Kidney Diseases
Conditions
Keywords
Randomized Controlled Trials, Immunosuppression, Adult, Kidney Transplantation, Treatment Outcome
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
Interventions
DRUGVoclosporin
voclosporin 0.4, 0.6, 0.8 mg/kg po BID
DRUGtacrolimus
tacrolimus 0.05 mg/kg po BID
Sponsors
Aurinia Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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. |
| Hypertension, Hyperlipidemia, or Hyperglycemia | Six months | — |
| A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. | Six months | — |
| Graft Survival | Six months | — |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 334 de novo renal transplant patients were recruited in 36 US and 4 Canadian transplant centres between January 2006 and December 2007.
Pre-assignment details
PROMISE was open to adult recipients of a first deceased or living donor renal transplant. Patients with established renal function (as demonstrated by urine output of at least 40 mL/h and a decline of creatinine of at least 15% from baseline during the first 24 h post-transplant) were randomized.
Participants by arm
| Arm | Count |
|---|---|
| High Dose Voclosporin High Dose Voclosporin: Initial dose of 0.8 mg/kg po BID | 87 |
| Mid Dose Voclosporin Mid Dose Voclosporin: Initial dose of 0.6 mg/kg po BID | 77 |
| Low Dose Voclosporin Low dose voclosporin: Initial dose of 0.4 mg/kg po BID | 84 |
| Tacrolimus Standard Dose Tacrolimus: Initial dose of 0.05 mg/kg po BID | 86 |
| Total | 334 |
Baseline characteristics
| Characteristic | High Dose Voclosporin | Mid Dose Voclosporin | Low Dose Voclosporin | Tacrolimus | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 1 Participants | 5 Participants | 4 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 82 Participants | 76 Participants | 79 Participants | 82 Participants | 319 Participants |
| Region of Enrollment Canada | 13 participants | 10 participants | 10 participants | 11 participants | 44 participants |
| Region of Enrollment United States | 74 participants | 67 participants | 74 participants | 75 participants | 290 participants |
| Sex: Female, Male Female | 24 Participants | 25 Participants | 33 Participants | 31 Participants | 113 Participants |
| Sex: Female, Male Male | 63 Participants | 52 Participants | 51 Participants | 55 Participants | 221 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 84 / 87 | 76 / 77 | 83 / 84 | 85 / 86 |
| serious Total, serious adverse events | 40 / 87 | 35 / 77 | 36 / 84 | 37 / 86 |
Outcome results
Primary
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.
Time frame: Six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Voclosporin | Biopsy Proven Acute Rejection (BPAR) | 2.3 percentage of participants |
| Mid Dose Voclosporin | Biopsy Proven Acute Rejection (BPAR) | 9.1 percentage of participants |
| Low Dose Voclosporin | Biopsy Proven Acute Rejection (BPAR) | 10.7 percentage of participants |
| Tacrolimus | Biopsy Proven Acute Rejection (BPAR) | 5.8 percentage of participants |
Comparison: The 6-month BPAR rate was used to calculate an estimate of the difference in rates between each VCS group and TAC, combining across pooled investigative center strata, weighted by the number of patients in each of the pooled center strata. The overall standard error was estimated for the linear combination of proportions. Using this statistic and its standard error, the upper bound one-sided 95% C.I. was constructed for the difference in BPAR rates between groups (VCS - TAC).t-test, 1 sided
t-test, 1 sided
t-test, 1 sided
Secondary
A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up.
Time frame: Six months
Population: Per Protocol Dataset
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Voclosporin | A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. | 5.6 Percentage of patients |
| Mid Dose Voclosporin | A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. | 7.4 Percentage of patients |
| Low Dose Voclosporin | A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. | 3.7 Percentage of patients |
| Tacrolimus | A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up. | 3.9 Percentage of patients |
Secondary
Graft Survival
Time frame: Six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Voclosporin | Graft Survival | 98.9 Percentage of patients |
| Mid Dose Voclosporin | Graft Survival | 100 Percentage of patients |
| Low Dose Voclosporin | Graft Survival | 100 Percentage of patients |
| Tacrolimus | Graft Survival | 97.7 Percentage of patients |
Secondary
Hypertension, Hyperlipidemia, or Hyperglycemia
Time frame: Six months
Population: Endpoint
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| High Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Treatment with an Antihypertensive | 96.6 Percentage of patients | 1 |
| High Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | New Onset of Diabetes Mellitus After Transplant | 17.7 Percentage of patients | — |
| High Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Triglyceride values > ULN | 28 Percentage of patients | 18 |
| Mid Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Treatment with an Antihypertensive | 97.4 Percentage of patients | 1 |
| Mid Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | New Onset of Diabetes Mellitus After Transplant | 5.7 Percentage of patients | — |
| Mid Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Triglyceride values > ULN | 30 Percentage of patients | 18 |
| Low Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Triglyceride values > ULN | 18 Percentage of patients | 22 |
| Low Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | Treatment with an Antihypertensive | 96.4 Percentage of patients | 1.2 |
| Low Dose Voclosporin | Hypertension, Hyperlipidemia, or Hyperglycemia | New Onset of Diabetes Mellitus After Transplant | 1.6 Percentage of patients | — |
| Tacrolimus | Hypertension, Hyperlipidemia, or Hyperglycemia | Treatment with an Antihypertensive | 95.3 Percentage of patients | 1.2 |
| Tacrolimus | Hypertension, Hyperlipidemia, or Hyperglycemia | New Onset of Diabetes Mellitus After Transplant | 16.4 Percentage of patients | — |
| Tacrolimus | Hypertension, Hyperlipidemia, or Hyperglycemia | Triglyceride values > ULN | 39 Percentage of patients | 16 |
Secondary
Patient Survival
Time frame: Six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Voclosporin | Patient Survival | 98.9 Percentage of patients |
| Mid Dose Voclosporin | Patient Survival | 100 Percentage of patients |
| Low Dose Voclosporin | Patient Survival | 100 Percentage of patients |
| Tacrolimus | Patient Survival | 97.7 Percentage of patients |
Secondary
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.
Time frame: Six months
Population: For subjects participating in the PK/PD portion of the study, a calcineurin sample was drawn prior to drug administration in order to assess baseline calcineurin levels. Blood samples were taken at Month 6 for the assessment of pharmacokinetics and pharmacodynamics. Participation by subjects was optional.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Voclosporin | The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition | 57.3 % Calcineurin (CNi) compared to baseline | Standard Deviation 14.4 |
| Mid Dose Voclosporin | The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition | 47.5 % Calcineurin (CNi) compared to baseline | Standard Deviation 16.4 |
| Low Dose Voclosporin | The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition | 38.8 % Calcineurin (CNi) compared to baseline | Standard Deviation 16.3 |
| Tacrolimus | The Pharmacokinetic-pharmacodynamic Relationship Between Voclosporin and Calcineurin Inhibition (CNi), or Tacrolimus and Calcineurin Inhibition | 23.0 % Calcineurin (CNi) compared to baseline | Standard Deviation 13.8 |
Secondary
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.
Time frame: Six months
Population: Standard deviation around Iothalamate GFR made results uninterpretable, therefore Nankivell GFR was reported as it was collected a priori.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Voclosporin | To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) | 68 mL/min | Standard Deviation 13 |
| Mid Dose Voclosporin | To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) | 72 mL/min | Standard Deviation 12 |
| Low Dose Voclosporin | To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) | 71 mL/min | Standard Deviation 13 |
| Tacrolimus | To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR) | 69 mL/min | Standard Deviation 29 |