Infection, Liver Transplantation
Conditions
Keywords
pediatric, liver transplantation, Simulect, Basiliximab, ciclosporin microemulsion, steroid reduction, pediatric liver transplantation
Brief summary
Systemic infection is still a major concern in young children with liver transplantation. The approach of this study is to reduce the risk of systemic infections by avoiding intraoperative steroids (another class of immunosuppressive drugs) given in combination with basiliximab, cyclosporine and steroids in pediatric de novo liver transplant recipients. The treatment is compared to the same treatment regimen including intraoperative steroids with respect to rejection episodes.
Interventions
DRUGBasiliximab
Basiliximab (10 mg) was supplied as a lyophilisate in vials with ampoules of sterile water for injection (5 mL) and had to be given of 10 mg (body weight \<35 kg) or 20 mg (body weight ≥35 kg) strength.
DRUGCyclosporine/cyclosporine microemulsion
Cyclosporine/cyclosporine microemulsion had to be started with 100 mg/m²/day intravenous (i.v) (2x4h) for 7 days and was to be continued i.v. or orally from day 8 onwards as per center practice. During the 6 months treatment period Cyclosporine doses had to be adjusted according to Cyclosporine A (CsA)-trough levels.
DRUGSteroid
Intravenous prednisolone (loading dose: 300 mg/m2, maximum 500 mg) had to be administered intraoperatively only in treatment arm 1 (day 0). The first dose of steroids in treatment arm 2 (day 0) had to be administered within 8 hours after reperfusion of the graft. Beginning from day 1 to day 6 doses of 15 mg/m2/day had to be given intravenously (i.v.) in both treatment arms. Then, the steroid doses (oral prednisone or its equivalent) were to be decreased from 10 mg/m²/day orally (day 7-13), to 7.5 mg/m²/day orally (day 14-30), to 4 mg/m²/day orally (until end of month 2), to 2.5 mg/m²/day orally (until end of month 3) and to 1 mg/m²/day orally (until end of month 6).
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 16 Years
Healthy volunteers
No
Inclusion criteria
* Pediatric patients undergoing primary orthotopic liver transplantation (whole organ or split liver or reduced size) * Cadaveric or living donor (related or unrelated)
Exclusion criteria
* Patients who are recipients of multiple solid organ transplants and/or who have previously received transplanted organs * If cold ischemia time of the transplanted organ is \>12 hours * Auxiliary liver transplant recipients * Fulminant hepatic failure * Autoimmune hepatitis * Primary sclerosing cholangitis * Severe acute systemic infections * Hepatitis B surface antigen/HCV/HIV positive * Known contraindication to intravenous (i.v.) or per os (orally) (p.o.) cyclosporine or corticoids * Non-ability to comply with the protocol * Relevant abnormal physical or laboratory findings within 2 weeks of inclusion * Relevant severe allergy, hypersensitivity to basiliximab or similar drugs * History/presence of relevant malignancy * Pregnancy/breastfeeding * Use of any investigational or immunomodulatory/immunosuppressive drug within 4 weeks prior to transplantation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | 3 months after treatment | Graft loss is defined as being listed for a re-transplantation. The analysis was based on the locally performed biopsy assessments. Generally, patients not experiencing a relevant event (i.e., acute rejection, graft loss or death) were censored with the last visit date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months | 3 and 6 months | To evaluate the efficacy of a regimen with intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids as measured by the incidence of steroid resistant rejection episodes within three and six months. |
| Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | 3 months and 6 months | Graft loss is defined as being listed for a re-transplantation. |
| Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months | 3 months | At biopsy of transplanted tissue sample, acute rejection has an onset 2-60 days after transplantation, with interstitial vascular endothelial cell swelling, interstitial accumulation of lymphocytes, plasma cells, immunoblasts, macrophages, neutrophils; tubular separation with edema/necrosis of tubular epithelium; swelling and vacuolization of the endothelial cells, vascular edema, bleeding and inflammation. Clinical signs and symptoms include malaise, fever, and hypertension. |
| Time of Onset of a First Biopsy Proven Acute Rejection | 6 months | Biopsied Tissue shows rejection at onset 2-60 days after transplantation, with interstitial vascular endothelial cell swelling, interstitial accumulation of lymphocytes, plasma cells, immunoblasts, macrophages, neutrophils; tubular separation with edema/necrosis of tubular epithelium; swelling and vacuolization of the endothelial cells, vascular edema, bleeding and inflammation. Clinical signs and symptoms include malaise, fever and hypertension . |
| Percentage of Participants With Treatment Failure Within Three and Six Months | 3 and 6 months | To evaluate the proportion of patients with treatment failure treated with a therapy consisting of intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids within three and six months. |
| Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | 6 months | To evaluate the safety of a regimen with intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids as measured by the episodes of bacterial, viral and fungal infections during six months. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| With Intraoperative Steroids Intraoperative steroids were administered during transplantation and Basiliximab was administered on Day 0 and 4 (10 mg if the body weight was \<35 kg; 20 mg if body weight was ≥35 kg) in combination with cyclosporine/cyclosporine microemulsion and steroids. Basiliximab was administered as an intravenous bolus injection within 8 hours after reperfusion of the graft. | 39 |
| Without Intraoperative Steroids No intraoperative steroids were administered during transplantation and Basiliximab was administered on Day 0 and 4 (10 mg if the body weight was \<35 kg; 20 mg if body weight was ≥35 kg) in combination with cyclosporine/cyclosporine microemulsion and steroids. Basiliximab and the first dose of steroids had to be administered within 8 hours after reperfusion of the graft and basiliximab was given as an intravenous bolus injection. | 38 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 8 |
| Overall Study | Graft Loss | 2 | 1 |
| Overall Study | Lack of Efficacy | 8 | 9 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | With Intraoperative Steroids | Without Intraoperative Steroids | Total |
|---|---|---|---|
| Age Continuous | 3.08 years STANDARD_DEVIATION 4.09 | 3.71 years STANDARD_DEVIATION 5.36 | 3.39 years STANDARD_DEVIATION 4.74 |
| Age, Customized <2 years | 21 participants | 24 participants | 45 participants |
| Age, Customized from 2 to 16 years | 18 participants | 14 participants | 32 participants |
| Sex: Female, Male Female | 21 Participants | 19 Participants | 40 Participants |
| Sex: Female, Male Male | 18 Participants | 19 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 39 | 38 / 38 |
| serious Total, serious adverse events | 18 / 39 | 23 / 38 |
Outcome results
Primary
Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation
Graft loss is defined as being listed for a re-transplantation. The analysis was based on the locally performed biopsy assessments. Generally, patients not experiencing a relevant event (i.e., acute rejection, graft loss or death) were censored with the last visit date.
Time frame: 3 months after treatment
Population: safety/Intent to Treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| With Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Stratum age < 2 years (N=21, 24) | 8 Participants |
| With Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Stratum age 2-16 years (N=18, 14) | 14 Participants |
| With Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Total (N= 39, 38) | 22 Participants |
| Without Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Stratum age < 2 years (N=21, 24) | 15 Participants |
| Without Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Stratum age 2-16 years (N=18, 14) | 11 Participants |
| Without Intraoperative Steroids | Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation | Total (N= 39, 38) | 26 Participants |
Secondary
Number of Participants With Bacterial, Viral and Fungal Infections During Six Months
To evaluate the safety of a regimen with intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids as measured by the episodes of bacterial, viral and fungal infections during six months.
Time frame: 6 months
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| With Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Fungal | 16 Participants |
| With Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Viral | 15 Participants |
| With Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Bacterial | 10 Participants |
| Without Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Viral | 14 Participants |
| Without Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Fungal | 16 Participants |
| Without Intraoperative Steroids | Number of Participants With Bacterial, Viral and Fungal Infections During Six Months | Bacterial | 18 Participants |
Secondary
Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months
At biopsy of transplanted tissue sample, acute rejection has an onset 2-60 days after transplantation, with interstitial vascular endothelial cell swelling, interstitial accumulation of lymphocytes, plasma cells, immunoblasts, macrophages, neutrophils; tubular separation with edema/necrosis of tubular epithelium; swelling and vacuolization of the endothelial cells, vascular edema, bleeding and inflammation. Clinical signs and symptoms include malaise, fever, and hypertension.
Time frame: 3 months
Population: safety/Intent to Treat (ITT) population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| With Intraoperative Steroids | Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months | 20 Participants |
| Without Intraoperative Steroids | Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months | 26 Participants |
Secondary
Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months
To evaluate the efficacy of a regimen with intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids as measured by the incidence of steroid resistant rejection episodes within three and six months.
Time frame: 3 and 6 months
Population: safety/Intent to Treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| With Intraoperative Steroids | Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months | Within 3 months post treatment | 2 Participants |
| With Intraoperative Steroids | Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months | Within 6 months post treatment | 2 Participants |
| Without Intraoperative Steroids | Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months | Within 3 months post treatment | 2 Participants |
| Without Intraoperative Steroids | Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months | Within 6 months post treatment | 2 Participants |
Secondary
Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation
Graft loss is defined as being listed for a re-transplantation.
Time frame: 3 months and 6 months
Population: safety/Intent to Treat (ITT) population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| With Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Death within 3 months post treatment | 0.0 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Death within 6 months post treatment | 0.0 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Graft Loss within 3 months post treatment | 5.1 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Graft Loss within 6 months post treatment | 5.1 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Graft Loss within 6 months post treatment | 5.3 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Death within 3 months post treatment | 2.6 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Graft Loss within 3 months post treatment | 2.6 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation | Death within 6 months post treatment | 2.6 Percentage of participants |
Secondary
Percentage of Participants With Treatment Failure Within Three and Six Months
To evaluate the proportion of patients with treatment failure treated with a therapy consisting of intraoperative versus without intraoperative steroids in combination with basiliximab, cyclosporine/cyclosporine microemulsion and steroids within three and six months.
Time frame: 3 and 6 months
Population: Intention to treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 Month: Total | 5.13 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 month: Age < 2 years (N= 21, 24) | 0.00 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 month: Age 2-16 years (N= 18, 14) | 11.11 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 month: Age 2-16 years (N= 18, 14) | 11.11 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 Month: Total | 5.13 Percentage of participants |
| With Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 month: Age < 2 years (N= 21, 24) | 0.00 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 Month: Total | 5.26 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 month: Age < 2 years (N= 21, 24) | 4.17 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 month: Age 2-16 years (N= 18, 14) | 7.14 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 month: Age < 2 years (N= 21, 24) | 4.17 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 6 month: Age 2-16 years (N= 18, 14) | 7.14 Percentage of participants |
| Without Intraoperative Steroids | Percentage of Participants With Treatment Failure Within Three and Six Months | 3 Month: Total | 5.26 Percentage of participants |
Secondary
Time of Onset of a First Biopsy Proven Acute Rejection
Biopsied Tissue shows rejection at onset 2-60 days after transplantation, with interstitial vascular endothelial cell swelling, interstitial accumulation of lymphocytes, plasma cells, immunoblasts, macrophages, neutrophils; tubular separation with edema/necrosis of tubular epithelium; swelling and vacuolization of the endothelial cells, vascular edema, bleeding and inflammation. Clinical signs and symptoms include malaise, fever and hypertension .
Time frame: 6 months
Population: safety/Intent to Treat (ITT) population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| With Intraoperative Steroids | Time of Onset of a First Biopsy Proven Acute Rejection | 1.93 Months |
| Without Intraoperative Steroids | Time of Onset of a First Biopsy Proven Acute Rejection | 0.75 Months |