Study of ISA247 (Voclosporin) in De Novo Renal Transplantation

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

Detailed Description
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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

Official Title
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A Phase IIb, Randomized, Multicenter, Open-Label, Concentration Controlled, Safety Study of ISA247 (Voclosporin) and Tacrolimus (Prograf®) in De Novo Renal Transplant Patients

Conditions
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Kidney Diseases

Intervention / Treatment
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* Drug: Voclosporin
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low Dose Voclosporin<br>Low dose voclosporin | Drug: Voclosporin<br>* voclosporin 0.4, 0.6, 0.8 mg/kg po BID<br>* Other names: ISA247;|
| Active Comparator: Mid Dose Voclosporin<br>Mid Dose Voclosporin | Drug: Voclosporin<br>* voclosporin 0.4, 0.6, 0.8 mg/kg po BID<br>* Other names: ISA247;|
| Active Comparator: High Dose Voclosporin<br>High Dose Voclosporin | Drug: Voclosporin<br>* voclosporin 0.4, 0.6, 0.8 mg/kg po BID<br>* Other names: ISA247;|
| Active Comparator: Tacrolimus<br>Standard Dose Tacrolimus | Drug: tacrolimus<br>* tacrolimus 0.05 mg/kg po BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biopsy Proven Acute Rejection (BPAR) | 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. | Six months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) | ANOVAs to test for differences in GFR at Month 6. | Six months | 
| The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition | 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. | Six months | 
| Patient Survival |  | Six months | 
| Graft Survival |  | Six months | 
| Hypertension, Hyperlipidemia, or Hyperglycemia |  | Six months | 
| A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. |  | Six months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized Controlled Trials, Immunosuppression, Adult, Kidney Transplantation, Treatment Outcome