Study of ISA247 (Voclosporin) in De Novo Renal Transplantation

Phase 2

Completed

Conditions: Kidney Diseases

Interventions: Drug: tacrolimus
Drug: Voclosporin

Registration Number: NCT00270634

Lead Sponsor: Aurinia Pharmaceuticals Inc.

Brief Summary: This study will see if voclosporin is safe and effective in preventing kidney transplant rejection.

Detailed Description: Prograf® (tacrolimus) is associated with numerous side effects, including neurotoxicity, nephrotoxicity, polyoma nephropathy, QT prolongation, and New Onset Diabetes Mellitus After Transplant (NODAT). Voclosporin is a novel calcineurin inhibitor intended for use in the prevention of organ graft rejection.

Comparison(s): Voclosporin at 3 dose levels (0.4, 0.6, and 0.8 mg/kg twice a day) compared to tacrolimus

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 334

Inclusion Criteria

Males and females aged 18 - 65 years inclusive at the time of screening.
Patients must be receiving a first cadaveric or living donor renal transplant.
Patients must be able to receive oral medication at time of randomization.
Females who are not pregnant or nursing or planning to become pregnant during the course of the study, or 3 months after last dose of study medication.
Sexually-active women of child-bearing potential (including those who are < 1 year postmenopausal) and sexually-active men who are practicing a highly effective method of birth control. A highly effective method of birth control is defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly and will include implants, injectables, combined oral contraceptives, double-barrier method, sexual abstinence, or a sterile partner. Sexually-active men and women of child-bearing potential should continue to practice contraception as outlined above during treatment and for ≥ 3 months after the last dose of voclosporin.
Able to give written informed consent prior to screening procedures.
Able to keep study appointments and cooperate with all study requirements, in the opinion of the investigator.

Exclusion Criteria

Receiving a HLA (human leukocyte antigen)identical living related transplant.
Cold ischemic time > 24 hours.
Peak PRA (panel reactive antibodies) > 30%
Cadaveric donors who are over age 60, non-heart beating donors, or any cadaveric donors positive for HIV, hepatitis B virus (HBV) or hepatitis C virus (HCV).
Transplantation of multiple grafts (e.g. kidney and pancreas).
Systemic infections requiring continued therapy at the time of entry into this study. (Prophylaxis against cytomegalovirus [CMV] and/or pneumocystis carinii pneumonia (PCP) infection will be permitted).
Serologic evidence or known latent human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) virus. Known negative serology prior to study entry may be used.
A current malignancy or history of malignancy within 5 years or a history of lymphoma at any time. Subjects can be enrolled with a history of squamous or basal cell carcinoma that has been surgically excised or removed with curettage and electrodesiccation.
Requires prohibited medications or treatment during the study.
Alanine transaminase (ALT), aspartate transaminase (AST), or gamma-glutamyl transferase (GGT) ≥ 3x upper limit of normal (ULN) at time of transplantation.
White blood cell count ≤ 2.8 x 10^9/L.
Triglycerides ≥ 3x ULN.
Pregnant women or nursing mothers.
Has used any investigational drug or device within 28 days or 5 half lives (whichever is longer) prior to enrollment.
Previous exposure to voclosporin.
A history of active alcoholism or drug addiction within 1 year prior to study entry.
Weighs < 45 kg (99 lbs) or > 140 kg (308 lbs).
A history of disease, including mental/emotional disorder that would interfere with the subject's participation in the study, or that might cause the administration of voclosporin to pose a significant risk to the subject, in the opinion of the investigator.
Allergy to iodine.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus	tacrolimus	Standard Dose Tacrolimus
Low Dose Voclosporin	Voclosporin	Low dose voclosporin
Mid Dose Voclosporin	Voclosporin	Mid Dose Voclosporin
High Dose Voclosporin	Voclosporin	High Dose Voclosporin

Primary Outcome Measures

Name	Time	Method
Biopsy Proven Acute Rejection (BPAR)	Six months	The primary objective of the PROMISE trial was to demonstrate noninferiority of biopsy proven acute rejection (BPAR) rate in de novo renal transplant patients at 6 months in at least one VCS treatment group.

Secondary Outcome Measures

Name	Time	Method
Graft Survival	Six months
Hypertension, Hyperlipidemia, or Hyperglycemia	Six months
To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR)	Six months	ANOVAs to test for differences in GFR at Month 6.
The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition	Six months	A sparse sampling protocol of whole blood samples obtained on Day 180 at time points immediately prior to drug administration and at 1, 2, and 4 hours post-dose were utilized. Standard non-compartmental analysis (NCA) was performed on whole blood concentration data for voclosporin and its metabolites, tacrolimus, MPA (mycophenolic acid) and MPAG (mycophenolic acid glucuronide). Tmax and Cmax were obtained directly from the concentration-time profiles without interpolation. AUC(0-4)\[area under the curve\] was calculated using log-linear trapezoidal rule. Cmax, AUC(0-4), C0 and C2 were summarized using descriptive statistics.
Patient Survival	Six months
A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up.	Six months