Primary Sclerosing CholangitisPhase 1NCT01088607
Safety and Efficacy Study of Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis
A Phase 1 study testing ursodeoxycholic acid (UDCA) in people with Primary Sclerosing Cholangitis, run by University of Tennessee at 12 sites in United States.
Trial summary
Primary sclerosing cholangitis (PSC), although uncommon, is a devastating and insidiously progressive liver disease, resulting from advancing inflammation, fibrosis and obliteration of the bile ducts in the liver, leading to cirrhosis and end-stage liver disease. Read more about this study
- Who is it for?
- Ages 5 to 21 years
- Conditions the study is for
- Primary Sclerosing Cholangitis
- What is being tested?
- ursodeoxycholic acid (UDCA)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 12 sitesUnited States
- Study dates
- Oct 2010to Jun 2017
- Phase
- Phase 1
- 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 5 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Male or female < 21 years of age, no racial or ethnic restrictions
- Pediatric PSC diagnosed as per the criteria developed by STOPSC (2 of 3 required):
- Serum GGT increased more than 50% above the upper limit of normal for age
- Endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) or magnetic resonance cholangiopancreatography (MRCP) findings of intrahepatic and/or extrahepatic bile duct irregularities consistent with PSC
- Liver biopsy abnormalities consistent with chronic biliary injury Note that these criteria will include patients with small duct PSC who have normal biliary imaging with the required biochemical and histologic criteria.
- Patients with PSC/AIH overlap will also be included who meet the criteria for PSC plus have liver histologic features of AIH.
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- Biochemically quiescent liver disease defined by an ALT and GGT < 2.0 X upper limit of normal (ULN) measured on two separate occasions > 2 weeks apart
- Prior and on-going UDCA therapy at a dose of at least 13 mg/kg/day or 600 mg/day for more than 6 months
- Ability to swallow pills
- Quiescent inflammatory bowel disease (IBD) as reflected by a modified Pediatric Ulcerative Colitis Activity Index score of less than 6 or a modified Pediatric Crohn's Disease Activity Index score of less than 15.
- Not excluded by the STOPSC pediatric PSC exclusion criteria (see Appendix) that are designed to minimize misdiagnosis due to other primary liver diseases, previous biliary injury/surgery, therapies, or systemic disorders that may secondarily affect the liver and/or biliary tract.
- Subjects will remain on all current medications, including those for IBD and immunosuppressive therapy.
- Female subjects of childbearing age will be required to have a pregnancy test, and if sexually active, will be required to use an accepted method of birth control during the course of the study.
- Parent or legal guardian must be willing to provide signed and dated informed consent documentation. Assent from the child or adolescent will be obtained as appropriate.
Who cannot join
- Evidence of decompensated cirrhosis:
- Cirrhosis as defined by biopsy findings or evidence of portal hypertension with no other known cause and:
- Platelet count < 100,000 or,
- Spleen palpable more than 2 cm below the left costal margin or,
- Ascites or,
- Varices or other GI manifestation of portal hypertension
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- Decompensated liver disease defined by:
- Serum total bilirubin (TB) > 5 mg/dl and direct bilirubin (DB) > 1 mg/dl or,
- Prothrombin time (PT) prolonged by more than 3 seconds after parenteral vitamin K administration or,
- Ascites requiring diuretic therapy or,
- Serum albumin < 3 g/dl
- Evidence of acute liver failure:
- No prior history of liver disease and
- PT > 20 seconds or INR > 2.0 unresponsive to parenteral vitamin K administration or,
- PT > 15 seconds or international normalized ratio (INR) > 1.5 with change in mental status ascribable to hepatic encephalopathy
- History of cholangitis or bile duct strictures requiring intervention
- Liver transplantation
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
United States12 sites
Children's Healthcare of Atlanta, Emory University School of Medicine
Atlanta, Georgia, 30322
Children's Hospital Colorado
Aurora, Colorado, 80045
Northwestern University
Chicago, Illinois, 60614
Texas Children's Hospital
Houston, Texas, 77030
Children's Hospital Los Angeles
Los Angeles, California, 90027
University of Tennessee Health Science Center
Memphis, Tennessee, 38103
Yale New Haven Children's Hospital
New Haven, Connecticut, 06510
Mount Sinai School of Medicine
New York, New York, 07624
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Phoenix Children's Hospital
Phoenix, Arizona, 85016
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: A Pilot Withdrawal/Reinstitution Trial
Primary sclerosing cholangitis (PSC), although uncommon, is a devastating and insidiously progressive liver disease, resulting from advancing inflammation, fibrosis and obliteration of the bile ducts in the liver, leading to cirrhosis and end-stage liver disease. Although prognosis in children may be somewhat better than that of adults, approximately one third of pediatric patients require transplantation by adulthood. Other than transplantation, there is to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly improve the long-term outcome in adults, and in a recent study may have actually worsened outcome. Childhood PSC is different from that of adult PSC in many ways, and children may derive more short-term, as well as long-term, benefit than adults. This unique multicenter study will carefully monitor the effects of withdrawal and restarting UDCA on liver injury and inflammation in children with PSC. The preliminary data will help in the design of a more definitive larger study to determine if UDCA has a beneficial role in the treatment of PSC in children. Funding Source - FDA OOPD
Read the detailed description
Primary sclerosing cholangitis (PSC), a devastating and insidiously progressive cholestatic liver disease, results from advancing inflammation, fibrosis and obliteration of the intra- and extrahepatic bile ducts, leading to cirrhosis and end-stage liver disease. PSC is an uncommon disorder (prevalence in the US of 8-14/100,000 with even lower prevalence in children). Although prognosis in children may be somewhat better, approximately one third of pediatric patients require transplantation by adulthood. Other than transplantation, there is to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly improve the long-term outcome in adults. Furthermore, a recent large adult trial of high-dose UDCA therapy suggested a higher incidence of serious adverse events and poor outcomes with UDCA treatment, leading many centers to discontinue UDCA therapy in adult patients. Childhood PSC is different from the adult disease including a stronger association with both autoimmune markers and histologic features and a trend to higher transaminases at diagnosis. Furthermore, in response to intermediate-dose UDCA therapy, there is a more striking and prompt improvement in biochemistries as compared to adults. In light of the prompt normalization of liver enzymes and the fact that UDCA is well tolerated in children, pediatric hepatologists are reluctant to generalize the adult UDCA study results to children and to stop UDCA therapy. This presents a significant dilemma: Should UDCA therapy be stopped in pediatric PSC patients to avoid a possible adverse influence on long-term prognosis at the risk of losing a possible beneficial effect on disease progression in children? Additional factors in children with PSC/autoimmune hepatitis (AIH) overlap are the long-term adverse effects of corticosteroids and azathioprine use. If UDCA therapy is effective as monotherapy, these complications may be avoided. Therefore, we propose a preliminary UDCA withdrawal and reinstitution trial in pediatric PSC patients to collect data to support the design of a larger, longer-term randomized, placebo-controlled trial of UDCA therapy in childhood PSC. This pilot study, which will utilize the infrastructure and participating centers of the STOPSC (Studies of Primary Sclerosing Cholangitis) consortium, will test the following hypotheses: 1) UDCA therapy yields a rapid biochemical response in children with PSC, thus withdrawal would lead to increased biochemical evidence of disease. 2) UDCA therapy suppresses liver and biliary inflammation in children with PSC, thus withdrawal of therapy would result in a burst of inflammatory activity and an increase in serum cytokine biomarkers, 3) Biochemical control of childhood PSC with histologic features of AIH is dependent upon treatment with immunosuppression in addition to UDCA, therefore childhood PSC without histologic features of AIH will worsen significantly with UDCA withdrawal compared to PSC with histological features of AIH.
- Conditions
- Primary Sclerosing Cholangitis
- Being tested
- ursodeoxycholic acid (UDCA)
- Keywords
- Primary sclerosing cholangitis, Autoimmune hepatitis, Cholestatic liver disease, Cirrhosis, Children, Primary Sclerosing Cholangitis/Autoimmune Hepatitis Overlap
- Medical subject headings
- Cholangitis, Sclerosing, Hepatitis, Autoimmune, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ursodeoxycholic acid (UDCA)Drug
Also called Ursodeoxycholic acid, URSO 250, URSO Forte, Actigall
Pediatric PSC patients already receiving UDCA therapy will enter a four-phase trial consisting of baseline data collection (phase I, 4 weeks), 50% reduction in UDCA dose (phase II, 4 weeks), discontinuation of UDCA (phase III, 8 weeks) and reinstitution of therapy at a dose of 20 mg/kg/day (phase IV, 8 weeks). Surveillance and endpoint evaluation for each phase will include liver chemistries and clinical data. Comparisons will be made between baseline and the end of phase III (primary outcome) and between the end of phase III and the end of phase IV (secondary outcome). Serum cytokine biomarkers will be measured and compared between baseline and the end of phase III and between the end of phases III and IV.
| Study group | Role | What they receive |
|---|---|---|
| UDCA Withdrawal and Reinstitution | Experimental | Each study subject will undergo serial UDCA withdrawal and reinstitution. Receives: Drug: ursodeoxycholic acid (UDCA) |
What is being measured
The primary outcome is the main question the study is designed to answer.
The primary outcome will be the change in alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or biomarkers for inflammation in study subjects at baseline compared to the end of Phase III (UDCA discontinuation) of the study.
Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks
Measured: 16 weeks
Secondary outcomes (1)
A secondary outcome will be the change in ALT, GGT or biomarkers for inflammation in study subjects at the end of Phase III (UDCA discontinuation) compared to the end of Phase IV (UDCA reinstitution) of the study.
Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2010 (estimated)
- Study startOct 2010
- Primary completionDec 2016
- Study completionJun 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Primary Sclerosing CholangitisStudies 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Tennessee
- Sponsor type
- University, hospital or other
- Collaborators
- Icahn School of Medicine at Mount Sinai, Ann & Robert H Lurie Children's Hospital of Chicago, University of Colorado, Denver, University of California, San Francisco, University of Pittsburgh, Phoenix Children's Hospital, Children's Hospital of Philadelphia, Children's Healthcare of Atlanta, Children's Hospital Los Angeles, Baylor College of Medicine, Yale University
- Responsible party
- Sponsor
- Investigators
- Dennis D Black, M.D., Principal investigator, University of TennesseeBenjamin Shneider, M.D., Principal investigator, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01088607
- Sponsor's protocol ID
- FD-003709
- Status last verified
- Sep 2017
- First submitted
- 12 Mar 2010
- Last updated
- 26 Oct 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 26 Oct 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: A Pilot Withdrawal/Reinstitution Trial
- ClinicalTrials.gov ID
- NCT01088607
- Acronym / sponsor ID
- FD-003709
- Conditions
- Primary Sclerosing Cholangitis
- Keywords
- Primary sclerosing cholangitis, Autoimmune hepatitis, Cholestatic liver disease, Cirrhosis, Children, Primary Sclerosing Cholangitis/Autoimmune Hepatitis Overlap
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- University of TennesseeUniversity, hospital or other
- Collaborators
- Icahn School of Medicine at Mount Sinai, Ann & Robert H Lurie Children's Hospital of Chicago, University of Colorado, Denver, University of California, San Francisco, University of Pittsburgh, Phoenix Children's Hospital, Children's Hospital of Philadelphia, Children's Healthcare of Atlanta, Children's Hospital Los Angeles, Baylor College of Medicine, Yale University
- Study start
- Oct 2010 (actual)
- Primary completion
- Dec 2016 (actual)
- Study completion
- Jun 2017 (actual)
- First posted
- 17 Mar 2010 (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.
Primary sclerosing cholangitis (PSC), although uncommon, is a devastating and insidiously progressive liver disease, resulting from advancing inflammation, fibrosis and obliteration of the bile ducts in the liver, leading to cirrhosis and end-stage liver disease. Although prognosis in children may be somewhat better than that of adults, approximately one third of pediatric patients require transplantation by adulthood. Other than transplantation, there is to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly improve the long-term outcome in adults, and in a recent study may have actually worsened outcome. Childhood PSC is different from that of adult PSC in many ways, and children may derive more short-term, as well as long-term, benefit than adults. This unique multicenter study will carefully monitor the effects of withdrawal and restarting UDCA on liver injury and inflammation in children with PSC. The preliminary data will help in the design of a more definitive larger study to determine if UDCA has a beneficial role in the treatment of PSC in children. Funding Source - FDA OOPD
Detailed description
Primary sclerosing cholangitis (PSC), a devastating and insidiously progressive cholestatic liver disease, results from advancing inflammation, fibrosis and obliteration of the intra- and extrahepatic bile ducts, leading to cirrhosis and end-stage liver disease. PSC is an uncommon disorder (prevalence in the US of 8-14/100,000 with even lower prevalence in children). Although prognosis in children may be somewhat better, approximately one third of pediatric patients require transplantation by adulthood. Other than transplantation, there is to date no therapy conclusively proven to improve the long-term outcome. Ursodeoxycholic acid (UDCA) improves biochemical markers of liver disease, although in high doses does not clearly improve the long-term outcome in adults. Furthermore, a recent large adult trial of high-dose UDCA therapy suggested a higher incidence of serious adverse events and poor outcomes with UDCA treatment, leading many centers to discontinue UDCA therapy in adult patients. Childhood PSC is different from the adult disease including a stronger association with both autoimmune markers and histologic features and a trend to higher transaminases at diagnosis. Furthermore, in response to intermediate-dose UDCA therapy, there is a more striking and prompt improvement in biochemistries as compared to adults. In light of the prompt normalization of liver enzymes and the fact that UDCA is well tolerated in children, pediatric hepatologists are reluctant to generalize the adult UDCA study results to children and to stop UDCA therapy. This presents a significant dilemma: Should UDCA therapy be stopped in pediatric PSC patients to avoid a possible adverse influence on long-term prognosis at the risk of losing a possible beneficial effect on disease progression in children? Additional factors in children with PSC/autoimmune hepatitis (AIH) overlap are the long-term adverse effects of corticosteroids and azathioprine use. If UDCA therapy is effective as monotherapy, these complications may be avoided. Therefore, we propose a preliminary UDCA withdrawal and reinstitution trial in pediatric PSC patients to collect data to support the design of a larger, longer-term randomized, placebo-controlled trial of UDCA therapy in childhood PSC. This pilot study, which will utilize the infrastructure and participating centers of the STOPSC (Studies of Primary Sclerosing Cholangitis) consortium, will test the following hypotheses: 1) UDCA therapy yields a rapid biochemical response in children with PSC, thus withdrawal would lead to increased biochemical evidence of disease. 2) UDCA therapy suppresses liver and biliary inflammation in children with PSC, thus withdrawal of therapy would result in a burst of inflammatory activity and an increase in serum cytokine biomarkers, 3) Biochemical control of childhood PSC with histologic features of AIH is dependent upon treatment with immunosuppression in addition to UDCA, therefore childhood PSC without histologic features of AIH will worsen significantly with UDCA withdrawal compared to PSC with histological features of AIH.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| UDCA Withdrawal and Reinstitution | Experimental | Drug: ursodeoxycholic acid (UDCA)Each study subject will undergo serial UDCA withdrawal and reinstitution. |
Who may qualify
- Ages
- 5 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (14 listed)
- Male or female < 21 years of age, no racial or ethnic restrictions
- Pediatric PSC diagnosed as per the criteria developed by STOPSC (2 of 3 required):
- Patients with PSC/AIH overlap will also be included who meet the criteria for PSC plus have liver histologic features of AIH.
- Biochemically quiescent liver disease defined by an ALT and GGT < 2.0 X upper limit of normal (ULN) measured on two separate occasions > 2 weeks apart
- Prior and on-going UDCA therapy at a dose of at least 13 mg/kg/day or 600 mg/day for more than 6 months
Key exclusion criteria (17 listed)
- Evidence of decompensated cirrhosis:
- Evidence of acute liver failure:
- History of cholangitis or bile duct strictures requiring intervention
- Liver transplantation
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 acid (UDCA)Also: Ursodeoxycholic acid, URSO 250, URSO Forte, ActigallPediatric PSC patients already receiving UDCA therapy will enter a four-phase trial consisting of baseline data collection (phase I, 4 weeks), 50% reduction in UDCA dose (phase II, 4 weeks), discontinuation of UDCA (phase III, 8 weeks) and reinstitution of therapy at a dose of 20 mg/kg/day (phase IV, 8 weeks). Surveillance and endpoint evaluation for each phase will include liver chemistries and clinical data. Comparisons will be made between baseline and the end of phase III (primary outcome) and between the end of phase III and the end of phase IV (secondary outcome). Serum cytokine biomarkers will be measured and compared between baseline and the end of phase III and between the end of phases III and IV. | Drug | UDCA Withdrawal and Reinstitution |
Primary outcome
The primary outcome will be the change in alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or biomarkers for inflammation in study subjects at baseline compared to the end of Phase III (UDCA discontinuation) of the study.
Time frame: 16 weeks
Phase I-4 weeks, Phase II-4 weeks, Phase III-8 weeks, Phase IV-8 weeks
1 secondary outcome
A secondary outcome will be the change in ALT, GGT or biomarkers for inflammation in study subjects at the end of Phase III (UDCA discontinuation) compared to the end of Phase IV (UDCA reinstitution) of the study.
Time frame: 8 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 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.
Dennis D Black, M.D. principal investigator
University of Tennessee
Benjamin Shneider, M.D. principal investigator
Baylor College of Medicine
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing ursodeoxycholic acid (UDCA) in people with Primary Sclerosing Cholangitis, run by University of Tennessee at 12 sites in United States.
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 14 inclusion and 17 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: finished, as of the sponsor's last update on 26 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 12 sites in United States. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
The primary outcome will be the change in alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or biomarkers for inflammation in study subjects at baseline compared to the end of Phase III (UDCA discontinuation) of the study. (time frame: 16 weeks). 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 26 Oct 2017.