Study of ISA247 (Voclosporin) in De Novo Renal Transplantation (PROMISE)

• To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) [ Time Frame: Six months ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: Six months ] [ Designated as safety issue: No ]

  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 [ Time Frame: Six months ] [ Designated as safety issue: Yes ]
• Graft Survival [ Time Frame: Six months ] [ Designated as safety issue: Yes ]
• Hypertension, Hyperlipidemia, or Hyperglycemia [ Time Frame: Six months ] [ Designated as safety issue: Yes ]
• A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. [ Time Frame: Six months ] [ Designated as safety issue: Yes ]

• • To demonstrate a 5% improvement in renal function at 6 months as measured by Nankivell GFR.
• • To determine the pharmacokinetic–pharmacodynamic relationship between ISA247 and calcineurin inhibition, or tacrolimus and calcineurin inhibition.
• • To determine patient survival at 6 months.
• • To determine graft survival at 6 months.
• • To determine the proportion of patients with hypertension, hyperlipidemia, or hyperglycemia at 6 months.
• • A composite of biopsy-proven chronic rejection graft loss, death, or lost to follow up.
• • A composite of biopsy-proven acute rejections, graft loss or death.
• • To establish the safety of ISA247.

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

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

• Drug: Voclosporin
  voclosporin 0.4, 0.6, 0.8 mg/kg po BID
  Other Name: ISA247
• Drug: tacrolimus
  tacrolimus 0.05 mg/kg po BID

• Active Comparator: Low Dose Voclosporin
  Low dose voclosporin
  Intervention: Drug: Voclosporin
• Active Comparator: Mid Dose Voclosporin
  Mid Dose Voclosporin
  Intervention: Drug: Voclosporin
• Active Comparator: High Dose Voclosporin
  High Dose Voclosporin
  Intervention: Drug: Voclosporin
• Active Comparator: Tacrolimus
  Standard Dose Tacrolimus
  Intervention: Drug: tacrolimus

• Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S, Huizinga RB, Meier-Kriesche HU; PROMISE Investigators. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant. 2011 Dec;11(12):2675-84. doi: 10.1111/j.1600-6143.2011.03763.x. Epub 2011 Sep 22.
• Gregory CR, Kyles AE, Bernsteen L, Wagner GS, Tarantal AF, Christe KL, Brignolo L, Spinner A, Griffey SM, Paniagua RT, Hubble RW, Borie DC, Morris RE. Compared with cyclosporine, ISATX247 significantly prolongs renal-allograft survival in a nonhuman primate model. Transplantation. 2004 Sep 15;78(5):681-5.
• Stalder M, Birsan T, Hubble RW, Paniagua RT, Morris RE. In vivo evaluation of the novel calcineurin inhibitor ISATX247 in non-human primates. J Heart Lung Transplant. 2003 Dec;22(12):1343-52.
• Abel MD, Aspeslet LJ, Freitag DG, Naicker S, Trepanier DJ, Kneteman NM, Foster RT, Yatscoff RW. ISATX247: a novel calcineurin inhibitor. J Heart Lung Transplant. 2001 Feb;20(2):161. No abstract available.

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.