Aurinia Renal Response in Active Lupus With Voclosporin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the efficacy of voclosporin compared with placebo in achieving renal response after 52 weeks of therapy in subjects with active lupus nephritis.

Detailed Description
-----------------
The aim of the current study is to investigate whether voclosporin, added to the standard of care treatment in active lupus nephritis (LN), is able to reduce disease activity over a treatment period of 52 weeks. The background therapy will be mycophenolate mofetil (MMF) and initial treatment with IV methylprednisolone, followed by a reducing course of oral corticosteroids. Subjects with active, flaring LN will be eligible to enter the study. They are required to have a diagnosis of LN according to established diagnostic criteria and clinical and biopsy features suggestive of active nephritis. Efficacy will be assessed by the ability of the drug combination to reduce the level of proteinuria (as measured by Urine Protein Creatinine Ratio (UPCR)) while demonstrating an acceptable safety profile.

Official Title
-----------------
A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety of Voclosporin (23.7 mg Twice Daily) With Placebo in Achieving Renal Response in Subjects With Active Lupus Nephritis

Conditions
-----------------
Lupus Nephritis

Intervention / Treatment
-----------------
* Drug: Voclosporin
* Drug: Placebo Oral Capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: - Subjects with evidence of active nephritis, defined as follows: Kidney biopsy result within 2 years prior to screening indicating Class III, IV-S, IV-G (alone or in combination with Class V), or Class V LN with a doubling or greater increase of UPCR within the last 6 months to a minimum of ≥1.5 mg/mg for Class III/IV or to a minimum of ≥2 mg/mg for Class V at screening. Biopsy results over 6 months prior to screening must be reviewed with a medical monitor to confirm eligibility. OR Kidney biopsy result within 6 months prior to screening indicating Class III, IV-S or IV-G (alone or in combination with Class V) LN with a UPCR of ≥1.5 mg/mg at screening. OR Kidney biopsy result within 6 months prior to screening indicating Class V LN and a UPCR of ≥2 mg/mg at screening. Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline. Exclusion Criteria: Estimated glomerular filtration rate (eGFR) of ≤45 mL/minute at screening. Current or medical history of: Congenital or acquired immunodeficiency. In the opinion of the Investigator, clinically significant drug or alcohol abuse within 2 years prior to screening. Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Lymphoproliferative disease or previous total lymphoid irradiation. Severe viral infection or known HIV infection. Active tuberculosis (TB), or known history of TB/evidence of old TB if not taking prophylaxis with isoniazid. Other known clinically significant active medical conditions, such as: Severe cardiovascular disease, liver dysfunction or chronic obstructive pulmonary disease or asthma requiring oral steroids or any other overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Voclosporin<br>oral, 23.7 mg twice daily (BID) | Drug: Voclosporin<br>* calcineurin inhibitor<br>* Other names: ISA247;|
| Placebo Comparator: Placebo Oral Capsule<br>Voclosporin placebo, oral, 3 capsules twice daily (BID) | Drug: Placebo Oral Capsule<br>* matching placebo capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adjudicated Renal Response at Week 52 | The primary efficacy endpoint was the number of subjects showing renal response at Week 52. Renal response was adjudicated based on blinded data by an independent Clinical Endpoints Committee based on meeting the following criteria UPCR of ≤0.5 mg/mg & eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20% & Received no rescue medication for LN & Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 44 through 52, prior to assessment Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR <60 mL/min/1.73 m2 & confirmed >20% drop from baseline) & have an associated treatment-related or disease-related AE that impacted eGFR Withdrawals prior to Week 52 with insufficient Week 52 data to determine response were defined non responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response | 52 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | Number of Participants With Reduction in Urine Protein Creatinine Ratio to 0.5 mg/mg or Less | 52 Weeks | 
| Time to Urine Protein Creatinine Ratio of ≤0.5 mg/mg (Number of Days) | Time in days to reduction in Urine Protein Creatinine Ratio to decrease to 0.5 mg/mg or less. | 52 Weeks | 
| Number of Participants With Renal Response at Week 24 | Number of subjects showing renal response at Week 24. Renal response was adjudicated based on blinded data by an Independent Clinical Endpoints Committee based on the following criteria: UPCR of ≤0.5 mg/mg, & eGFR ≥60 mL/min/1.73 m2 or no confirmed decrease from baseline in eGFR of >20%, and Received no rescue medication for LN & Did not receive more than 10 mg prednisone for ≥3 consecutive days or for ≥7 days in total during Weeks 16 through 24, just prior to the renal response assessment. Note:To be disqualified from renal response, the subject had to fail both eGFR measures (i.e., confirmed eGFR <60 mL/min/1.73 m2 AND confirmed >20% drop from BL) & have an associated treatment-related or disease-related AE that impacted eGFR. Subjects who withdrew prior to the Week 24 assessment and provided insufficient Week 24 data to determine response were defined as non-responders. Subjects who discontinued study drug but continued to attend study visits had their data assessed for response. | Week 24 | 
| Number of Subjects With Partial Renal Response at Weeks 24 & 52 | Number of subjects with partial Renal Response (defined as a 50% reduction in UPCR from baseline) at Week 24 and at Week 52. Baseline UPCR is the average of 2 pre-randomisation values. | Weeks 24 and 52 | 
| Number of Subjects Achieving, and Remaining in, Renal Response (Urine Protein Creatinine Ratio ≤0.5 mg/mg) | Number of subjects achieving, and remaining in, renal response (Urine Protein Creatinine ratio ≤0.5 mg/mg) | Week 52 | 
| Duration of Renal Response (Number of Days) | Duration in days until second occurrence of UPCR >0.5 mg/mg in those subjects who achieve a reduction in UPCR to below 0.5 mg/mg | Week 52 | 
| Number of Subjects Achieving 50% Reduction in Urine Protein Creatinine Ratio | Number of subjects achieving 50% reduction in Urine Protein Creatinine ratio | 52 Weeks | 
| Time to 50% Reduction in UPCR (Number of Days) | Time in days to reduction in Urine Protein Creatinine Ratio to decrease by 50% compared to baseline. Baseline is the average of two pre-randomisation values. | 52 weeks | 
| Change From Baseline in eGFR | Change from baseline by visit in estimated Glomerular Filtration rate. eGFR is corrected to a maximum value of 90 mL/min/1.73 m2 | Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52. | 
| Change From Baseline in UPCR | Change from baseline by visit in Urine Protein Creatinine Ratio. Baseline is the average of two pre-randomisation values. | Baseline and Weeks 2, 4, 8, 12, 16, 16, 20, 24, 30, 36, 42, 48 and 52. | 
| Number of Subjects With Renal Response With Low Dose Steroids | Programmed Renal Response whilst on low dose steroids (<2.5 mg/day) for the preceding 8 Weeks at Weeks 24 and 52 | Week 24 and Week 52 | 
| Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA - SLEDAI) | Change from baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score at Week 24 and 52. The SELENA-SLEDAI tool is a cumulative and weighted index used to assess disease activity across 24 different disease descriptors in patients with lupus. A patient's SELENA-SLEDAI total score is the sum of all marked lupus related descriptors (seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, cerebrovascular accident, vasculitis, arthritis, myositis, urinary casts, hematuria, proteinuria, pyuria, new rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, increased DNA binding, fever, thrombocytopenia, leukopenia). A total score can fall between 0 and 105, with a higher score representing a more significant degree of disease activity. | Week 24 and Week 52 | 
| Change From Baseline in Patient Reported Outcomes | Health-related quality of life (HRQoL) information was collected using the Short Form Health Survey (SF-36) HRQoL assessment and the LupusPRO (v1.7) assessment. The SF-36 is a participant self-rated questionnaire that is a general measure of perceived health status comprising 36 questions, which yields an 8-scale health profile. Scoring ranges from 0 to 100 with higher scores reflecting better health. LupusPro assessment is a patient-reported questionnaire regarding the effect of lupus or its treatment on the patient's health, quality of life, and the medical care received related to lupus. The questionnaire consists of 43 questions within 8 HRQOL domains and 4 Non-HRQoL domains. Scores range from 0 to 100 with higher scores reflecting better quality of life. | Week 24 and Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
calcineurin inhibitors, lupus nephritis, voclosporin