Biliary AtresiaEarly Phase 1BA_GCSFNCT03395028
GCSF Adjunct Therapy for Biliary Atresia
A Early Phase 1 study testing Granulocyte Colony-Stimulating Factor in people with Biliary Atresia, run by Holterman, Ai-Xuan, M.D. at 2 sites in 2 countries.
Trial summary
The Investigators propose to test the hypothesis that GCSF therapy enhances the clinical outcome of Kasai operated Biliary Atresia (BA) patients. In this study, Investigators will conduct a dose determination for GCSF use in post Kasai subjects to support a future phase 2 efficacy study. Read more about this study
- Who is it for?
- Ages 2 weeks to 180 days
- Conditions the study is for
- Biliary Atresia
- What is being tested?
- Granulocyte Colony-Stimulating Factor
- How many people
- 6 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 15 Jan 2018to 31 Jan 2020
- Phase
- Early 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 2 weeks to 180 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Completed the preliminary work up for cholestasis with suspected or inconclusive diagnosis of BA
- Gestational Age > 36wks
- Weight > 2 Kg
- Age >-2 weeks-<180 days at diagnosis
- Serum Direct Bilirubin > 2 mg/dL GGT > 100 U/L
- Kasai operated patients for Type 3 or 4 anatomy of BA
- Cholangiogram/porta hepatis findings diagnostic of BA
- Liver biopsy supporting BA diagnosis
Who cannot join
- Having access to liver transplantation for immediate Kasai failure
- Prior Kasai patients
- Major cardiac, renal, CNS malformations with poor prognosis
- Intracranial hemorrhage
- History of recent TPN use within the last 2 weeks of surgery
- GI tract obstruction
- Laparoscopic Kasai repair
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
United States1 site
Children's National Medical Center
Washington D.C., District of Columbia, 20010
About this study
Official title: Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
The Investigators propose to test the hypothesis that GCSF therapy enhances the clinical outcome of Kasai operated Biliary Atresia (BA) patients. In this study, Investigators will conduct a dose determination for GCSF use in post Kasai subjects to support a future phase 2 efficacy study. The first 3 post Kasai BA subjects with liver biopsy-confirmed BA will be given 5 ug/kg/d of GCSF in 3 daily subcutaneous doses starting on post Kasai day 3. A second group of 3 subjects will be assigned to the 10 ug/Kg/d dose after the 5ug/kg/d dose has been proven to be safe. The levels of circulating hematopoietic stem cells and a 1-month safety profile will be analyzed.
Read the detailed description
In BA, neonatal fibrous obliteration of the biliary tract obstructs biliary drainage and promotes biliary fibrosis. BA is the leading cause of pediatric chronic end-stage liver disease and pediatric liver transplantation. Relief of cholestasis by the Kasai portoenterostomy is only partly successful with continued progression of fibrosis to hepatic insufficiency and, for long term survival, with eventual need for liver transplantation in the majority of the patients. In animal models of liver injury, GCSF enhances hematopoietic stem cell HSC mobilization and engraftment in the liver with associated improved liver repair response and attenuated hepatic necrosis and fibrosis. Randomized controlled trials of GCSF intervention for chronic liver failure in adult patients with acute hepatic decompensation showed improved short-term survival and hepatic indices such the model for end-stage liver disease (MELD) scores.
The Investigators propose that post Kasai GCSF therapy attenuates biliary fibrosis and progression to cirrhosis. The objectives are meant to demonstrate that Kasai-GCSF sequential therapy improves biliary drainage, and delays the progression of hepatic insufficiency. Toward this goal, Investigators will first evaluate in post Kasai subjects the maximum tolerated dose of GCSF in mobilizing circulating CD34+ hematopoietic stem cells, with the limiting dose based on GCSF-related severe adverse effects. A one-month safety of GCSF will be tested with the 2 standard doses of 5 ug/kg/d and 10 ug/kg/d.
- Conditions
- Biliary Atresia
- Being tested
- Granulocyte Colony-Stimulating Factor
- Keywords
- Biliary Atresia, Granulocyte Colony Stimulating Factor, GCSF
- Medical subject headings
- Biliary Atresia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Granulocyte Colony-Stimulating FactorDrug
Also called Filgrastim
G-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology with NEUPOGEN® as the Amgen Inc. trademark for filgrastim. G-CSF regulates the production, proliferation and differentiation of neutrophils and hematopoietic stem cell precursors within the bone marrow leading to dose-dependent increase in circulating neutrophils and hematopoietic stem cells in the blood. It is indicated to reduce the incidence of infection in patients with severe neutropenia, for neutrophil recovery in neutropenic patients with bone marrow depletion, to mobilize hematopoietic progenitor stem cell for collection by leukapheresis in hematopoietic stem cell transplantation.
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose determination GCSF
To determine the maximum tolerated dose of GCSF based on GCSF dose limiting toxicity and the extent of peripheral blood stem cell mobilization as measured by increases in CD34+cells with upper levels limited by white blood cells (WBCs) less than 50,000 per microliter (mcL) of blood.
Measured: 13 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2018
- Study start15 Jan 2018
- Primary completion31 Jan 2020
- Study completion31 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Biliary AtresiaStudies 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
- Early Phase 1
- Primary purpose
- Supportive care
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Dose determination for GCSF
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Holterman, Ai-Xuan, M.D.
- Collaborators
- T. Rose Clinical, Inc., United States, Children's National Research Institute, Big Leap Research
- Responsible party
- Sponsor
- Investigators
- Evan P Nadler, MD, Principal investigator, Children's National Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03395028
- Sponsor's protocol ID
- CR00005169
- Other IDs
- IND 119679-0007
- Acronym
- BA_GCSF
- Status last verified
- Feb 2020
- First submitted
- 22 Dec 2017
- Last updated
- 17 Feb 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012 Aug;21(3):175-84. doi: 10.1053/j.sempedsurg.2012.05.010.
PubMed 22800970Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis. Cytokine. 2008 Jun;42(3):277-88. doi: 10.1016/j.cyto.2008.03.002. Epub 2008 Apr 8.
PubMed 18400509Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A. G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005 Jan;33(1):108-19. doi: 10.1016/j.exphem.2004.09.005.
PubMed 15661404Takami T, Terai S, Sakaida I. Stem cell therapy in chronic liver disease. Curr Opin Gastroenterol. 2012 May;28(3):203-8. doi: 10.1097/MOG.0b013e3283521d6a.
PubMed 22395569Prajapati R, Arora A, Sharma P, Bansal N, Singla V, Kumar A. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial. Eur J Gastroenterol Hepatol. 2017 Apr;29(4):448-455. doi: 10.1097/MEG.0000000000000801.
PubMed 27930386Nguyen HPA, Ren J, Butler M, Li H, Qazi S, Sadiq K, Dao HT, Holterman A. Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int. 2022 Jul;38(7):1019-1030. doi: 10.1007/s00383-022-05115-0. Epub 2022 Apr 7.
PubMed 35391541
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Granulocyte-Colony Stimulating Factor Adjunct Therapy for Biliary Atresia
- ClinicalTrials.gov ID
- NCT03395028
- Acronym / sponsor ID
- BA_GCSF / CR00005169
- Conditions
- Biliary Atresia
- Keywords
- Biliary Atresia, Granulocyte Colony Stimulating Factor, GCSF
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Holterman, Ai-Xuan, M.D.
- Collaborators
- T. Rose Clinical, Inc., United States, Children's National Research Institute, Big Leap Research
- Study start
- 15 Jan 2018 (actual)
- Primary completion
- 31 Jan 2020 (actual)
- Study completion
- 31 Jan 2020 (actual)
- First posted
- 9 Jan 2018 (actual)
- 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.
The Investigators propose to test the hypothesis that GCSF therapy enhances the clinical outcome of Kasai operated Biliary Atresia (BA) patients. In this study, Investigators will conduct a dose determination for GCSF use in post Kasai subjects to support a future phase 2 efficacy study. The first 3 post Kasai BA subjects with liver biopsy-confirmed BA will be given 5 ug/kg/d of GCSF in 3 daily subcutaneous doses starting on post Kasai day 3. A second group of 3 subjects will be assigned to the 10 ug/Kg/d dose after the 5ug/kg/d dose has been proven to be safe. The levels of circulating hematopoietic stem cells and a 1-month safety profile will be analyzed.
Detailed description
In BA, neonatal fibrous obliteration of the biliary tract obstructs biliary drainage and promotes biliary fibrosis. BA is the leading cause of pediatric chronic end-stage liver disease and pediatric liver transplantation. Relief of cholestasis by the Kasai portoenterostomy is only partly successful with continued progression of fibrosis to hepatic insufficiency and, for long term survival, with eventual need for liver transplantation in the majority of the patients. In animal models of liver injury, GCSF enhances hematopoietic stem cell HSC mobilization and engraftment in the liver with associated improved liver repair response and attenuated hepatic necrosis and fibrosis. Randomized controlled trials of GCSF intervention for chronic liver failure in adult patients with acute hepatic decompensation showed improved short-term survival and hepatic indices such the model for end-stage liver disease (MELD) scores.
The Investigators propose that post Kasai GCSF therapy attenuates biliary fibrosis and progression to cirrhosis. The objectives are meant to demonstrate that Kasai-GCSF sequential therapy improves biliary drainage, and delays the progression of hepatic insufficiency. Toward this goal, Investigators will first evaluate in post Kasai subjects the maximum tolerated dose of GCSF in mobilizing circulating CD34+ hematopoietic stem cells, with the limiting dose based on GCSF-related severe adverse effects. A one-month safety of GCSF will be tested with the 2 standard doses of 5 ug/kg/d and 10 ug/kg/d.
Study design
- Primary purpose
- Supportive care
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Model description
- Dose determination for GCSF
Who may qualify
- Ages
- 2 weeks to 180 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (8 listed)
- Completed the preliminary work up for cholestasis with suspected or inconclusive diagnosis of BA
- Gestational Age > 36wks
- Weight > 2 Kg
- Age >-2 weeks-<180 days at diagnosis
- Serum Direct Bilirubin > 2 mg/dL GGT > 100 U/L
Key exclusion criteria (7 listed)
- Having access to liver transplantation for immediate Kasai failure
- Prior Kasai patients
- Major cardiac, renal, CNS malformations with poor prognosis
- Intracranial hemorrhage
- History of recent TPN use within the last 2 weeks of surgery
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 |
|---|---|---|
| Granulocyte Colony-Stimulating FactorAlso: FilgrastimG-CSF is a glycoprotein produced by monocytes, fibroblasts, and endothelial cells. Filgrastim is a human granulocyte colony stimulating factor (G-CSF) produced by recombinant DNA technology with NEUPOGEN® as the Amgen Inc. trademark for filgrastim. G-CSF regulates the production, proliferation and differentiation of neutrophils and hematopoietic stem cell precursors within the bone marrow leading to dose-dependent increase in circulating neutrophils and hematopoietic stem cells in the blood. It is indicated to reduce the incidence of infection in patients with severe neutropenia, for neutrophil recovery in neutropenic patients with bone marrow depletion, to mobilize hematopoietic progenitor stem cell for collection by leukapheresis in hematopoietic stem cell transplantation. | Drug | – |
Primary outcome
Dose determination GCSF
Time frame: 13 months
To determine the maximum tolerated dose of GCSF based on GCSF dose limiting toxicity and the extent of peripheral blood stem cell mobilization as measured by increases in CD34+cells with upper levels limited by white blood cells (WBCs) less than 50,000 per microliter (mcL) of blood.
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 17 Feb 2020.
- Background: PubMed 22800970Davenport M. Biliary atresia: clinical aspects. Semin Pediatr Surg. 2012 Aug;21(3):175-84. doi: 10.1053/j.sempedsurg.2012.05.010.
- Background: PubMed 18400509Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis. Cytokine. 2008 Jun;42(3):277-88. doi: 10.1016/j.cyto.2008.03.002. Epub 2008 Apr 8.
- Background: PubMed 15661404Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A. G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005 Jan;33(1):108-19. doi: 10.1016/j.exphem.2004.09.005.
- Background: PubMed 22395569Takami T, Terai S, Sakaida I. Stem cell therapy in chronic liver disease. Curr Opin Gastroenterol. 2012 May;28(3):203-8. doi: 10.1097/MOG.0b013e3283521d6a.
- Background: PubMed 27930386Prajapati R, Arora A, Sharma P, Bansal N, Singla V, Kumar A. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial. Eur J Gastroenterol Hepatol. 2017 Apr;29(4):448-455. doi: 10.1097/MEG.0000000000000801.
- Derived from this study: PubMed 35391541Nguyen HPA, Ren J, Butler M, Li H, Qazi S, Sadiq K, Dao HT, Holterman A. Study protocol of Phase 2 open-label multicenter randomized controlled trial for granulocyte-colony stimulating factor (GCSF) in post-Kasai Type 3 biliary atresia. Pediatr Surg Int. 2022 Jul;38(7):1019-1030. doi: 10.1007/s00383-022-05115-0. Epub 2022 Apr 7.
- Individual participant dataSharing planned: No
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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.
Evan P Nadler, MD principal investigator
Children's National Research Institute
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Granulocyte Colony-Stimulating Factor in people with Biliary Atresia, run by Holterman, Ai-Xuan, M.D. at 2 sites in 2 countries.
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 8 inclusion and 7 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 17 Feb 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States, Vietnam. 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?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
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?
Dose determination GCSF (time frame: 13 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03395028, which also lists 6 linked publications.
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 17 Feb 2020.