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

• Sponsor: Aurinia Pharmaceuticals Inc.
• Information provided by (Responsible Party): Aurinia Pharmaceuticals Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Lupus Nephritis	Drug: Voclosporin High Dose; Drug: Voclosporin Low Dose; Drug: Placebo	Phase 2

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.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	265 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
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
Study Start Date :	June 2014
Actual Primary Completion Date :	July 2016
Actual Study Completion Date :	January 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: Voclosporin Low Dose; Voclosporin, oral, 23.7 mg BID	Drug: Voclosporin Low Dose; Other Name: ISA247
Experimental: Voclosporin High Dose; Voclosporin, oral 23.7 mg BID until Week 2, then voclosporin, oral, 39.5 mg BID	Drug: Voclosporin High Dose; Other Name: ISA247
Placebo Comparator: Placebo; 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

Outcome Measures

Primary Outcome Measures :

1. The number of subjects achieving complete remission at 24 Weeks [ Time Frame: 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 receive rescue medication for lupus or ≥10 mg prednisone for >3 consecutive days or >7 days total from Weeks 16-26 will not be considered as achieving complete remission.

Secondary Outcome Measures :

1. Complete remission as per the primary endpoint analyzed at Week 48 compared to placebo in subjects with active lupus nephritis. [ Time Frame: Week 48 ]
2. Complete remission in the presence of low dose steroids at Week 24 and Week 48. [ Time Frame: Weeks 24 and 48 ]
   Complete remission in the presence of low dose steroids at Week 24 (defined as confirmed complete remission and ≤5 mg prednisone for ≥8 weeks) and Week 48 (defined as confirmed complete remission and ≤5 mg prednisone for ≥12 weeks).
3. Time to (and proportion achieving) early, sustained complete remission [ Time Frame: 24 Weeks ]
   defined as complete remission which occurs on or before Week 24 which is sustained through Week 48.
4. Time to sustained partial remission [ Time Frame: 48 Weeks ]
   Defined as the first occurrence of partial remission which is sustained through Week 48
5. Duration of complete remission (in months) [ Time Frame: 48 Weeks ]
6. Complete remission at 48 weeks [ Time Frame: 48 Weeks ]
7. Time to complete remission [ Time Frame: 48 weeks ]
8. Partial remission [ Time Frame: Weeks 24 and 48 ]
   Defined by 50% reduction in protein/creatinine ratio from baseline at Weeks 24 and 48.
9. Time to partial remission [ Time Frame: 48 Weeks ]
10. Time to (and proportion achieving) early, sustained partial remission [ Time Frame: 48 Weeks ]
    Partial remission which occurs on or before Week 24 which is sustained through Week 48).
11. Time to sustained partial remission [ Time Frame: 48 Weeks ]
    Defined as the first occurrence of partial remission which is sustained through Week 48.
12. Change from baseline in UPCR at Weeks 24 and 48. [ Time Frame: Weeks 24 and 48 ]
13. Change from baseline in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) - SLEDAI score at Weeks 24 and 48. [ Time Frame: Weeks 24 and 48 ]
14. Change from baseline in serum creatinine, urine protein, serum albumin, eGFR at each visit measured. [ Time Frame: 50 Weeks ]
15. Proportion of subjects with active urinary sediment at each visit measured. [ Time Frame: 50 Weeks ]
    Defined by >10 red blood cells per high powered field (RBC/hpf) with dysmorphic red blood cells (RBC) and/or RBC casts on urinalysis of a urine sample which has a minimum volume of 50 mL
16. Change from baseline in immunology parameters (C3, C4, and anti-double-stranded deoxyribonucleic acid (dsDNA) and biomarkers at each visit measured. [ Time Frame: 50 Weeks ]

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

  Show 86 Study Locations

Sponsors and Collaborators

Aurinia Pharmaceuticals Inc.

Investigators

Layout table for investigator information

Principal Investigator:	Mary Anne Dooley, MD, MPH	University of North Carolina, Chapel Hill

More Information

Publications of Results:

Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056/NEJMoa1014460.

Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15.

Layout table for additonal information

Responsible Party:	Aurinia Pharmaceuticals Inc.
ClinicalTrials.gov Identifier:	NCT02141672 History of Changes
Other Study ID Numbers:	AUR-VCS-2012-01
First Posted:	May 19, 2014
Last Update Posted:	September 25, 2017
Last Verified:	March 2017

Keywords provided by Aurinia Pharmaceuticals Inc.:

lupus nephritis; calcineurin inhibitors; voclosporin

Additional relevant MeSH terms:

Layout table for MeSH terms

Nephritis; Lupus Nephritis; Kidney Diseases; Urologic Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Cyclosporine	Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Calcineurin Inhibitors