Safety Study of AMG 811 in Subjects With Systemic Lupus Erythematosus With and Without Glomerulonephritis

Study Overview
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Brief Summary
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This is a 2-part, multi-center, randomized, double-blind, placebo-controlled, multiple dose escalation study, enrolling approximately 48 subjects. Part A of the study will enroll subjects with Systemic Lupus Erythematosus (SLE) without Glomerulonephritis (GN) into 3 cohorts. Part B of the study will enroll SLE subjects with GN into 3 cohorts. The purpose of the study is to evaluate the multiple dose of AMG 811 on safety. Tolerability and pharmacokinetics.

Detailed Description
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Part A of the study will enroll SLE without GN (non-renal) subjects into 3 cohorts (6 AMG 811: 2 placebo). All subjects will receive a dose of AMG 811 or placebo every 4 weeks beginning with Day 1 (D1) for a total of 3 injections. Subjects will be followed through to study day 197, 5 months from the last dose of study medication. Part B of the study will enroll SLE subjects with GN into Cohorts 4, 5, and 6 (6 AMG 811: 2 placebo). Similar to Part A, subjects in Cohorts 4, 5, and 6 will be dosed every 4 weeks with AMG 811 or placebo for a total of 3 injections followed by a 5 month follow-up period. For Cohort 6, subjects will be followed by a 6 month follow-up period.

Official Title
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A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AMG 811 in Subjects With Systemic Lupus Erythematosus With and Without Glomerulonephritis

Conditions
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Nephritis, Systemic Lupus Erythematosus

Intervention / Treatment
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* Drug: AMG 811


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, between the ages of 18 and 70 years of age; Body mass index from 18 to 40 kg/m2 [Body Weight (kg)/Height2 (m2)] at screening; Diagnosis of SLE at least 6 months before randomization, including a positive antinuclear antibodies (ANA) during screening; if screening ANA is negative, documented historical ANA with a titer of at least 1:80 will be acceptable; Any concurrent SLE pharmacologic regimen (including mycophenolate mofetil, azathioprine, leflunomide, methotrexate, and anti-malarials) must be stable for at least 30 days before randomization; Prednisone ≤ 20 mg/day (or equivalent) is permitted; one increase or one decrease of ≤ 5 mg/day prednisone equivalent will be allowed within 30 days before randomization; Additional inclusion criteria for Part B: - Active SLE with GN with no other apparent cause, defined by the following: Renal biopsy evidence (within 18 months) of nephritis using the WHO or International Society of Nephrology (ISN)/Renal Pathology Society (RPS) classification of SLE with GN (Class III or IV); Urine protein/creatinine ratio (UP/Cr) > 1 or 24 hour urine protein > 1g after at least 12 weeks of treatment with mycophenolate mofetil (at least 1.5 grams/day) or azathioprine (at least 100 mg orally per day); Superimposed membranous changes are allowed for those with Class III or Class IV SLE with GN; - Prednisone ≤ 20 mg/day (or equivalent) at the time of randomization. Exclusion Criteria: Any disorder (including psychiatric), condition or clinically significant disease (other than a diagnosis of SLE) that would, by its progressive nature and/or severity, interfere with the study evaluation, completion and/or procedures per the investigator's discretion; Creatinine clearance within the screening period of less than 50 mL/min as calculated by the Cockcroft-Gault method Signs or symptoms of a viral, bacterial or fungal infection within 30 days of study randomization, or recent history of repeated infections; Underlying condition other than SLE or being on allowed immunosuppressants that predisposes one to infections Prior use of the following agents: Administration of an investigational biologic agent that primarily targets the immune system Administration of cyclosporine, tacrolimus, sirolimus, IV immunoglobulin, and/or plasmapheresis within 3 months of randomization; Administration of oral or IV cyclophosphamide (or any other alkylating agent) within 12 months (Part A) or 3 months (Part B) of randomization; History of ethanol or drug abuse within the last one year prior to randomization; Additional exclusion criteria for Part B: Rapidly progressive GN (defined as a doubling of serum creatinine within the past 3 months); Evidence of significant chronicity, defined as: > 50% glomeruli with sclerosis or > 50% interstitial fibrosis on renal biopsy; or International Society of Nephrology (ISN)/Renal Pathology Society (RPS) 2003 Class III (C), IV-S (C) or IV-G (C).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>2 subjects of each cohort (cohort 1 to 6) will receive placebo | Drug: AMG 811<br>* Part A of the study will enroll SLE without GN (non-renal) subjects into 3 cohorts (6 AMG 811: 2 placebo). All subjects will receive a dose of AMG 811 or placebo every 4 weeks beginning with day 1 (D1) for a total of 3 injections. Subjects will be followed through to study day 197, 5 months from the last dose of study medication. Part B of the study will enroll SLE subjects with GN into Cohorts 4, 5 and 6 (6 AMG 811: 2 placebo). Similar to Part A, subjects in Cohorts 4, 5 and 6 will be dosed every 4 weeks with AMG 811 or placebo for a total of 3 injections followed by a 5 month follow-up period. For Cohort 6, subjects will be followed by a 6 month follow-up period.<br>|
| Other: AMG811<br>Six subjects in each cohort (cohort 1 to 6) will receive AMG 811 | Drug: AMG 811<br>* Part A of the study will enroll SLE without GN (non-renal) subjects into 3 cohorts (6 AMG 811: 2 placebo). All subjects will receive a dose of AMG 811 or placebo every 4 weeks beginning with day 1 (D1) for a total of 3 injections. Subjects will be followed through to study day 197, 5 months from the last dose of study medication. Part B of the study will enroll SLE subjects with GN into Cohorts 4, 5 and 6 (6 AMG 811: 2 placebo). Similar to Part A, subjects in Cohorts 4, 5 and 6 will be dosed every 4 weeks with AMG 811 or placebo for a total of 3 injections followed by a 5 month follow-up period. For Cohort 6, subjects will be followed by a 6 month follow-up period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation: Subject incidence of treatment-emergent adverse events, clinically significant changes in vital signs, physical examination endpoints, clinical laboratory safety tests, ECGs and the development of anti-AMG811 antibodies |  | 197 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum and urine PK parameters of AMG 811 |  | 197 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lupus, Nephritis