therapy in hemolytic disorders.
Time frame: 12 months
Improved biochemical evidence of gallstone disease
Time frame: 12m
Results and safety
The study was stopped early (reason given: Study not feasible - very low recruitment rate). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Oren Ledder, MD principal investigator
Shaare Zedek Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ursodeoxycholic Acid in people with Hemolytic Disorders and Gallstones, run by Shaare Zedek Medical Center at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 10 Oct 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Study not feasible - very low recruitment rate). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Lack of sonographic, clinical or biochemical evidence of progression of cholelithiasis or biliary sludge. (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2017.