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

• ClinicalTrials.gov Identifier: NCT00149890
• Recruitment Status: Completed
• First Posted: September 8, 2005
• Results First Posted: September 22, 2011
• Last Update Posted: September 22, 2011
• Sponsor: Novartis
• Information provided by: Novartis

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Liver Transplantation; Infection	Drug: Basiliximab; Drug: Cyclosporine/cyclosporine microemulsion; Drug: Steroid	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 77 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (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
• Study Start Date: March 2004
• Actual Primary Completion Date: March 2009
• Actual Study Completion Date: March 2009

Arms and Interventions

Arm	Intervention/treatment
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).

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   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 :

1. Number of Participants With Biopsy Proven Acute Rejection (BPAR) Episodes Within the First Three Months [ Time Frame: 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.
2. Number of Participants With Steroid Resistant Rejection Episodes Within Three and Six Months [ Time Frame: 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.
3. Percentage of Participants Experiencing Death or Graft Loss Within Three and Six Months After Transplantation [ Time Frame: 3 months and 6 months ]
   Graft loss is defined as being listed for a re-transplantation.
4. Number of Participants With Bacterial, Viral and Fungal Infections During Six Months [ Time Frame: 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.
5. Time of Onset of a First Biopsy Proven Acute Rejection [ Time Frame: 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

   .

6. Percentage of Participants With Treatment Failure Within Three and Six Months [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: up to 16 Years (Child)
• Sexes Eligible for Study: All
• 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

Locations

Germany

Novartis Investigational Site

Various Cities, Germany

Sponsors and Collaborators

Novartis

Investigators

• Study Director: Novartis; Novartis

More Information

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00149890
• Other Study ID Numbers: CCHI621ADE04
• First Posted: September 8, 2005
• Results First Posted: September 22, 2011
• Last Update Posted: September 22, 2011
• Last Verified: August 2011

Keywords provided by Novartis:

pediatric; liver transplantation; Simulect; Basiliximab; ciclosporin microemulsion; steroid reduction; pediatric liver transplantation

Additional relevant MeSH terms:

Cyclosporine; Cyclosporins; Basiliximab; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Calcineurin Inhibitors