Pilot Study of Raptiva to Treat Sjogren's Syndrome
| Status: | Terminated |
|---|---|
| Conditions: | Rheumatology |
| Therapuetic Areas: | Rheumatology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | June 2006 |
| End Date: | January 2009 |
A Randomized, Placebo Controlled, Proof of Concept, Study of Raptiva, a Humanized Anti-CD-11a Monoclonal Antibody, in Patients With Sjogren's Syndrome
This study will examine the effect of the drug Raptiva (efalizumab) in patients with
Sjögren's syndrome (SS), an autoimmune disease affecting the glands producing saliva &
tears. The cause of SS is not known, but inflammation plays an important role. Raptiva is
approved by the Food and Drug Administration to treat psoriasis, an inflammatory skin
disease. Patients 18 years of age & older with SS may be eligible for this study. Candidates
are screened with a history & physical examination, chest x-ray, and oral & 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 & placebo are injected under the skin
once a week. Evaluation during treatment & for 2 months after treatment as follows:
Full comprehensive evaluations (beginning of the study, at weeks 13 & 25 and 2 months after
treatment ends):
- Physical examination & blood draw.
- Saliva collection done 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 & sides of the tongue at 30-second intervals
to stimulate saliva production.
- Eye exam for tear gland function.
- Questionnaires about mouth & eye dryness, energy level and overall well-being.
- Lip biopsy (screening & week 13 visits only). A few minor salivary glands are removed
for examination under a microscope. The lower lip is numbed, a small cut is made on the
inside of the lip, and several glands are removed. The cut is closed with a few
stitches that are removed after 5 to 7 days.
- Magnetic resonance imaging 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
metal cylinder containing a strong magnetic field). The head is held in place during
the scan. The study lasts about 90 minutes.
- Short evaluations at weeks 3, 5, 9, 15, 17, 21 and 1 month after treatment ends.
- Medical history & 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
Sjögren's syndrome (SS), an autoimmune disease affecting the glands producing saliva &
tears. The cause of SS is not known, but inflammation plays an important role. Raptiva is
approved by the Food and Drug Administration to treat psoriasis, an inflammatory skin
disease. Patients 18 years of age & older with SS may be eligible for this study. Candidates
are screened with a history & physical examination, chest x-ray, and oral & 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 & placebo are injected under the skin
once a week. Evaluation during treatment & for 2 months after treatment as follows:
Full comprehensive evaluations (beginning of the study, at weeks 13 & 25 and 2 months after
treatment ends):
- Physical examination & blood draw.
- Saliva collection done 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 & sides of the tongue at 30-second intervals
to stimulate saliva production.
- Eye exam for tear gland function.
- Questionnaires about mouth & eye dryness, energy level and overall well-being.
- Lip biopsy (screening & week 13 visits only). A few minor salivary glands are removed
for examination under a microscope. The lower lip is numbed, a small cut is made on the
inside of the lip, and several glands are removed. The cut is closed with a few
stitches that are removed after 5 to 7 days.
- Magnetic resonance imaging 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
metal cylinder containing a strong magnetic field). The head is held in place during
the scan. The study lasts about 90 minutes.
- Short evaluations at weeks 3, 5, 9, 15, 17, 21 and 1 month after treatment ends.
- Medical history & 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
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.
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.
- 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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