AURA-LV: Aurinia Urinary Protein Reduction Active - Lupus With Voclosporin (AURA-LV)

Study Overview
=================
Brief Summary
-----------------
To assess the efficacy of 2 doses of voclosporin compared to placebo in achieving complete remission after 24 weeks of therapy in subjects with active lupus nephritis.

Detailed Description
-----------------
Voclosporin is a next generation CNI intended for use in the prevention of organ graft rejection and for the treatment of autoimmune diseases. The aim of the current study is to investigate whether voclosporin added to the standard of care treatment in active LN is able to reduce disease activity, as measured by a reduction in proteinuria. Two doses of voclosporin will be studied and compared in a placebo controlled trial on a background of MMF and corticosteroids. Patients 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 (American College of Rheumatology) 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 while demonstrating an acceptable safety profile.

Official Title
-----------------
A Randomized, Controlled Double-blind Study Comparing the Efficacy and Safety of Voclosporin (23.7 mg BID, or 39.5 mg BID) With Placebo in Achieving Remission in Patients With Active Lupus Nephritis

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

Intervention / Treatment
-----------------
* Drug: Voclosporin High Dose
* Drug: Voclosporin Low Dose
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects aged 18 to 75 years. Diagnosis of systemic lupus erythematosus (SLE) according to the American College of Rheumatology criteria. Kidney biopsy within 6 months prior to Screening (Visit 1) with a histologic diagnosis of lupus nephritis (International Society of Nephrology/Renal Pathology Society 2003 classification of lupus nephritis) Classes III, IV-S or IV-G, (A) or (A/C); or Class V, alone or in combination with Class III or IV. Laboratory evidence of active nephritis at screening, defined as: Class III, IV-S or IV-G: Confirmed proteinuria ≥1,500 mg/24 hours when assessed by 24 hour urine collection, defined by a UPCR of ≥1.5 mg/mg assessed in a first morning void urine specimen (2 samples). Class V (alone or in combination with Class III or IV): Confirmed proteinuria ≥2,000 mg/24 hours when assessed by 24 hour urine collection, defined by a UPCR of ≥2 mg/mg assessed in a first morning void urine specimen (2 samples). Exclusion Criteria: Estimated glomerular filtration rate (eGFR) as calculated by the Chronic Kidney Disease Epidemiology Collaboration equation of ≤45 mL/min/1.73 m2. Currently requiring renal dialysis (hemodialysis or peritoneal dialysis) or expected to require dialysis during the study period. A previous kidney transplant or planned transplant within study treatment period. In the opinion of the Investigator, subject does not require long-term immunosuppressive treatment (in addition to corticosteroids). Current or medical history of: Pancreatitis or gastrointestinal hemorrhage within 6 months prior to screening. Active unhealed peptic ulcer within 3 months prior to screening. If an ulcer has healed and the subject is on adequate therapy, the subject may be randomized. Congenital or acquired immunodeficiency. Clinically significant drug or alcohol abuse 2 years prior to screening. Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia 1, but have been treated with conization or loop electrosurgical excision procedure, and have had a normal repeat PAP are allowed. Lymphoproliferative disease or previous total lymphoid irradiation. Severe viral infection (such as CMV, HBV, HCV) within 3 months of screening; or known human immunodeficiency virus 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 including congestive heart failure, history of cardiac dysrhythmia or congenital long QT syndrome. Liver dysfunction (aspartate aminotransferase, alanine aminotransferase, or bilirubin greater than 2.5 times the upper limit of normal) at screening and confirmed before randomization. Chronic obstructive pulmonary disease or asthma requiring oral steroids. Bone marrow insufficiency unrelated to active SLE (according to Investigator judgment) with white blood cell count <2,500/mm3; absolute neutrophil count <1.3 x 103/μL; thrombocytopenia (platelet count <50,000/mm3). Active bleeding disorders. Current infection requiring IV antibiotics. Any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes. Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes are not excluded. Subjects who are pregnant, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions.

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 Low Dose<br>Voclosporin, oral, 23.7 mg BID | Drug: Voclosporin Low Dose<br> <br> * Other names: ISA247;|
| Experimental: Voclosporin High Dose<br>Voclosporin, oral 23.7 mg BID until Week 2, then voclosporin, oral, 39.5 mg BID | Drug: Voclosporin High Dose<br> <br> * Other names: ISA247;|
| Placebo Comparator: Placebo<br>Low dose: Voclosporin placebo, oral, 3 capsules BID High dose: Voclosporin placebo, oral, 3 capsules BID until Week 2 then voclosporin placebo, oral, 5 capsules BID | Drug: Placebo<br> <br> |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving Complete Renal Remission at 24 Weeks | Complete remission is defined as: Confirmed protein/creatinine ratio of ≤0.5 mg/mg and eGFR ≥60 mL/min/1.73m2 or no confirmed decrease from baseline in eGFR of ≥20%. Subjects who received rescue medication for lupus nephritis or >10 mg prednisone for >3 consecutive days or >7 days total from 56 days prior to remission assessment until the time of the remission assessment were considered not achieving complete remission. | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Achieving Complete Renal Remission at 48 Weeks | Complete remission is defined as: Confirmed protein/creatinine ratio of ≤0.5 mg/mg and eGFR ≥60 mL/min/1.73m2 or no confirmed decrease from baseline in eGFR of ≥20%. Subjects who received rescue medication for lupus nephritis or >10 mg prednisone for >3 consecutive days or >7 days total from 56 days prior to remission assessment until the time of the remission assessment were considered not achieving complete remission. | Week 48 | 
| Number of Subjects Achieving Complete Renal Remission at 24 and 48 Weeks in the Presence of Low Dose Steroids | Complete remission is defined as: Confirmed protein/creatinine ratio of ≤0.5 mg/mg and eGFR ≥60 mL/min/1.73m2 or no confirmed decrease from baseline in eGFR of ≥20%. Subjects who received rescue medication for lupus nephritis or >10 mg prednisone for >3 consecutive days or >7 days total from 56 days prior to remission assessment until the time of the remission assessment were considered not achieving complete remission. Low-dose steroids is defined as use of ≤5 mg prednisone for 8 weeks leading up to the Week 24 visit date or for 12 weeks leading up to the Week 48 visit date. | Weeks 24 and 48 | 
| Time to Complete Remission (Number of Weeks) | Time to Complete Remission is defined as time from first dose of voclosporin/placebo to UPCR ≤ 0.5mg in the absence of rescue medication. | week 48 | 
| Time to Sustained Early Complete Remission (Number of Weeks) | Time to Sustained Complete Remission is defined as time from first dose of voclosporin/placebo to UPCR ≤ 0.5mg occurring at week 24 or earlier and sustained until week 48 in the absence of rescue medication. | week 48 | 
| Number of Subjects Achieving Sustained Early Complete Remission | Sustained early complete remission defined as complete remission that occurred on or before Week 24 and was sustained through Week 48 | week 48 | 
| Time to Partial Remission (Number of Weeks) | Time to partial Remission is defined as time from first dose of voclosporin/placebo to 50% UPCR reduction sustained until week 48 in the absence of rescue medication. | week 48 | 
| Number of Subjects Achieving Partial Remission | Partial remission is defined as a 50% reduction in UPCR from baseline at Week 24 and Week 48. | week 48 | 
| Number of Subjects Achieving, and Remaining in, Complete Remission | Sustained complete remission defined as the first occurrence of complete remission that was sustained through Week 48 | week 48 | 
| Duration of Complete Remission (Number of Weeks) | Duration of Complete Remission is defined as time of first occurrence of UPCR ≤ 0.5 mg/mg until the second increase above 0.5 mg/mg (i.e. a single occurrence above 0.5 is permitted) or use of rescue medication. | week 48 | 
| Number of Subjects Achieving Partial Renal Remission at 24 and 48 Weeks | Number of patients with partial Remission is defined as time from first dose of voclosporin/placebo to 50% UPCR reduction at week 24 or week 48 in the absence of rescue medication. | week 24 and 48 | 
| Time to Sustained Partial Remission (Number of Weeks) | Time to sustained partial Remission is defined as time from first dose of voclosporin/placebo to 50% UPCR reduction sustained until week 48 in the absence of rescue medication. | week 48 | 
| Number of Subjects Achieving Sustained Partial Remission | Sustained partial remission defined as the first occurrence of partial remission that was sustained through Week 48 | week 48 | 
| Time to Sustained Early Partial Remission (Number of Weeks) | Time to sustained early partial Remission is defined as time from first dose of voclosporin/placebo to 50% UPCR reduction occurring at week 24 or earlier and sustained until week 48 in the absence of rescue medication. | week 48 | 
| Number of Subjects Achieving Sustained Early Partial Remission | Early partial remission defined as partial remission that occurred on or before Week 24 and was sustained through Week 48 | week 48 | 
| Change From Baseline in UPCR at Weeks 24 and 48 | Change from baseline in urine protein creatinine ratio at weeks 24 and 48 | Baseline, Week 24 and Week 48 | 
| Change From Baseline in Safety of Estrogens in Systemic Lupus Erythematosus National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) Score | The SELENA-SLEDAI assesses disease activity within the last 10 days. Twenty-four items are scored for nine organ systems, and summed to a maximum of 105 points. A score of 6 is considered clinically significant and indicates active disease. For analysis purposes, a score ≥6 was categorized as high. The 24 items are as follows: 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, and leukopenia. | Baseline, Week 24 and Week 48 | 

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