Trial Outcomes & Findings for Study of ISA247 (Voclosporin) in De Novo Renal Transplantation (NCT NCT00270634)

Last Updated: 2013-02-12

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

334 participants

Primary outcome timeframe

Six months

Results posted on

2013-02-12

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	High Dose Voclosporin High Dose Voclosporin: Initial dose of 0.8 mg/kg po BID	Mid Dose Voclosporin Mid Dose Voclosporin: Initial dose of 0.6 mg/kg po BID	Low Dose Voclosporin Low dose voclosporin: Initial dose of 0.4 mg/kg po BID	Tacrolimus Standard Dose Tacrolimus: Initial dose of 0.05 mg/kg po BID
Overall Study STARTED	87	77	84	86
Overall Study COMPLETED	70	64	62	81
Overall Study NOT COMPLETED	17	13	22	5

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of ISA247 (Voclosporin) in De Novo Renal Transplantation

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	High Dose Voclosporin n=87 Participants High Dose Voclosporin: Initial dose of 0.8 mg/kg po BID	Mid Dose Voclosporin n=77 Participants Mid Dose Voclosporin: Initial dose of 0.6 mg/kg po BID	Low Dose Voclosporin n=84 Participants Low dose voclosporin: Initial dose of 0.4 mg/kg po BID	Tacrolimus n=86 Participants Standard Dose Tacrolimus: Initial dose of 0.05 mg/kg po BID	Total n=334 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	82 Participants n=5 Participants	76 Participants n=7 Participants	79 Participants n=5 Participants	82 Participants n=4 Participants	319 Participants n=21 Participants
Age, Categorical >=65 years	5 Participants n=5 Participants	1 Participants n=7 Participants	5 Participants n=5 Participants	4 Participants n=4 Participants	15 Participants n=21 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	25 Participants n=7 Participants	33 Participants n=5 Participants	31 Participants n=4 Participants	113 Participants n=21 Participants
Sex: Female, Male Male	63 Participants n=5 Participants	52 Participants n=7 Participants	51 Participants n=5 Participants	55 Participants n=4 Participants	221 Participants n=21 Participants
Region of Enrollment United States	74 participants n=5 Participants	67 participants n=7 Participants	74 participants n=5 Participants	75 participants n=4 Participants	290 participants n=21 Participants
Region of Enrollment Canada	13 participants n=5 Participants	10 participants n=7 Participants	10 participants n=5 Participants	11 participants n=4 Participants	44 participants n=21 Participants

PRIMARY outcome

Timeframe: Six months

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=87 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=77 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=84 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=86 Participants Standard dose
Biopsy Proven Acute Rejection (BPAR)	2.3 percentage of participants Interval to 1.3	9.1 percentage of participants Interval to 10.8	10.7 percentage of participants Interval to 11.4	5.8 percentage of participants Interval 0.0 to 0.0

SECONDARY outcome

Timeframe: Six months

Population: Standard deviation around Iothalamate GFR made results uninterpretable, therefore Nankivell GFR was reported as it was collected a priori.

ANOVAs to test for differences in GFR at Month 6.

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=87 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=77 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=84 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=86 Participants Standard dose
To Demonstrate a 5% Improvement in Renal Function as Measured by Iothalamate Glomerular Filtration Rate (GFR)	68 mL/min Standard Deviation 13	72 mL/min Standard Deviation 12	71 mL/min Standard Deviation 13	69 mL/min Standard Deviation 29

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=33 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=25 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=20 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=28 Participants Standard dose
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	47.5 % Calcineurin (CNi) compared to baseline Standard Deviation 16.4	38.8 % Calcineurin (CNi) compared to baseline Standard Deviation 16.3	23.0 % Calcineurin (CNi) compared to baseline Standard Deviation 13.8

SECONDARY outcome

Timeframe: Six months

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=87 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=77 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=84 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=86 Participants Standard dose
Patient Survival	98.9 Percentage of patients	100 Percentage of patients	100 Percentage of patients	97.7 Percentage of patients

SECONDARY outcome

Timeframe: Six months

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=87 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=77 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=84 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=86 Participants Standard dose
Graft Survival	98.9 Percentage of patients	100 Percentage of patients	100 Percentage of patients	97.7 Percentage of patients

SECONDARY outcome

Timeframe: Six months

Population: Endpoint

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=87 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=77 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=84 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=86 Participants Standard dose
Hypertension, Hyperlipidemia, or Hyperglycemia Treatment with an Antihypertensive	96.6 Percentage of patients 1	97.4 Percentage of patients 1	96.4 Percentage of patients 1.2	95.3 Percentage of patients 1.2
Hypertension, Hyperlipidemia, or Hyperglycemia Triglyceride values > ULN	28 Percentage of patients 18	30 Percentage of patients 18	18 Percentage of patients 22	39 Percentage of patients 16
Hypertension, Hyperlipidemia, or Hyperglycemia New Onset of Diabetes Mellitus After Transplant	17.7 Percentage of patients	5.7 Percentage of patients	1.6 Percentage of patients	16.4 Percentage of patients

SECONDARY outcome

Timeframe: Six months

Population: Per Protocol Dataset

Outcome measures

Outcome measures
Measure	High Dose Voclosporin n=54 Participants Starting dose of 0.8 mg/kg	Mid Dose Voclosporin n=54 Participants Starting dose of 0.6 mg/kg	Low Dose Voclosporin n=54 Participants Starting dose of 0.4 mg/kg	Tacrolimus n=76 Participants Standard dose
A Composite of Biopsy-proven Chronic Rejection Graft Loss, Death, or Lost to Follow up.	5.6 Percentage of patients	7.4 Percentage of patients	3.7 Percentage of patients	3.9 Percentage of patients

Adverse Events

High Dose Voclosporin

Serious events: 40 serious events

Other events: 84 other events

Deaths: 0 deaths

Mid Dose Voclosporin

Serious events: 35 serious events

Other events: 76 other events

Deaths: 0 deaths

Low Dose Voclosporin

Serious events: 36 serious events

Other events: 83 other events

Deaths: 0 deaths

Tacrolimus

Serious events: 37 serious events

Other events: 85 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Robert Huizinga

Isotechnika Pharma Inc.

Phone: 780 487 1600

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Serious adverse events
Measure	High Dose Voclosporin n=87 participants at risk High Dose Voclosporin: Initial dose of 0.8 mg/kg po BID	Mid Dose Voclosporin n=77 participants at risk Mid Dose Voclosporin: Initial dose of 0.6 mg/kg po BID	Low Dose Voclosporin n=84 participants at risk Low dose voclosporin: Initial dose of 0.4 mg/kg po BID	Tacrolimus n=86 participants at risk Standard Dose Tacrolimus: Initial dose of 0.05 mg/kg po BID
Skin and subcutaneous tissue disorders Angioedema	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Surgical and medical procedures Cyst Drainage	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Surgical and medical procedures Lymphocele Marsupialisation	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Surgical and medical procedures Nephrectomy	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Aortic Aneurysm	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Deep Vein Thrombosis	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Haemorrhage	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Hypertension	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.4% 2/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Hypertensive Crisis	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Orthostatic Hypotension	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Peripheral Ischaemia	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Steal Syndrome	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Vascular disorders Subclavian Vein Thrombosis	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders Coagulopathy	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders Febrile Neutropenia	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders Leukopenia	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders Lymphocele	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders Neutropenia	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Acute Coronary Syndrome	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Acute Myocardial Infarction	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Arrhythmia	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Atrial Fibrillation	2.3% 2/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Bradycardia	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Cardiac Arrest	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders In-Stent Coronary Artery Restenosis	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Myocardial Infarction	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Tachycardia	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders Unstable Angina	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Abdominal Pain	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Abdominal Pain Upper	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Abdominal Strangulated Hernia	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Ascites	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Colonic Pseudo-Obstruction	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Diarhhoea	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Ileus	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Inguinal Hernia, Obstructive	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Large Intestine Perforation	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Nausea	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Oesophageal Ulcer	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders Peridontal Disease	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.

Other adverse events
Measure	High Dose Voclosporin n=87 participants at risk High Dose Voclosporin: Initial dose of 0.8 mg/kg po BID	Mid Dose Voclosporin n=77 participants at risk Mid Dose Voclosporin: Initial dose of 0.6 mg/kg po BID	Low Dose Voclosporin n=84 participants at risk Low dose voclosporin: Initial dose of 0.4 mg/kg po BID	Tacrolimus n=86 participants at risk Standard Dose Tacrolimus: Initial dose of 0.05 mg/kg po BID
Blood and lymphatic system disorders ANAEMIA	31.0% 27/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	31.2% 24/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	35.7% 30/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	31.4% 27/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders LEUKOCYTOSIS	8.0% 7/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.4% 2/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	4.7% 4/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Blood and lymphatic system disorders LEUKOPENIA	14.9% 13/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	19.5% 15/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	16.7% 14/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	14.0% 12/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Cardiac disorders TACHYCARDIA	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	10.7% 9/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	8.1% 7/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Ear and labyrinth disorders EAR PAIN	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	7.0% 6/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Endocrine disorders HYPERCALCAEMIA	5.7% 5/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.1% 7/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	4.8% 4/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Eye disorders VISION BLURRED	5.7% 5/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders ABDOMINAL DISTENSION	4.6% 4/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	6.5% 5/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	15.5% 13/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	7.0% 6/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders ABDOMINAL PAIN	13.8% 12/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	11.7% 9/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.5% 8/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	8.1% 7/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders CONSTIPATION	40.2% 35/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	44.2% 34/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	51.2% 43/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	36.0% 31/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders DIARRHOEA	35.6% 31/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	37.7% 29/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	19.0% 16/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	50.0% 43/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders DYSPEPSIA	11.5% 10/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	7.8% 6/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.5% 8/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	20.9% 18/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders FLATULENCE	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.6% 2/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.6% 3/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders GASTROOESOPHAGEAL REFLUX DISEASE	3.4% 3/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	7.1% 6/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders NAUSEA	41.4% 36/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	36.4% 28/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	42.9% 36/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	40.7% 35/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Gastrointestinal disorders VOMITING	16.1% 14/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	18.2% 14/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	15.5% 13/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	22.1% 19/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders ASTHENIA	4.6% 4/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.6% 2/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	4.8% 4/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.3% 8/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders CHEST PAIN	9.2% 8/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.6% 3/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.3% 8/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders CHILLS	4.6% 4/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	6.0% 5/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders FATIGUE	18.4% 16/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	14.3% 11/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	25.0% 21/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	14.0% 12/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders OEDEMA	23.0% 20/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	27.3% 21/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	23.8% 20/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	17.4% 15/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders OEDEMA PERIPHERAL	32.2% 28/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	40.3% 31/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	28.6% 24/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	26.7% 23/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders PAIN	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	9.1% 7/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.6% 3/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
General disorders PYREXIA	17.2% 15/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	11.7% 9/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	11.9% 10/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	15.1% 13/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Immune system disorders KIDNEY TRANSPLANT REJECTION	4.6% 4/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	8.3% 7/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.3% 2/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Infections and infestations CANDIDIASIS	5.7% 5/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.9% 3/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.6% 3/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Infections and infestations NASOPHARYNGITIS	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	6.5% 5/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.4% 2/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.3% 2/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Infections and infestations SINUSITIS	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	8.0% 7/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.9% 3/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	8.3% 7/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Infections and infestations URINARY TRACT INFECTION	12.6% 11/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	6.0% 5/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	7.0% 6/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Injury, poisoning and procedural complications INCISION SITE COMPLICATION	19.5% 17/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	26.0% 20/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	29.8% 25/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	25.6% 22/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Injury, poisoning and procedural complications PERINEPHRIC COLLECTION	6.9% 6/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.6% 2/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	4.8% 4/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Injury, poisoning and procedural complications PROCEDURAL PAIN	33.3% 29/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	36.4% 28/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	33.3% 28/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	34.9% 30/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Injury, poisoning and procedural complications WOUND DEHISCENCE	0.00% 0/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	0.00% 0/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Investigations BLOOD CREATININE INCREASED	23.0% 20/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	14.3% 11/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	23.8% 20/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	11.6% 10/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Investigations BLOOD PRESSURE INCREASED	5.7% 5/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.9% 3/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	2.4% 2/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.5% 3/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Investigations LIVER FUNCTION TEST ABNORMAL	1.1% 1/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.2% 4/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	6.0% 5/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Investigations URINE OUTPUT DECREASED	5.7% 5/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.3% 1/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.6% 3/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	4.7% 4/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Investigations WEIGHT INCREASED	11.5% 10/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	15.6% 12/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	13.1% 11/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	14.0% 12/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.
Metabolism and nutrition disorders DEHYDRATION	4.6% 4/87 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	3.9% 3/77 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	1.2% 1/84 • 6 month treatment AEs were assessed at each clinic visit throughout the study.	5.8% 5/86 • 6 month treatment AEs were assessed at each clinic visit throughout the study.