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A Phase I, Open-Labeled, Dose-Ascending Clinical Trial of Immunotherapy of MRA, A Humanized Anti-IL 6 Receptor Monoclonal Antibody, In Patients With Systemic Lupus Erythematosus

Phase 1
18 Years
Not Enrolling
Systemic Lupus Erythematosus

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Trial Information

A Phase I, Open-Labeled, Dose-Ascending Clinical Trial of Immunotherapy of MRA, A Humanized Anti-IL 6 Receptor Monoclonal Antibody, In Patients With Systemic Lupus Erythematosus

Interleukin-6 (IL-6) levels are elevated in both human and murine systemic lupus
erythematosus (SLE). Blocking the action of IL-6 ameliorates disease activity in murine
models of SLE. MRA is a humanized monoclonal antibody against the human IL-6 receptor.
Data from clinical trials in patients with rheumatoid arthritis suggest that MRA may be a
safe agent to block the effect of IL-6 and therefore may be used to evaluate the effects of
IL-6 blockade in patients with SLE. In this open label, dose-escalating, Phase I study, up
to 27 subjects with moderately active SLE may be enrolled. Subjects will be treated with
bi-weekly infusions of one of three doses (2mg/kg, 4 mg/kg or 8 mg/kg) of MRA for 12 weeks
and followed for 8 weeks after the last dose. Patients with or without lupus nephritis may
be enrolled if they do not require immediate immunosuppressive therapy other than prednisone
at doses of less than or equal to 0.3 mg/kg/day. Safety will be evaluated using standard
clinical and laboratory parameters. To assess the potential effect of MRA on SLE, clinical
and laboratory evaluations and surrogate markers of inflammation and disease activity, such
as autoantibody production and lymphocyte subsets, will be compared before and after the
treatment. Patients who either do not tolerate the drug or those who have a clinically
significant increase in their disease activity that does not respond to moderate doses of
corticosteroids will be withdrawn from the protocol.

If this regimen is shown to be well tolerated, studies of efficacy will be planned. This
agent is expected to be devoid of the most common toxicities of therapies commonly used in
the treatment of SLE, such as myelosuppression, amenorrhea and osteoporosis.

This study will provide important preliminary information about the safety and possible
effect of IL-6 blockade in SLE patients, an intervention that has been successful in animal
models but has not yet been studied in humans.

Inclusion Criteria


Age at entry at least 18 years

Must give written informed consent prior to entry in the protocol

Must fulfill at least 4 of the following criteria for SLE as defined by the American
College of Rheumatology:

- Malar rash. Fixed Erythema, flat or raised, over the malar eminences.

- Discoid rash. Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur.

- Photosensitivity. Exposure to UV light causes rash.

- Oral Ulcers. Includes oral and nasopharyngeal, observed by physician.

- Arthritis. Nonerosive arthritis involving two or more peripheral joints,
characterized by tenderness, swelling or effusion.

- Serositis. Pleuritis or pericarditis documented by ECG or rub or evidence of
pericardial effusion.

- Renal disorder. Proteinuria greater than 0.5 g/d or greater than 3+, or cellular

- Neurologic disorder. Seizures without other cause or psychosis without other cause.

- Hematologic disorder. Hemolytic anemia or leukopenia (less than 4000/microL) or
lymphopenia (less than 1500/microL) or thrombocytopenia (less than 100,000/microL) in
the absence of offending drugs.

- Immunologic disorder. Anti-dsDNA, anti-Sm, and/or anti-phospholipid.

- Antinuclear antibodies. An abnormal titer of ANAs by immunofluorescence or an
equivalent assay at any point in time in the absence of drugs known to induce ANAs.

Moderately active lupus not requiring immediate immunosuppressive therapy other than oral
prednisone less than or equal to 0.3 mg/kg/day (or its equivalent). Moderately active
lupus is defined by either of these two (a and b) sets of criteria:

a. Chronic glomerulonephritis with inadequate response to at least 6 months of adequate
immunosuppressive therapy (with pulse methylprednisolone, cyclophosphamide, azathioprine,
cyclosporine, mycophenolate mofetil or high dose daily corticosteroids, MTX or IV Ig), and

i. less than 30% increase in creatinine compared to lowest level during treatment,

ii. proteinuria less than or equal to 1.5 times the baseline before treatment,

iii. less than or equal to 2+ cellular casts in the urinary sediment (on a scale of 0-4),

iv. Extra-renal disease activity does not exceed 10 on the non-renal components of the

b. Patients with moderately active extra-renal lupus defined as an extra-renal
SELENA-SLEDAI score in the range of 3 to 10, inclusive. The SELENA-SLEDAI score should
have been stable for at least two weeks prior to screening.

One or more of the following:

i) Serum dsDNA level greater than or equal to 30 IU

ii) IgG anticardiolipin antibody levels greater than or equal to 20 GPL

iii) CRP greater than 0.8 mg/dL

iv) ESR greater than 25 mm/hr for men; ESR greater than 42 mm/hr for women.

Stable doses of prednisone less than or equal to 0.3 mg/kg/day (or its equivalent) for at
least 2 weeks before the first treatment.


Pregnant or lactating women. Women of childbearing potential are required to have a
negative pregnancy test at screening.

Women of childbearing potential and fertile men who are not practicing or who are
unwilling to practice birth control during and for a period of three months after the
completion of the study

Any therapy with human or murine antibodies or any experimental therapy within 3 months

Therapy with cyclophosphamide; pulse methylprednisolone or IV Ig within 4 weeks; or
azathioprine, mycophenolate mofetil, cyclosporine or methotrexate within 2 weeks of first
study treatment

Initiation or a change in the dose of an ACE-inhibitor within 2 weeks of first study

Allergy to murine or human antibodies

History of anaphylaxis

Serum creatinine greater than 3.0 mg/dL

Active severe CNS lupus (encephalopathy, cerebrovascular accident, transverse myelitis,
severe depression, psychosis)

Previous history of ischemic heart disease or evidence of ischemic heart disease on ECG

Congestive heart failure or cardiomyopathy

History of thrombosis or recurrent 2nd trimester abortions (3 or more) and elevated levels
of anti-cardiolipin antibodies or lupus anticoagulant unless the patient is on

History of malignancy with the exception of basal cell or squamous cell carcinoma of the
skin or in situ carcinoma of the cervix within the last 3 years

Active infection that requires the use of intravenous antibiotics and does not resolve
within 1 week of Day 1

Any active viral infection that does not resolve within 10 days prior to Day 1

History of reactivation on EB viral infection or greater than 1,000 EBV genome
equivalent/10(6) cells in PBMC preparations

Active hepatitis B, hepatitis C or HIV infection

WBC less than 3500/microL or ANC less than 3000/microL or Hgb less than 8.0 g/dL or
platelets less than 50,000/microL or absolute lymphocyte count less than or equal to

ALT and/or AST greater than 2 times the upper limit of normal (ULN) or alkaline
phosphatase greater than 1.5 times the ULN

Significant concurrent medical condition that, in the opinion of the principal
investigator, could affect the patient's ability to tolerate or complete the study

Live vaccines within 4 weeks of first infusion

Type of Study:


Study Design:

Primary Purpose: Treatment

Principal Investigator

Sarfaraz A Hasni, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)


United States: Federal Government

Study ID:




Start Date:

September 2002

Completion Date:

July 2007

Related Keywords:

  • Systemic Lupus Erythematosus
  • Safety
  • Nephritis
  • Biologic Therapy
  • Lymphocytes
  • Response
  • Lupus
  • Systemic Lupus Erythematosus
  • SLE
  • Lupus Erythematosus, Systemic



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892