Abatacept in Lupus Nephritis

Overview

Status: Recruiting
Keywords: chronic kidney disease , lupus nephritis , abatacept
IRB Number: 00063500
Specialty: Nephrology and Hypertension
Sub Specialties:

Brief Summary

 

Research Hypothesis
Abatacept will be more effective than placebo in inducing complete renal response of active lupus glomerulonephritis after 1 year of treatment in subjects receiving background MMF and corticosteroids (CS).
 
Objectives(s)
The study comprises a 104 week double-blind treatment period. The primary endpoint will be assessed at Day 365.
 
Primary Objective
The primary objective of this study is to compare the proportion of subjects with Complete Renal Response (CR) of lupus glomerulonephritis at Day 365 following 1 year treatment with abatacept or placebo administered on a background of MMF and corticosteroids.
 
Secondary Objectives
1) Assess the proportion of subjects with Complete Renal Response (CR) of lupus glomerulonephritis at Day 729 following 2 years treatment with abatacept or placebo administered on a background of MMF and corticosteroids.
2) Assess the proportion of subjects achieving the ranked outcomes of Complete Renal Response (CR), Partial Renal Response (PR) or No Response (NR) at Day 365 and Day 729 following 2 years treatment with abatacept or placebo administered on a background of MF plus corticosteroids.
3) Assess the time to first achievement of CR, and the time to first achievement of CR and/or PR between the abatacept and placebo arms (a) in all subjects, (b) in subjects who achieved CR and/or PR at Day 365, and (c) in subjects who achieved CR and who achieve CR and/or PR at Day 729.
4) Assess each of the components of response over time including the proportion of subjects who meet each component of the criteria (eg, UPCR < 0.5, UPCR 50% reduced and reaching target for PR; eGFR at or above target for CR and PR; no cellular casts; dose of prednisone or prednisone equivalent no greater than 10 mg/day) and the values of UPCR and eGFR over time.
5) Assess the safety and immunogenicity of abatacept in subjects with lupus nephritis.
6) Assess the change in overall disease activity using the BILAG 2004 disease activity index from Study Day 1 through Day 365 and Day 729, and from Day 365 through Day 729.
7) Assess durability of CR and PR achieved during the treatment period, assessed as time to, and proportion with:
  • Change from a sustained higher level of response to a sustained lower level of response (eg, CR to PR or NR; PR to NR), where sustained is defined as present at 2 consecutive visits approximately 4 weeks apart.
  • Lupus treatment failure occurring after achievement of CR or PR. 
  • Overall treatment failure occurring after achievement of CR or PR. 
 
Exploratory Objectives
1) Assess the proportion with, and time to, lupus treatment failure and overall treatment
failure.
2) Assess proportion with, and time to, renal flare.
3) Assess the number, time to occurrence, and proportion of subjects who develop, new severe (BILAG A) or moderate (BILAG B) increase in non-renal activity of SLE.
4) Evaluate and compare corticosteroid use in abatacept and placebo arms, assessed as cumulative dose over time.
5) Assess biomarkers potentially associated with SLE, LN, or abatacept mechanism of action, including complement components C3 and C4 levels, titer of anti-ds DNA/other auto antibodies, UPCR, and changes from baseline in serum/plasma biomarkers (eg chemokines, cytokines, soluble receptors, RNA, total IgG, total IgM, total IgA), RNA transcripts discovered in whole blood, proteins discovered in urine, lymphocyte phenotype, and pharmacogenomic markers. Selected assessments including lymphocyte phenotype, may be performed in only a subset of subjects.
6) Assess the following health outcomes: improvement in quality of life using the Short Form-36 (SF-36); reduction in fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Fatigue Visual Analog Scale (VAS); SLICC/ACR Damage Index at Day 365 compared with baseline, and use of Emergency Room/Hospitalization.
7) Characterize the pharmacokinetics of abatacept in subjects with lupus nephritis.

 

Principal Investigator: Jo Abraham
Department: Nephrology
Co Investigator:

Contact Information

Name:Masha Boguslavsky
Phone: 801-581-6177
Email: masha.boguslavsky@hsc.utah.edu

Inclusion Criteria

1) Signed Written Informed Consent
 
2) Target Population
a) SLE as defined by meeting at least 4 of the 11 classification criteria of the American College of Rheumatology for the classification of Systemic Lupus Erythematosus, either sequentially or coincidentally. The 4 criteria need not be present at the time of study entry (see Appendix 1 of full protocol).
b) Urine protein creatinine ratio (UPCR) ≥ 1.0 at Screening
c) Biopsy within 12 months prior to screening visit indicating active proliferative lupus glomerulonephritis ISN/RPS 2003 classification Class III or IV [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 Classification Class III or IV (excluding IIIc, IVd) (see Appendix 2 of full protocol). NOTE: If no prior biopsy was done for the subject at the time of the screening visit yet, the procedure can be performed during the screening period as a study procedure only after the subject meets all other inclusion and
exclusion criteria.
d) Evidence of active disease within 3 months of Screening, based on at least one of the following:
i) Renal Flare
ii) UPCR > 3 at Screening
iii) Active urine sediment, defined as at least one of the following:
• ≥ 5 red blood cells (RBC) per high power field (hpf)
• ≥ 5 white blood cells (WBC) per hpf
• presence of cellular casts
iv) Biopsy within 3 months prior to screening visit indicating active proliferative lupus glomerulonephritis ISN/RPS 2003 classification Class III or IV [excluding Class III (C), IV-S (C) and IV-G (C)] or WHO 1982 Classification Class III or IV (excluding IIIc, IVd) (see Appendix 2). NOTE: If no prior biopsy was done for the subject at the time of the screening visit yet, the procedure can be performed during the screening period as a study procedure.
v) Subjects may be re-screened for urinary sediment and/or proteinuria ONCE within 2 weeks of the original screening visit.
e) Serum creatinine ≤ 3 mg/dL (ie, ≤ 265 micromol/L). Subjects not meeting this criterion but meeting all other inclusion and exclusion criteria may be re-screened for serum creatinine ONCE within 2 weeks of the original screening visit.
f) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized / has not been treated). If re-enrolled, the subject must be re-consented.
 
3) Age and Reproductive Status
Definition: Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 in the absence of other biological or physiological causes. In additional, women under the age of 62 must have a documented serum follicle stimulating hormone, (FSH) level > 40mIU/mL.
 
Women treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH level. The duration of the washout period is a function of the type of HRT used:
• 1 week minimum for vaginal hormonal products, (rings, creams, gels)
• 4 week minimum for transdermal products
• 8 week minimum for oral products
 
Other parenteral products may require washout periods as long as 6 months.
 
a) Men and women, at least 18 years of age.
b) Women of childbearing potential (WOCBP) must use method(s) of contraception based on the tables in Appendix 8 of the full protocol. For a teratogenic study drug and/or when there is insufficient information to assess teratogenicity (preclinical studies have not been done), a highly effective method(s) of contraception (failure rate of less than 1% per year) is required. The individual methods of contraception and duration should be determined in consultation with the investigator. WOCBP must follow
instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 30 days plus the time required for the investigational drug to undergo five half lives.
c) Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.
d) Women must not be breastfeeding
e) Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. The investigator shall review contraception methods and the time period that contraception must be followed. Men that are sexually active with WOCBP must follow instructions for birth control when the half life of the investigational drug is greater than 24 hours, contraception should be continued for a period of 90 days plus the time required for the investigational drug to undergo five half lives.
f) Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile) and
azoospermic men do not require contraception.
 
4) Disease Activity and Concomitant Medication
a) Eligibility of subjects for entry into the study is based on their current renal disease activity which may represent:
i) The first manifestation of SLE
ii) The first renal manifestation of SLE
iii) Recent worsening of glomerulonephritis that had been diagnosed previously
iv) Persistence of renal disease despite current therapies, including MMF and/or corticosteroids. MMF can have been used for no more than 3 months for the current flare of LN.

Exclusion Criteria

1) Target Disease
a) Subjects with drug-induced SLE, as opposed to idiopathic SLE.
b) Subjects who are renal transplant recipients or candidates.
c) Subjects who are diagnosed as end-stage renal disease.
d) Subjects with persistent non-lupus related pyuria or hematuria (eg, hemorrhagic cystitis).
e) Subjects with a degree of tubulo-interstitial changes that suggests a significant and irreversible decrease in renal function.
 
2) Medical History and Concurrent Diseases
a) Subjects with autoimmune disease other than SLE as their main diagnosis [eg; Rheumatoid Arthritis (RA), Multiple Sclerosis (MS)].
b) Current symptoms of severe, progressive, or uncontrolled non-SLE related renal, hepatic, hematological, gastrointestinal, pulmonary, cardiac, neurological, or cerebral disease, or other concomitant medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
c) Active CNS lupus (BILAG A or B) with the exception of fatigue or mild stable cognitive dysfunction (screening MRI or other imaging of the brain is not required to rule-out CNS disease in subjects who have no clinical features suggesting active CNS disease).
d) Concomitant illness that in the opinion of the investigator, is likely to require additional moderate to high dose oral corticosteroid therapy (ie, > 10 mg prednisone or prednisone equivalent per day) during the study, (eg; asthma).
e) Female subjects who have evidence of cervical dysplasia that require definitive therapy according to local guidelines or the Consensus Guidelines and have not been definitively treated.
f) Subjects with a history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to dosing. Subjects with carcinoma in situ, treated with definitive surgical intervention prior to study entry, are allowed.
g) Subjects with any serious acute bacterial infection (such as pneumonia or pyelonephritis unless treated and complete resolved with antibiotics).
h) Subjects with severe chronic or recurrent bacterial infections (such as recurrent pneumonia, chronic bronchiectasis)
i) Subjects at risk for tuberculosis. Specifically, subjects with:
i) Current clinical, radiographic or laboratory evidence of active or latent TB.
ii) A history of active TB within the last 3 years even if it was treated.
iii) A history of active TB greater than 3 years ago unless there is documentation that the prior anti-TB treatment was appropriate in duration and type.
j) Subjects with herpes zoster that resolved less than 2 months prior to enrollment.
k) Subjects with evidence (as assessed by the Investigator) of active or latent bacterial or viral infections at the time of potential enrollment, including subjects with evidence of Human Immunodeficiency Virus (HIV) infection.
l) Subjects who are impaired, incapacitated, or incapable of completing study related assessments.
 
3) Physical and Laboratory Test Findings
a) Subjects currently on hydroxychloroquine or chloroquine with evidence of retinopathy within 6 months of screening visit. If local standards for routine ophthalmologic follow-up suggest such formal examinations are needed, then subjects who have had no ophthalmologic evaluation and will not have this examination done will be excluded.
b) Hepatitis-B surface antigen-positive or Hepatitis B DNA positive subjects.
c) Hepatitis C RNA-positive subjects.
d) Subjects with serum ALT or AST > 3 times upper limit of normal unless in the judgment of the investigator the elevation is explicitly related to SLE.
e) Any other laboratory test results that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study.
 
4) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 10 weeks after the study.
b) Women who are pregnant or breastfeeding.
c) Women with a positive pregnancy test on enrollment or prior to study drug administration.
d) Males unwilling or unable to follow recommendations for use of contraception specified by the manufacturer of any protocol-permitted disease sparing medication (biologic or non-biologic) being used during the study.
 
5) Prohibited Therapies and/or Medications
a) Subjects who have at any time in the past received treatment with CTLA4Ig or abatacept for treatment of lupus or lupus nephritis.
b) Subjects not discontinuing azathioprine, leflunomide, methotrexate, cyclophosphamide, belimumab, cyclosporine (or any other calcineurin inhibitor) or any other agents for the treatment of SLE or proteinuria that are not specifically permitted by protocol at least 2 weeks prior to randomization (Day 1).
c) Subjects who have received treatment with any investigational drug within 28 days or within less than 5 terminal half lives of elimination (whichever is longer) of randomization (Day 1). 
d) Subjects who have received treatment with rituximab < 6 months prior to the screening visit. (NOTE: subjects who received treatment with rituximab ≥ 6 months prior to the screening visit will be eligible provided their CD 19+ peripheral blood cell count is normal within 2 months of the first dose of study
medication. Subjects not meeting this requirement will be excluded from the study)
e) Subjects who have received therapy with plasmapheresis or lymphapheresis or absorption column within 1 year of screening visit or are scheduled to receive such therapy.
f) Subject who will have need of a live vaccine at any time between enrollment (initiation of screening) or during the treatment period.
g) Subjects who are scheduled for, or anticipate the need for, non-protocol related surgery (aside from dermatologic procedures and renal biopsies).
h) Subjects in whom MMF treatment is contraindicated or considered inappropriate.
i) Subjects who require dialysis or have been on dialysis within 9 months of the screening visit.
j) Subjects having any transplant surgery requiring maintenance immunosuppressive therapy.
 
6) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated.
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.