Biliary Atresia
Conditions
Keywords
Biliary atresia, Hepatic portoenterostomy, Intravenous immunoglobulin
Brief summary
The Children Liver Disease Research and Education Network (ChiLDREN) is conducting a clinical trial to determine the feasibility, acceptability, tolerability and safety profile of IVIG treatment administered to infants after hepatic portoenterostomy (HPE) for biliary atresia, as well as investigate preliminary evidence of activity and explore mechanisms of action.
Detailed description
In this multicenter prospective phase 1/2A open label trial, the feasibility, tolerability and safety of intravenous immunoglobulin (IVIG) therapy following hepatic portoenterostomy (HPE) will be assessed in 29 infants with biliary atresia (BA), efficacy will be estimated and exploratory mechanistic research studies will be performed. After written consent is obtained from the parent or guardian, the subject will be enrolled and will receive three intravenous doses of IVIG at designated intervals over the first 60 days following HPE and will be followed for 360 days after enrollment. Blood will also be obtained during this study to assess potential mechanisms by which the IVIG may alter or reduce bile duct inflammation and injury and improve bile flow. All infants in this trial will also be treated with standardized doses of other routine standard-of-care treatments for BA during this trial (ursodeoxycholic acid, trimethoprim-sulfamethoxasole, and fat-soluble vitamin supplements). This routine clinical care will not be modified by participation in this study. Subjects in this study will not receive corticosteroid therapy for treatment of biliary atresia, as this is of unproven benefit at the present time.
Interventions
All participants will receive the same dose of IVIG at the same intervals in an open-label fashion as long as the subject does not have any increased risk for toxicity for any IVIG infusion. IVIG will be initiated on day 3 (up to day 5) after HPE surgery (HPE is day 0) at a dose of 1 gm/kg body weight by slow intravenous infusion over at least 4 hours. The same dose (1 gm/kg) and duration of infusion will be repeated on day 30 and day 60 after HPE.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Days to 120 Days
Healthy volunteers
No
Inclusion criteria
* Infant under 120 days old with established diagnosis of BA. Subjects in this trial must start treatment within 3-5 days of the Kasai procedure and be part of a prospective study of the natural history of biliary atresia also being conducted by ChiLDREN (http://www.clinicaltrials.gov/ct/show/NCT00061828?order=3). * Standard HPE operation has been performed for BA within the previous 3 days * Post-conception age ≥ 36 weeks at time of enrollment * Weight at enrolment ≥ 2000 gm * Written informed consent to participate in the study obtained within 3 days of completion of HPE.
Exclusion criteria
* Laparoscopic HPE or gall bladder Kasai (cholecysto-portostomy) surgery was performed * Biliary atresia splenic malformation syndrome (presence of asplenia, polysplenia or double spleen) * History of a hypercoagulable disorder * Renal Disease defined as serum creatinine \> 1.0 mg/dl prior to enrollment or presence of complex renal anomalies found on imaging * Evidence of congestive heart failure or fluid overload * Presence of significant systemic hypertension for age (defined as persistent systolic blood pressure ≥112 mmHg measured on at least 3 occasions following HPE) * Infants whose mother is known to have human immunodeficiency virus infection * Infants whose mother is known to be serum HBsAg or hepatitis C virus antibody positive * Previous treatment with intravenous immunoglobulin therapy or corticosteroid therapy * Previous treatment with any other investigational agent * History of allergic reaction to any human blood product infusion * Infants with other severe concurrent illnesses, such as neurological, cardiovascular, pulmonary, metabolic, endocrine, and renal disorders, that would interfere with the conduct and results of the study * Any other clinical condition that is a contraindication to the use of IVIG
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Events | 360 days post-HPE | Percentage of subjects with other expected adverse events |
| Feasibility of IVIG Treatment | 60 days post-HPE | Percentage of subjects for whom administration of IVIG is feasible, defined as the successful administration (at least 80% of each dose) of all 3 doses of IVIG |
| Acceptability of IVIG | 60 days post-HPE | Percentage of subjects for whom the study is acceptable, defined as the ability of the subject's family or guardian to allow intravenous line placements, blood draws, and other study procedures for the study subjects. |
| Serious Adverse Events | 360 days post-HPE | Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant |
| Level 3-5 Toxicity | 360 days post-HPE | Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Good Bile Drainage at 90 Days Post-HPE | 90 days post-HPE | Percentage of subjects who survive 90 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 90 days after HPE |
| Good Bile Drainage at 180 Days Post-HPE | 180 days post-HPE | Percentage of subjects who survive 180 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 180 days after HPE |
| Good Bile Drainage at 360 Days Post-HPE | 360 days post-HPE | Percentage of subjects who survive 360 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 360 days after HPE |
| Transplant-free Survival | 360 days post-HPE | Percentage of subjects who survive with their native liver at 360 days after HPE. |
| Circulating Regulatory T-Cells, Inflammatory Cytokines, and Specific Autoantibodies. | Over 360 days after HPE | Percentage and absolute number of Tregs (CD4+CD25+FoxP3+), CD3/4 T cells, CD3/8 T cells, NK cells (CD56), NK T cells (CD3/56), CD19/20 B cells, macrophages (CD14/11b), and neutrophils; plasma levels of anti-enolase antibody; and plasma cytokine levels (Th1/Th2 multiplex and IL17) |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IVIG Active Treatment Intravenous Immunoglobulin (IVIG) active treatment for infants with biliary atresia | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
Baseline characteristics
| Characteristic | IVIG Active Treatment |
|---|---|
| Age, Continuous | 60.0 Days STANDARD_DEVIATION 18.6 |
| Race/Ethnicity, Customized Ethnicity Hispanic | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Non-Hispanic | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Region of Enrollment Canada | 7 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 29 |
| other Total, other adverse events | 29 / 29 |
| serious Total, serious adverse events | 26 / 29 |
Outcome results
Primary
Acceptability of IVIG
Percentage of subjects for whom the study is acceptable, defined as the ability of the subject's family or guardian to allow intravenous line placements, blood draws, and other study procedures for the study subjects.
Time frame: 60 days post-HPE
Population: MITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Acceptability of IVIG | 23 Participants |
Primary
Adverse Events
Percentage of subjects with other expected adverse events
Time frame: 360 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Adverse Events | 8 Participants |
Primary
Feasibility of IVIG Treatment
Percentage of subjects for whom administration of IVIG is feasible, defined as the successful administration (at least 80% of each dose) of all 3 doses of IVIG
Time frame: 60 days post-HPE
Population: MITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Feasibility of IVIG Treatment | 23 Participants |
Primary
Level 3-5 Toxicity
Percentage of subjects with any level 3, 4, or 5 toxicity (per NCI CTEP grading system)
Time frame: 360 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Level 3-5 Toxicity | 26 Participants |
Primary
Serious Adverse Events
Percentage of subjects with any serious adverse events (SAEs) prior to liver transplant
Time frame: 360 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Serious Adverse Events | 26 Participants |
Secondary
Circulating Regulatory T-Cells, Inflammatory Cytokines, and Specific Autoantibodies.
Percentage and absolute number of Tregs (CD4+CD25+FoxP3+), CD3/4 T cells, CD3/8 T cells, NK cells (CD56), NK T cells (CD3/56), CD19/20 B cells, macrophages (CD14/11b), and neutrophils; plasma levels of anti-enolase antibody; and plasma cytokine levels (Th1/Th2 multiplex and IL17)
Time frame: Over 360 days after HPE
Secondary
Good Bile Drainage at 180 Days Post-HPE
Percentage of subjects who survive 180 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 180 days after HPE
Time frame: 180 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Good Bile Drainage at 180 Days Post-HPE | 14 Participants |
Comparison: IVIG was compared for superiority to the historical control of START study placebo (N=64). PMID: 24794368 NCT00294684p-value: 0.8455Regression, Logistic
Secondary
Good Bile Drainage at 360 Days Post-HPE
Percentage of subjects who survive 360 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 360 days after HPE
Time frame: 360 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Good Bile Drainage at 360 Days Post-HPE | 7 Participants |
Comparison: IVIG was compared for superiority to the historical START placebo control (N=64).p-value: 0.8431Regression, Logistic
Secondary
Good Bile Drainage at 90 Days Post-HPE
Percentage of subjects who survive 90 days after HPE with both their native liver and serum total bilirubin \<1.5 mg/dL at 90 days after HPE
Time frame: 90 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Good Bile Drainage at 90 Days Post-HPE | 11 Participants |
Comparison: IVIG was compared to the historical placebo control from the START study (n=64): PMID: 24794368 NCT00294684p-value: 0.5486Regression, Logistic
Secondary
Transplant-free Survival
Percentage of subjects who survive with their native liver at 360 days after HPE.
Time frame: 360 days post-HPE
Population: mITT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG Active Treatment | Transplant-free Survival | 17 Participants |
Comparison: K-M estimates for survival for IVIG vs the historical START placebo control are provided, along with one-sided 90% upper bounds of the confidence intervals.