Safety and Efficacy of Basiliximab, Delayed Dose Tacrolimus Plus ECMPA Following Liver Transplantation

• ClinicalTrials.gov Identifier: NCT02123108
• Recruitment Status: Unknown
• First Posted: April 25, 2014
• Last Update Posted: April 25, 2014
• Sponsor: University of California, Los Angeles
• Collaborator: Novartis
• Information provided by (Responsible Party): Fady M Kaldas, M.D., F.A.C.S., University of California, Los Angeles

Study Description

Brief Summary:

This is an investigator initiated study at the University of California, Los Angeles (UCLA) funded by Novartis looking at using a combination of immunosuppressive drugs in liver transplant patients that are at risk of developing kidney problems. Kidney problems following liver transplants is the most problematic issue facing liver transplant patients today.

This study will generate information in this area of high unmet medical need utilizing basiliximab and Myfortic and using a reduced dose of tacrolimus, one of the current standard of care medications, after kidney function has normalized.

This study will enroll 60 subjects. 30 subjects in each of the two groups. Subjects will be followed for 1 year after liver transplant.

Condition or disease	Intervention/treatment	Phase
Liver Transplantation	Drug: Basiliximab	Phase 4

Detailed Description:

Since basiliximab works on the same receptor system as tacrolimus and has not been shown to cause significant adverse effects, such as nephrotoxicity or the cytokine release syndrome, the investigators are proposing induction therapy with basiliximab in liver transplant patients with concomitant preoperative renal dysfunction. This will combat acute rejection and allow the delay of tacrolimus therapy until post-operative day #7. The delay in tacrolimus therapy should allow renal function to improve and reduce the chance of continued renal dysfunction. Also, the addition of basiliximab to the immunosuppressive regimen should allow for a reduction in tacrolimus dose (normal tacrolimus concentrations at UCLA are 7-10ng/mL. Our goal will be 3-5ng/mL) in the immediate post-transplant period thereby reducing the chance of acute and long-term efficacy-limiting adverse effects associated with the tacrolimus while maintaining adequate immunosuppression to reduce acute rejection episodes. This would be the most convincing prospective randomized study utilizing basiliximab as a renal sparing agent in liver transplantation.

Objectives Primary objectives

• To evaluate renal recovery/ function following OLT in patients undergoing orthotopic liver transplant at 6 and 12 months post-transplant.

Secondary objectives (comparing the two treatment arms)

• To determine the tolerability and adverse event profile during the first year post-transplant.
• To determine incidence and severity acute rejection episodes
• To determine the incidence of death and/or graft failure within the first year post-transplant

Study design The study is a single center prospective randomized trial wherein the investigators will have two groups. Patients will be screened and eligible patients will be enrolled pre-transplant. Patients will then be randomized at time of transplant to either the control or treatment arm. Post transplant laboratory data (chemistry, tacrolimus level and liver function tests) will be collected on a daily basis. For the duration of the patients' hospital stay (average 2-3 weeks). This will provide the early data set for early post operative results. Patients will subsequently be followed on a weekly outpatient basis upon discharge as per protocol. During these visits, laboratory data (chemistry, tacrolimus level and liver function tests) are also collected and will provide the continued flow of data for our follow up analysis. Any evidence of rejection will prompt treatment with rescue therapy and if necessary disenrollment from the study.

Study Population

In a 1:1 fashion, 60 patients (inpatients and outpatients) meeting preset criteria awaiting liver transplantation will be randomized at UCLA Medical Center as part of this exploratory study. Each patient will be followed for 1 year post-transplant.

Patients may be consented up to 30 days prior to transplantation. Patients can be screened for the study from 7 days prior to transplantation to 7 days prior randomization. Patients will be evaluated based on inclusion exclusion criteria depicted in the study protocol and will be assigned a patient number if eligible for study entry. Patient must meet all the inclusion criteria and none of the exclusion criteria on the day of study entry.

Clinical Assessments

• Weight, height and blood pressure (in sitting position after 5 minutes)
• Concomitant medications
• Pre-existing clinical conditions
• Laboratory evaluations (Appendix 2):
• Complete blood count (CBC)
• Chemistry Panel: glucose, Na, K, Cl, carbon dioxide (CO2), Ca, P, Mg, blood urea nitrogen (BUN), albumin and total protein, and serum creatinine
• Hepatic Profile: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin (total direct), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH)
• Urinary protein and creatinine concentration
• Calculated glomerular filtration rate (GFR) by Modification of Diet in Renal Disease (MDRD) (Appendix 1)
• Pregnancy test (serum beta- human chorionic gonadotropin (HCG) sensitivity must be equal to 50 milli-International unit (mIU)/ millilitre (mL)), will be documented within 7 days prior to randomization
• Lipid Panel

Inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

• > 18 years old
• Undergoing first or second OLT
• Meld score >25
• Serum creatinine >1.5 or ongoing hemodialysis for less than 4 weeks at the time of transplant
• Able and agreeable to conform to requirements of the study
• Patients or proxy must give written informed consent before any assessment is performed.

Exclusion criteria

• <18 years old
• Serum creatinine <1.5
• MELD Score < 25
• Ongoing hemodialysis for 4 or more weeks (those patients become eligible for renal transplants at that point per UCLA practice).
• Receiving Muromonab-cluster of differentiation 3 (OKT3), antithymocyte globulin (ATG), or intravenous immunoglobulin (IVIG) therapy around time of transplant
• Participating in another clinical research study involving the evaluation of another investigational drug or device
• Prior documented allergy to any of the study medications
• Active Fungal infection

Treatment Investigational and control drugs

Investigational drug, Basiliximab will be the investigational drug supplied by Novartis in 20 mg vials

Control drugs, Mycophenolate/ Mycophenolic acid delayed release (will be provided by Novartis in 360 mg tablets) / Tacrolimus/ corticosteroids will be used in both arms as control drugs. For subjects unable to tolerate po medications, mycophenolate mofetil oral suspension will be supplied from regular commercial supply to be administered via nasogastric tube.

Treatment arms Patients will be assigned to one of the following 2 treatment arms in a ratio of 1:1

Adverse events Subjects will be carefully monitored for adverse events. This monitoring includes clinical Laboratory tests. Adverse events will be assessed on a daily basis according to clinical practice. Adverse event will be assessed in terms in terms of seriousness, severity, and relationship to the study drugs. All unexpected or severe adverse events will be reviewed by the Principle Investigator. The PI will also continuously monitor the number of patients at each respective follow-up period and perform the required toxicity evaluation intervals to assure the conduct of the trial complies with protocol design. Study conduct and timeliness and accuracy of data will be monitored regularly for the first 12 patients of the trial. The PI will submit appropriate safety reports as needed throughout the study period.

Data review and database management Data collection Data will be collected per study protocol and prospectively recorded in the case report form (CRF) by the study coordinator. The principle investigator will oversee this process.

Database management and quality control The study coordinator will be responsible for all data management/accuracy under the supervision of the principle investigator.

Data analysis (Any or all sections may be included based on type of study) Populations for analysis All patients consented and enrolled will be analyzed.

Patient demographics/other baseline characteristics No specific patient demographics aside from inclusion/exclusion criteria

Treatments (study drug, rescue medication, other concomitant therapies, compliance) Study coordinator will conduct pill counts on return visits to clinic to ascertain compliance after discharge.

Analysis of the primary objective(s)

Variable The primary efficacy endpoint is renal function measured by epidermal growth factor receptor (eGFR) as calculated using abbreviated MDRD-4 formula at 6 and 12 months post-transplantation.

Statistical analysis:

Baseline comparisons - The investigators will confirm that the randomization was successful by comparing potential predictors such as baseline age, hepatitis C (HCV) status (yes/no), baseline MELD score, pre transplant dialysis duration, and bypass (yes/no) status between the two arms. The investigators will also compare gender and ethnicity. If any important potential confounder is clinically different or beyond chance different (statistically significant) between the two groups, it will be considered for use in adjustment as described below.

Primary outcomes - Renal function

The investigators will use a repeated measure analysis of variance model on the original or transformed (possibly log) scale or the non parametric analog (Friedman procedure) to compare mean/median profiles of the continuous kidney function outcomes (GRR, serum Cr, Cr clearance, time on dialysis) between the two groups over time. The investigators will report the mean/median absolute values as well as the absolute and percent change from baseline over time in both groups.

While they anticipate the randomization to be successful, if needed the investigators will extend this repeated measure model to a general regression model with random patient effects (mixed model) using the confounders as covariates. Alternately, if a convenient regression model cannot be identified, they will create adjustment strata based on the confounders and compute stratum adjusted means/medians. The investigators will report both the unadjusted and covariate adjusted values as necessary.

Secondary outcomes - Time to event

The investigators will use Kaplan-Meier methods and the corresponding log rank test to compare time to event curves for time to first acute graft rejection (ie percent rejection free) as well as patient and graft survival. The investigators will use the Cox proportional hazard model, if needed, to adjust for covariates that are different between the two arms. The investigators will carry out a similar analysis for cluster of differentiation 25 (CD25) levels on the appropriate scale.

Adverse events - The investigators will report the proportion and severity of patients with adverse events over time and score them as none, mild, moderate or severe (0-3). The investigators will use the non parametric Freedman methods to compare the score distributions between groups across time.

Dropouts - The investigators do not anticipate more than 5% dropouts at most. However, they will compare baseline variables such as age and MELD score to determine if the dropping out is at random and is comparable between the two groups. If not, they will comment on the direction of any possible bias. The maximum likelihood repeated measure model above gives unbiased estimates with the correct standard errors if the dropouts are at random.

Potential benefits of participants in Group 1 include improved renal function and reduced chance of continued renal dysfunction from the delay in tacrolimus therapy. Participants will possibly maintain adequate immunosuppression to reduce acute rejection episodes.

Group 2 will receive standard of care but will have increased post-transplant monitoring by the study team.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Immunosuppression With Basiliximab, Delayed Dose Tacrolimus Plus Enteric Coated Mycophenolic Acid, Versus Standard Dose Tacrolimus, Enteric Coated Mycophenolic Acid Plus Corticosteroids in Patients Undergoing Orthotopic Liver Transplantation (OLT)
• Study Start Date: January 2011
• Estimated Primary Completion Date: June 2014
• Estimated Study Completion Date: June 2015

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Basiliximab; Basiliximab Basiliximab Peri-transplant • 40mg IV infusion within 4 hours of transplant x1 Basiliximab Post-transplant • 20mg IV infusion Post Operative Day #4 (POD 4) x1 Tacrolimus (with basiliximab induction) • Post Operative Day #7 (POD 7) or subclinical acute rejection (SCr) < 1.8 mg/dl to one year: 0.03-0.1mg/kg q12h; Mycophenolate/mycophenolic acid will be started Post Operatively Day 1: 720 mg po bid will be administered once the patient is able to tolerate PO medication. Corticosteroids • Intraoperative: hydrocortisone 1000mg intravenous push (IVP) Followed by: • Standard steroid taper:	Drug: Basiliximab; Peri-operative 40 mg IV dose and 20mg IV postoperative dose will be given in the treatment arm; Other Name: Simulect
No Intervention: Tacrolimus Group; Tacrolimus (without basiliximab induction); standard of care group; Beginning Post Operative Day #1 to six months: 0.03-0.1 mg/kg q12h po to maintain whole blood trough concentration of 7-10 ng/mL; Six months to one year: maintain whole blood trough concentration of 5-8ng/mL Mycophenolate/mycophenolic acid will be started Post Operatively Day 1. Immediately post transplant, while subjects have nasogastric (ng) tube; this will be delivered as CellCept (mycophenolate mofetil) oral suspension 1,000 mg BID administered via the ng tube. Enteric coated mycophenolic acid (Myfortic) - 720 mg po bid will be administered once the patient is able to tolerate PO medication. Corticosteroids • Intraoperative: hydrocortisone IVP Followed by: • Standard steroid taper

Outcome Measures

Primary Outcome Measures :

1. To evaluate renal recovery/ function following OLT in patients undergoing orthotopic liver transplant at 6 and 12 months post-transplant. [ Time Frame: 12 months post-transplant ]
   We will evaluate renal recovery/ function following OLT in patients undergoing orthotopic liver transplant at 6 and 12 months post-transplant.

Secondary Outcome Measures :

1. To determine the tolerability during the first year post-transplant and to determine incidence and severity acute rejection episodes [ Time Frame: 12 months post liver transplantation ]
   We will determine the tolerability and adverse event profile during the first year post-transplant.

Other Outcome Measures:

1. To determine the adverse event profile during the first year post-transplant. [ Time Frame: 12 months post liver transplantation ]
   We will look to determine the adverse event profile during the first year post-transplant.
2. To determine incidence and severity acute rejection episodes [ Time Frame: 12 months post liver transplant ]
   We will look to determine incidence and severity acute rejection episodes
3. To determine the incidence of death within the first year post-transplant [ Time Frame: 12 months post liver transplant ]
   We will look to determine the incidence of death within the first year post-transplant
4. To determine the incidence of graft failure within the first year post-transplant [ Time Frame: 12 months post transplant ]
   We will look to determine the incidence of graft failure within the first year post-transplant

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Patients eligible for inclusion in this study have to fulfill all of the following criteria:

• >18 years old
• Undergoing first or second OLT
• Meld score >25
• Serum creatinine > 1.5 or ongoing hemodialysis for less than 4 weeks at the time of transplant
• Able and agreeable to conform to requirements of the study
• Patients or proxy must give written informed consent before any assessment is performed.

Exclusion Criteria:

• <18 years old
• Serum creatinine <1.5
• MELD Score < 25
• Ongoing hemodialysis for 4 or more weeks (those patients become eligible for renal transplants at that point per UCLA practice).
• Receiving OKT3, ATG, or IVIG therapy around time of transplant
• Participating in another clinical research study involving the evaluation of another investigational drug or device
• Prior documented allergy to any of the study medications
• Active Fungal infection

Contacts and Locations

Contacts

Contact: Fady M Kaldas, MD; 310-825-5318; fkaldas@mednet.ucla.edu

Contact: Curtis D Holt, PharmD; 310-206-4952; cholt@mednet.ucla.edu

Locations

United States, California

Ronald Reagan UCLA Medical Center; Recruiting

Los Angeles, California, United States, 90095

Contact: Fady M Kaldas, MD 310-825-5318 fkaldas@mednet.ucla.edu

Contact: Curtis D Holt, PharmD 310-206-4952 cholt@mednet.ucla.edu

Principal Investigator: Fady M Kaldas, MD

Sponsors and Collaborators

University of California, Los Angeles

Novartis

Investigators

• Principal Investigator: Fady M Kaldas, MD; UCLA Department of Surgery

More Information

Publications:

Ramirez CB, Marino IR. The role of basiliximab induction therapy in organ transplantation. Expert Opin Biol Ther. 2007 Jan;7(1):137-48. Review.

Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, Gritsch A, McCauley J, Starzl T, Demetris AJ, Randhawa PS. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant. 1997 Jun;11(3):237-42.

Rimola A, Gavaler JS, Schade RR, el-Lankany S, Starzl TE, Van Thiel DH. Effects of renal impairment on liver transplantation. Gastroenterology. 1987 Jul;93(1):148-56.

Klintmalm GB, Gonwa TA. Nephrotoxicity associated with cyclosporine and FK506. Liver Transpl Surg. 1995 Sep;1(5 Suppl 1):11-9. Review.

Guckelberger O, Bechstein WO, Neuhaus R, Luesebrink R, Lemmens HP, Kratschmer B, Jonas S, Neuhaus PL. Cardiovascular risk factors in long-term follow-up after orthotopic liver transplantation. Clin Transplant. 1997 Feb;11(1):60-5.

Neuhaus P, Clavien PA, Kittur D, Salizzoni M, Rimola A, Abeywickrama K, Ortmann E, Chodoff L, Hall M, Korn A, Nashan B; CHIC 304 International Liver Study Group. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial. Liver Transpl. 2002 Feb;8(2):132-42.

Calmus Y, Scheele JR, Gonzalez-Pinto I, Jaurrieta EJ, Klar E, Pageaux GP, Scudamore CH, Cuervas-Mons V, Metselaar HJ, Prestele H, Girault D. Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients. Liver Transpl. 2002 Feb;8(2):123-31.

Onrust SV, Wiseman LR. Basiliximab. Drugs. 1999 Feb;57(2):207-13; discussion 214. Review.

Cherqui D, Duvoux C, Charlotte F, Humeres R, Lauzet JY, Métreau JM, Salvat A, Rotman N, Julien M, Fagniez PL, et al. [Value of a powerful initial immunosuppression after liver transplantation. Prospective study of 60 cases]. Gastroenterol Clin Biol. 1994;18(2):115-22. Review. French.

Berard JL, Velez RL, Freeman RB, Tsunoda SM. A review of interleukin-2 receptor antagonists in solid organ transplantation. Pharmacotherapy. 1999 Oct;19(10):1127-37. Review.

• Responsible Party: Fady M Kaldas, M.D., F.A.C.S., Principle-Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT02123108
• Other Study ID Numbers: UCLA: CCHI621AUS17T
• First Posted: April 25, 2014
• Last Update Posted: April 25, 2014
• Last Verified: April 2014

Keywords provided by Fady M Kaldas, M.D., F.A.C.S., University of California, Los Angeles:

Simulect, Myfortic, OLT, Renal Dysfunction, Liver Transplant, Orthotopic Liver Transplantation

Additional relevant MeSH terms:

Basiliximab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs