Efficacy and Safety of Basiliximab, Cyclosporine/Cyclosporine Microemulsion, and Steroids in Pediatric de Novo Liver Transplant Recipients Avoiding Intraoperative Steroids - Full Text View

Sponsor:	Novartis
Information provided by:	Novartis
ClinicalTrials.gov Identifier:	NCT00149890

Purpose

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.

Condition	Intervention	Phase
Liver Transplantation Infection	Drug: Basiliximab Drug: Cyclosporine/cyclosporine microemulsion Drug: Steroid	Phase III

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Prevention
Official Title:	A Multicenter, Open-label, Randomized, Two Arm Study to Investigate the Efficacy and Safety of a Therapy Avoiding Intraoperative Steroids in Combination With Basiliximab, Cyclosporine/Cyclosporine Microemulsion, and Steroids in Pediatric de Novo Liver Transplant Recipients

Resource links provided by NLM:

MedlinePlus related topics: Liver Transplantation

Drug Information available for: Cyclosporine Cyclosporin Basiliximab

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

Number of Participants With at Least One Biopsy Proven Acute Rejection (BPAR) Episode, Graft Loss or Death Within the First Three Months Post-transplantation [ Time Frame: 3 months after treatment ] [ Designated as safety issue: No ]
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 Outcome Measures:

Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months [ Time Frame: 3 months ] [ Designated as safety issue: No ]
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.
Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months [ Time Frame: 3 and 6 months ] [ Designated as safety issue: No ]
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 [ Time Frame: 3 months and 6 months ] [ Designated as safety issue: Yes ]
Graft loss is defined as being listed for a re-transplantation.
Number of Participants With Bacterial, Viral and Fungal Infections During Six Months [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
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 of Onset of a First Biopsy Proven Acute Rejection [ Time Frame: 6 months ] [ Designated as safety issue: No ]
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 [ Time Frame: 3 and 6 months ] [ Designated as safety issue: No ]
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.

Enrollment:	77
Study Start Date:	March 2004
Study Completion Date:	March 2009
Primary Completion Date:	March 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 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.	Drug: Basiliximab 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. Other Name: Simulect® Drug: Cyclosporine/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. Other Name: Sandimmun®/Sandimmun® Optoral Drug: Steroid 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).
Active Comparator: 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.	Drug: Basiliximab 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. Other Name: Simulect® Drug: Cyclosporine/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. Other Name: Sandimmun®/Sandimmun® Optoral Drug: Steroid 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).

Arms

Assigned Interventions

Experimental: 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.

Drug: Basiliximab

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.

Other Name: Simulect®

Drug: Cyclosporine/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.

Other Name: Sandimmun®/Sandimmun® Optoral

Drug: Steroid

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).

Active Comparator: 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.

Drug: Basiliximab

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.

Other Name: Simulect®

Drug: Cyclosporine/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.

Other Name: Sandimmun®/Sandimmun® Optoral

Drug: Steroid

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).

Eligibility

Ages Eligible for Study:	up to 16 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00149890

Locations

Germany
Novartis Investigational Site
Various Cities, Germany

Sponsors and Collaborators

Novartis

Investigators

Study Director:

Novartis

More Information

No publications provided

Responsible Party:	Novartis
ClinicalTrials.gov Identifier:	NCT00149890 History of Changes
Other Study ID Numbers:	CCHI621ADE04
Study First Received:	September 6, 2005
Results First Received:	January 20, 2011
Last Updated:	August 17, 2011
Health Authority:	Germany: Paul-Ehrlich-Institut

Keywords provided by Novartis:

pediatric
liver transplantation
Simulect
Basiliximab

ciclosporin microemulsion
steroid reduction
pediatric liver transplantation

Additional relevant MeSH terms:

Cyclosporins
Cyclosporine
Basiliximab
Antibodies, Monoclonal
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents

Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on February 09, 2012