Raptiva to Treat Sjogren's Syndrome

This study has been completed.
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00344448
First received: June 23, 2006
Last updated: February 20, 2010
Last verified: December 2009
  Purpose

This study will examine the effect of the drug Raptiva (efalizumab) in patients with Sjogren's syndrome, an autoimmune disease that mainly affects the glands producing saliva and tears. The cause of Sjogren's syndrome is not known, but inflammation plays an important role in the disease. Raptiva is approved by the Food and Drug Administration to treat psoriasis, an inflammatory skin disease.

Patients 18 years of age of age and older with Sjogren's syndrome may be eligible for this study. Candidates are screened with a history and physical examination, chest x-ray, and oral and eye examinations.

Participants are randomly assigned to receive either Raptiva or placebo (an inactive substance that looks like Raptiva) for the first 3 months of the study. For the next 3 months, all participants receive Raptiva. Both Raptiva and placebo are injected under the skin once a week. During treatment and for 2 months after treatment, patients are evaluated as follows:

Full comprehensive evaluations (at the beginning of the study, at week 13, at week 25 and 2 months after treatment ends):

  • Physical examination and blood draw.
  • Saliva collection. Saliva samples are collected in two ways: 1) suctions cups connected to collection tubes are placed over the salivary gland ducts in the mouth and under the tongue; and 2) a sour-tasting liquid is applied to the top and sides of the tongue at 30-second intervals to stimulate saliva production.
  • Eye exam to evaluate tear gland function.
  • Questionnaires about mouth and eye dryness, energy level and overall well being.
  • Lip biopsy (at screening and week 13 visits only). A few minor salivary glands under the skin of the lower lip are removed for examination under a microscope. The lower lip is numbed, a small cut is made, and several tiny glands are removed. The cut is then closed with a few tiny stitches that are removed after 5 to 7 days.
  • Magnetic resonance imaging (MRI) of the parotid glands (salivary glands near the ear) at weeks 1, 13 and 25. The patient lies on a stretcher that is moved into the scanner (a narrow metal cylinder containing a strong magnetic field). The head is held in place during the scan with a plastic strap and foam pads. The study lasts about 90 minutes.

Short evaluations (at weeks 3, 5, 9, 15, 17, 21 and 1 month after treatment ends):

  • Medical history and physical examination, blood draw, evaluation for changes in symptoms and side effects, review of current medications at weeks 3, 9, 15 and 21
  • Laboratory tests, evaluation for changes in symptoms and side effects, review of current medications, saliva collection without the sour liquid and short evaluation of tear production at weeks 5 and 17
  • Blood tests at week 29.

Condition Intervention Phase
Sjogren's Syndrome
Drug: Raptiva
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Placebo Controlled, Proof of Concept, Study of Raptiva, a Humanized Anti-CD-11a Monoclonal Antibody, in Patients With Sjogren's Syndrome

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Improvement in exocrine function [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Response defined by a composite criteria [ Time Frame: 3 months ] [ Designated as safety issue: No ]

Enrollment: 10
Study Start Date: June 2006
Study Completion Date: January 2009
Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Raptiva
    N/A
Detailed Description:

The LFA-1/ICAM-1 interaction is important in migration of lymphocytes to inflammatory sites, T-lymphocyte activation, antigen presentation, and maintaining the integrity of the immunologic synapse. In both murine and human Sjogren's Syndrome, increased expression of LFA-1 was found on activated lymphocytes, and increased expression of ICAM-1 was present on the activated endothelial cells in the diseased salivary and lacrimal glands. In animal models, blockade of the LFA-1/ICAM-1 interaction resulted in reduction of glandular inflammation.

Raptiva (efalizumab) is a recombinant humanized monoclonal antibody that binds to human CD11a, the alpha-subunit of Leukocyte Function Antigen-1 (LFA-1) and inhibits the LFA-1/ICAM-1 interaction. Raptiva is an FDA-approved medication for treatment of mild-to-moderate psoriasis.

In this pilot, proof of concept, randomized, double-blind, placebo-controlled study, up to 25 patients with Sjogren's syndrome may be enrolled. In the first, double-blind phase of the study, patients will be randomized and treated with weekly subcutaneous (SC) injections of either Raptiva (1mg/kg) or placebo for 12 weeks. In the second open label phase, all patients will be treated with weekly SC injections of Raptiva (1mg/kg) for another 12 weeks and then followed for an additional 8 weeks. Safety will be evaluated using standard clinical and laboratory parameters. To assess the potential effect of Raptiva on Sjogren's syndrome, minor salivary gland biopsy, oral and ocular evaluations, and measurements of surrogate markers of inflammation will be compared between the Raptiva and placebo treated groups before and after the treatment. Patients who either do not tolerate the drug or have worsening in their disease activity will be withdrawn from the protocol.

If Raptiva is well tolerated in this study and the treatment is associated with improvement in clinical parameters of Sjogren's Syndrome, further large studies of efficacy are planned.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Up to 25 patients may be enrolled in this study to obtain at least 20 patients to complete the study and to allow for an estimated up to 20% early attrition rate. Eligible patients will have primary SS diagnosed according to the American-European Consensus Group Sjogren's Syndrome Classification Criteria. Subjects will be chosen based on their potential capacity to reverse the inflammatory process and at least partially recover the exocrine function in the salivary and lacrimal glands, as indicated in the inclusion criteria by requiring a minimal level of salivary flow as a marker of functional gland tissue. Pre-screening, which would include ophthalmologic evaluation, standard laboratory tests, and minor salivary gland biopsy, will be performed under the natural history protocol, and eligible patients will be offered to sign the informed consent for this protocol.

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 6 following criteria for Primary SS as defined by the American-European Consensus Group Sjogren's Syndrome Classification Criteria, including either item IV or VI, or fulfill 3 of the 4 objective criteria (III, IV, V, VI) [53] :

Ocular symptoms (at least one):

Dry eyes greater than 3 months

Foreign body sensation in the eyes

Use of artificial tears greater than 3x/day

Oral symptoms (at least one):

Dry mouth greater than 3 months

Swollen salivary glands

Need liquids to swallow dry foods

Ocular signs (at least one):

Schirmer test (without anesthesia) less than or equal to 5 mm/5 min

Positive vital dye staining (van Bijsterveld greater than or equal to 4)

Histopathology: Minor salivary gland biopsy showing focal lymphocyte sialoadenitis (focus score greater than or equal to 1 per 4 mm(2))

Oral signs (at least one):

Unstimulated whole salivary flow (less than or equal to 1.5 ml in 15 min)

Abnormal parotid sialography

Abnormal salivary scintigraphy

Autoantibodies (at least one):

Anti-SSA or Anti-SSB

One or more of the following:

Serum ANA level greater than or equal to 1EU

Serum Anti-SSA level greater than or equal to 20EU

Serum Anti-SSB level greater than or equal to 20EU

Serum RF level greater than or equal to 20 IU/ml

One or more of the following:

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

Serum IgG level greater than or equal to 1750 mg/dl

Serum CRP level greater than or equal to 0.8 mg/dl

Stimulated salivary flow of at least 0.1 ml/min.

Minor salivary gland biopsy with a focus score of greater than or equal to 4 within at most 12 months prior to the study enrollment.

Score of 3 or more on Oxford scale in at least one eye at the study entry.

Negative age- and gender- appropriate malignancy screening for breast, cervical, colorectal cancer for women; and prostate and colorectal cancer for men. Specifically:

  • All women: pelvic exam with Papanicolaou smear within one year of study entry.
  • Women age 40 and older: mammogram within 1 year of study entry,
  • Both genders age 50 and older; stool screening for occult blood within one year, or flexible sigmoidoscopy or colonoscopy within five years
  • Men age 50 and older: rectal examination or prostate specific antigen testing

EXCLUSION CRITERIA:

Past head and neck irradiation.

Hepatitis B, C, HIV, or HTLV infection.

History of lymphoma or monoclonal gammopathy of unknown significance (MGUS).

Sarcoidosis.

Graft-versus-host disease.

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 IVIg, azathioprine, mycophenolate mofetil, oral cyclosporine or methotrexate within 4 weeks of first study treatment.

History of rituximab therapy.

Prednisone dose greater than or equal to 10 mg/day.

Allergy to murine or human antibodies.

History of anaphylaxis.

Serum creatinine greater than 2.0 mg/dl.

History of any malignancy.

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.

WBC less than 2000/microL or ANC less than 1500/microL or Hgb less than 9.0 g/dL or platelets less than 150,000/microL or absolute lymphocyte count less than or equal to 500/microL.

ALT and/or AST greater than 1.5x upper limit of normal (ULN) or alkaline phosphatase greater than 1.5x 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 12 weeks of first treatment.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00344448

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
  More Information

Additional Information:
Publications:
Responsible Party: Gabor G. Illei, M.D./National Institute of Dental and Craniofacial Research, National Institutes of Health
ClinicalTrials.gov Identifier: NCT00344448     History of Changes
Other Study ID Numbers: 060181, 06-D-0181
Study First Received: June 23, 2006
Last Updated: February 20, 2010
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Adhesion Molecule
Interventional Study
Immunomodulation
MRI
Autoimmunity
Sjogren Syndrome
SS

Additional relevant MeSH terms:
Syndrome
Sjogren's Syndrome
Disease
Pathologic Processes
Arthritis, Rheumatoid
Arthritis
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Xerostomia
Salivary Gland Diseases
Mouth Diseases
Stomatognathic Diseases
Dry Eye Syndromes
Lacrimal Apparatus Diseases
Eye Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on September 30, 2014