Immunopharmacological Effects of Rituximab in Atopic Dermatitis
Immunopharmacological Effects of Rituximab in Atopic Dermatitis
Protocol Title: Immunopharmacological effects of Rituximab in atopic dermatitis

 Study Phase: Investigator driven study

 Study Design: Open-label, single center.

 Primary Study Objective: To determine the efficacy, safety and immunopharmacological effects
 of Rituximab (anti-CD20) administered as a 1000mg intravenous infusion on days 1 and 15 to
 patients with atopic dermatitis.

 Secondary Study Objective: To investigate key immunological parameters involved in the
 pathology of this common skin disease to interpret the clinical findings.

 Number of Patients: 6

 Study Population: Male and female patients, at least 18 years of age with atopic dermatitis,
 active inflammation, a severity score of 6-9 according to Langeland and Rajika.

 Treatment Group: Rituximab will be administered as 1000 mg infusion intravenously at day 1
 and 15, followed by a 24-week follow-up period.

 Visit Schedule: Screening Visit (within 28 days prior to Visit 1) Treatment visits (Visits
 days 1, 3, 8, 15, 17) Follow-up Visits (Visits weeks 4, 8, 12, 16, 20, 24)

 Visit 11/Early Termination Visit (if applicable) Visit 11 will serve as the Early Termination
 Visit for any patient who withdraws from the study between Visit 1 and 10.

 Efficacy Parameters:

 Clinical parameters:

 EASI Patient Assessment of Pruritus / Pruritus score Physician Global Assessment (PGA)
 Photography

 Laboratory analysis:

 Differential blood count Total IgE, specific IgE (aeroallergen panel) Immunophenotyping of
 PBMC Lymphocyte proliferation following pan-T stimulation with PHA Cytokine release from
 blood T cells following pan-T stimulation with PHA

 Skin tests Histopathology of skin biopsies

 Safety Parameters: Physical examinations; vital signs; selected blood chemistry, including
 liver function tests, creatinine; white blood cell count (WBC; including total lymphocyte
 count); platelets, lymphocyte subset analysis; complement, immunoglobulins (IgA, IgM, IgG,
 IgE), monitoring for infections; monitoring for concomitant therapies; monitoring for adverse
 events.
Investigator driven study

 Immunopharmacological Effects of Rituximab in Atopic Dermatitis

 Investigators

 1. Prof. Dr. Hans-Uwe Simon (Dept. of Pharmacology, University of Bern, Switzerland)

 2. Dr. Dagmar Simon, Prof. Dr. Lasse R. Braathen (Dept. of Dermatology, University of Bern,
 Switzerland)

 SUMMARY

 Protocol Title: Immunopharmacological effects of Rituximab in atopic dermatitis

 Study Phase: Investigator driven study

 Study Design: Open-label, single center.

 Primary Study Objective: To determine the efficacy, safety and immunopharmacological
 effects of Rituximab (anti-CD20) administered as a 1000mg intravenous infusion on days 1
 and 15 to patients with atopic dermatitis.

 Secondary Study Objective: To investigate key immunological parameters involved in the
 pathology of this common skin disease to interpret the clinical findings.

 Number of Patients: 6

 Study Population: Male and female patients, at least 18 years of age with atopic
 dermatitis, active inflammation, a severity score of 6-9 according to Langeland and
 Rajika.

 Treatment Group: Rituximab will be administered as 1000 mg infusion intravenously at day
 1 and 15, followed by a 24-week follow-up period.

 Visit Schedule: Screening Visit (within 28 days prior to Visit 1) Treatment visits
 (Visits days 1, 3, 8, 15, 17) Follow-up Visits (Visits weeks 4, 8, 12, 16, 20, 24)

 Visit 11/Early Termination Visit (if applicable) Visit 11 will serve as the Early
 Termination Visit for any patient who withdraws from the study between Visit 1 and 10.

 Efficacy Parameters:

 Clinical parameters:

 EASI Patient Assessment of Pruritus / Pruritus score Physician Global Assessment (PGA)
 Photography

 Laboratory analysis:

 Differential blood count Total IgE, specific IgE (aeroallergen panel) Immunophenotyping
 of PBMC Lymphocyte proliferation following pan-T stimulation Cytokine release from blood
 T cells following pan-T stimulation Skin tests Histopathology of skin biopsies
 Immunohistochemistry

 Safety Parameters: Physical examinations; vital signs; selected blood chemistry,
 including liver function tests, creatinine; white blood cell count (WBC; including total
 lymphocyte count); platelets, lymphocyte subset analysis; complement, immunoglobulins
 (IgA, IgM, IgG, IgE), monitoring for infections; monitoring for concomitant therapies;
 monitoring for adverse events.

 Time schedule: All six patients will be recruited within 1 year following approval of
 the study by both Cantonal Ethics Commission (Bern) and Swissmedic.

 Aim of the study In this study we want to investigate the clinical efficacy and safety
 as well as the immunopharmacological effects in particular the inflammatory cells and
 their cytokine production in AD skin and blood under the treatment of rituximab.

 Primary Objective

 To determine the efficacy and safety of Rituximab when administered as a 1000 mg
 intravenous infusion to patients with atopic dermatitis.

 Additional Objectives

 The additional objectives of this study are:

 To investigate the influence of Rituximab treatment on key immunological parameters
 involved in immunopathology of AD.

 STUDY DESIGN

 Study Outline

 This is a open-label, single center study to evaluate the efficacy and safety of
 Rituximab when administered as a 1000 mg intravenous infusion to patients with atopic
 dermatitis. 6 patients should be enrolled.

 During the treatment course, all patients will receive Rituximab administered as 1000 mg
 intravenous infusion at day 1 and 15, followed by a 22-week follow-up period.

 STUDY POPULATION

 Number of Patients

 Approximately 6 patients will be enrolled.

 Study Entry Inclusion Criteria

 To be eligible for entry into this study, candidates must meet the following eligibility
 criteria at the time of enrollment:

 1. Must give written informed consent.

 2. Must be at least 18 years of age

 3. Must have been diagnosed with atopic dermatitis fulfilling the diagnostic criteria of
 Hanfin and Rajka and having active inflammation.

 4. Must have a severity score of 6-9 according to Langeland and Rajka.

 5. Must have a PGA of "moderate", "severe" or "very severe" and a pruritus score of
 "moderate" or "severe" at baseline.

 Study Entry Exclusion Criteria

 Candidates will be excluded from study entry if any of the following exclusion criteria exist
 at the time of enrollment:

 1. Patients with other skin diseases, that might interfere with the evaluation of AD

 2. Patients with severe diseases of other organ systems (e.g. cardiovascular, liver,
 kidney, psychiatric, neurologic) that might put the patient on risk during the study or
 might interfere with the evaluations (in the opinion of the investigator)

 3. Patient older than 65 years

 4. Systemic treatment for atopic dermatitis (e. g. corticosteroids, cyclosporine,
 mycophenolat- mofetil, interferon-gamma, UVB, UVA, PUVA) or systemic treatment with
 immunosuppressive/immunomodulating substances (e.g. azathioprin, methotrexate, biologics
 or hyposensitization -therapy) within 28 days prior to baseline.

 5. Local treatment for atopic dermatitis with pimecrolimus/tacrolimus, steroids > class
 III, instable use of steroids class <III, emollients or local antiseptics/antibiotics
 within 14 days prior to day 1.

 6. Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g.,
 pneumonia, septicemia) within 3 months prior to the first dose of Rituximab.

 7. History of recurrent clinically significant infection.

 8. Congenital or acquired immunodeficiency syndrome.

 9. History of or a new diagnosis or treatment of an invasive malignancy within 5 years of
 enrollment. Patients with a history of treated squamous cell and/or basal cell
 carcinomas limited to the skin are not excluded.

 10. For female patients, unless postmenopausal or surgically sterile, unwillingness to
 practice effective contraception, as defined by the investigator, during the study. The
 rhythm method is not to be used as the sole method of contraception. Female patients
 considering becoming pregnant while in the study are excluded.

 11. Female patients who are currently pregnant or breast-feeding.

 12. Current enrollment in any other investigational drug study.

 13. Previous participation in this study or previous studies with Rituximab.

 Screening Log

 Participating investigational site is required to document all screened candidates
 initially considered for inclusion in this study and to specifically state the reason(s)
 for their exclusion.

 STUDY MEDICATION, DESCRIPTION, AND ALLOCATION

 Investigational Drug

 Rituximab is supplied by Roche Pharma (Schweiz) AG. Rituximab is registered for the
 treatment of B cell lymphoma in Switzerland. Investigational site personnel should refer
 to the Directions for Handling and Administration (DHA) for specific instructions on the
 handling and administration of Rituximab.

 Enrollment Procedure

 Patients are officially enrolled into the study and assigned a subject identification
 number after all screening evaluations have been completed and all study inclusion
 criteria have been met.

 Drug Accountability

 Rituximab accountability must be maintained by the investigator. The investigator must
 maintain accurate records demonstrating the dates and amount of Rituximab received, to
 whom dispensed (patient-by-patient accounting), and accounts of any Rituximab
 accidentally or deliberately destroyed. Unless otherwise notified, all vials, both used
 and unused will be saved.

 THERAPY

 Once therapy (that is, dose number 1) has begun, in order for a patient to receive a
 subsequent dose of Rituximab, the following must occur:

 -  administration of each dose of Rituximab must be separated by an interval of at
 least 7 days

 -  no clinical evidence of significant viral, bacterial, or fungal infection at the
 time of the study visit

 Treatment Schedule

 During the treatment course, all patients will receive Rituximab administered as a 1000
 mg intravenous infusion, followed by a 24-week follow-up period.

 Dosing will be according to the schedule provided unless there is evidence of clinically
 significant infection (as determined by the investigator) or leukopenia, neutropenia or
 thrombocytopenia.

 Treatment Compliance

 Compliance with Rituximab dosing will be monitored and recorded by investigational site
 personnel.

 Concomitant Therapy

 For patients on any prescription medication, every attempt should be made to keep the
 patient on a stable dose of that medication for at least 14 days prior to the first dose
 of Rituximab in any treatment course.

 Any medication and any non-drug procedure or therapy (including topical emollients) used
 from study entry until the patient's final study visit must be recorded in the patient's
 CRF.

 Allowed Concomitant Therapy

 Patients will two intravenous infusions of Rituximab either as monotherapy or in
 combination the following classes of treatments as described below. Treatments should be
 kept stable through the period from 14 days before baseline until Visit 13.

 -  Topical low or medium potency corticosteroids

 -  Topical emollients

 -  Topical antiseptics and antibiotics

 -  Oral Antihistamines

 Disallowed Concomitant Therapy

 At no time during study participation may patients receive treatment with:

 • live vaccines or live attenuated vaccines

 • therapy for active tuberculosis or tuberculosis prophylaxis

 -  UVB, UVA, UVA1

 -  Psoralen plus ultraviolet A (PUVA)

 -  cyclosporine, methotrexate, prednisone, azathioprine, thioguanine or other systemic
 immunosuppressant agents

 -  topical pimecrolimus or tacrolimus

 -  high potency topical corticosteroids

 -  another investigational drug or approved therapy for investigational use.

 -  any kind of allergenspecific immunotherapy

 EFFICACY ASSESSMENTS

 Clinical Efficacy Assessments

 All efficacy assessments are to be performed by the same investigator for each patient.

 • PGA

 • EASI

 • Patient´s Pruritus Assessment

 • Photography

 Laboratory/Histologic Efficacy Assessments

 Laboratory analysis:

 Differential blood count, platelets Total IgE, specific IgE (aeroallergen panel)
 Immunophenotyping of PBMC (Lymphocyte proliferation following pan-T stimulation)
 Cytokine release from blood T cells following pan-T stimulation

 Skin tests Histopathology of skin biopsies Immunohistochemistry

 SAFETY ASSESSMENTS

 Clinical Safety Assessments

 -  Physical examinations (including vital signs, signs for infection)

 -  Monitoring for new or ongoing infections

 -  Monitoring for concomitant therapies

 -  Monitoring for adverse events

 Laboratory Safety Assessments

 -  Selected blood chemistry

 -  pregnancy testing.

 Product/Trial-Specific Assessments

 -  WBC (Including total lymphocyte count)

 -  Platelets

 Adverse Events: Definition and Management

 The terms "relationship" and "severity" (used throughout this section) are defined in
 the table.

 At the time of written informed consent, the patient must be given the name and phone
 number of investigational site personnel who can be called in the event of an emergency
 or to report any medical symptom or untoward medical occurrence that is of concern to
 the patient.

 Definitions Predosing Signs and Symptoms

 For the purposes of this study, any sign (including an abnormal laboratory result, as
 determined by the investigator) or medical diagnosis noted by medical personnel, or
 symptom reported by the patient that occurs prior to the start of investigational drug
 treatment is considered to be a predosing sign/symptom. Any predosing sign/symptom
 classified as serious will be reported to the IRB/REB/IEC.

 Adverse Events

 For the purposes of this study, any sign (including an abnormal laboratory result, as
 determined by the investigator) or medical diagnosis noted by medical personnel, or
 symptom reported by the patient, regardless of relationship to investigational drug,
 that is treatment-emergent is considered to be an adverse event. 'Treatment-emergent' is
 defined as follows:

 1. Has onset any time after the start of investigational drug treatment

 OR

 2. Has worsened since the event was previously reported (this includes worsening of signs,
 symptoms, or diagnoses that were present prior to the first dose of investigational drug
 but then worsened any time after the start of investigational drug treatment)

 Classification of Event as Serious

 As soon as a patient has given written informed consent to participate in the study, any
 abnormal sign (including an abnormal laboratory result, as determined by the
 investigator) or medical diagnosis noted by medical personnel, or symptom reported by
 the patient regardless of whether or not the patient has received investigational drug
 is to be classified by the investigator as either a serious or non-serious event using
 the following definition:

 Serious Event

 Events are classified as serious if they meet any of the following criteria (in
 accordance with 21 CFR Part 312.32 and the recommendations of the International
 Conference on Harmonization [Federal Register, October 7, 1997, Vol. 62, No. 194, pp
 52239-45]):

 • Any death.

 • Any life-threatening event, i.e., an event that places the patient, in the view of the
 investigator, at immediate risk of death from the event as it occurred (does not include
 an event that, had it occurred in a more severe form, might have caused death).

 • Any event that requires or prolongs in-patient hospitalization.

 • Any event that results in persistent or significant disability/incapacity.

 -  Any congenital anomaly/birth defect diagnosed in a child of a patient who
 participated in this study.

 -  Other medically important events that in the opinion of the investigator may
 jeopardize the patient or may require intervention to prevent one of the other
 outcomes listed in the definition above.

 Immediate Telephone Reporting of Serious Events

 Roche Pharma (Schweiz) AG must immediately be made aware of events classified as SERIOUS
 in order to adhere to all applicable laws and regulations for reporting serious events.
 Therefore, it is the investigator's responsibility to ensure the following:

 Any serious event that occurs any time after the patient signs the informed consent form
 for this study, regardless of whether or not the patient has undergone any study-related
 procedures or received investigational drug, up to the patient's final study visit
 (i.e., Visit 11), inclusive, must be reported to Roche Pharma (Schweiz) AG within 24
 hours following report of the event, regardless of severity or relationship to
 investigational drug.

 When telephoning a serious event report to Roche Pharma (Schweiz) AG, the investigator
 must provide specific information regarding the patient and the event. Roche Pharma
 (Schweiz) AG must also receive written confirmation of the above information. For deaths
 that occur following a patient's enrollment into the study a Record of Death CRF as well
 as a copy of the autopsy report (when/if available) must be submitted to Roche Pharma
 (Schweiz) AG. The investigator must keep a copy of all documentation related to the
 event in the site's study files.

 The investigator must also notify the local review committee, i.e., the Institutional
 Review Board (IRB), Research Ethics Board (REB), as per local IRB/REB/IEC requirements.
 Documentation of these reports will be kept in the site's study files.

 Any serious event that has onset after the patient's first dose of investigational drug
 and that is unresolved at the time the patient permanently discontinues the study must
 be followed until the event resolves or until the patient's clinical course has
 stabilized.

 Reporting of Serious Events to Regulatory Agencies After receipt of a serious event
 report Roche Pharma (Schweiz) AG will notify all appropriate regulatory authorities, as
 necessary, within the required time frames. Written safety reports submitted to
 regulatory authorities will be completed by Roche Pharma (Schweiz) AG with the
 assistance of the investigator and other investigational site personnel, as needed.

 Primary Endpoints

 Primary endpoint is the change of EASI at Visit 7 and 24 compared to baseline via paired
 t-Test.

 Additional Endpoints Additional endpoints are the percentage of patients reaching a PGA
 of "clear" or "almost clear" and/or a reduction of EASI of >= 50 or >= 75% compared to
 baseline at any visit after baseline.

 Other additional endpoints are:

 the percentage of patients reaching a pruritus score of "none" or "mild" Several
 immunological endpoints

 Criteria for the Endpoints

 Patients with missing PGA scores at the visit being analyzed will be considered
 treatment failures for that visit. Patients who received disallowed therapies as listed
 prior to the visit of the course being analyzed will be considered treatment failures
 for the course in the efficacy analysis.

 Statistical Methods

 Analysis Populations 1.1.1.1 Safety

 The safety population is defined as all patients who received at least 1 dose of study
 drug and have at least 1 post-baseline assessment of the safety parameter.

 1.1.1.2 Efficacy

 The efficacy population will be based on the intent-to-treat principle and is defined as
 all patients who received at least 1 dose of study drug.

 Demographics and statistical aspects

 All appropriate background data will be summarized by presenting frequency distributions
 and/or basic summary statistics (mean, standard deviation, median, minimum, and
 maximum).

 Study question and hypothesis

 Due to the pilot character of this study no formal hypotheses are issued. We expect
 clear improvement with Rituximab. The effect of Rituximab is of special interest,
 because this may become a new therapeutic approach with reasonable costs and handling.
 Our investigation should be a pilot trial for a following study enrolling a larger
 population to elucidate the clinical use for treatment of patients with atopic
 dermatitis.

 Statistical methods

 Changes in the investigated variables before and after treatment will be compared using
 the Wilcoxon's signed ranks test. Subgroups will be compared using the Mann Whitney
 U-test. Otherwise, the data will be analysed and presented in a desriptive manner (see
 above).

 Safety Analyses

 All clinical adverse events and laboratory abnormalities will be evaluated for safety.
 The number of patients with at least 1 dose withheld will also be evaluated.

 1.1.1.3 White blood cell counts, platelets

 Lymphocyte and lymphocyte subset (CD4+ and CD8+) counts over time will be presented.

 1.1.1.4 Laboratory Abnormalities

 Selected blood chemistry evaluations will be assessed to determine incidence of
 laboratory abnormalities that emerge within the course. Shift tables will be used to
 present changes in each laboratory parameter relative to the parameter's normal range.

 1.1.1.5 Physical Examinations and Vital Signs

 The incidences of abnormalities in physical examination and in vital signs,
 respectively, will be presented.

 Efficacy Analyses

 The proportion of patients who achieve a PGA of "almost clear" or "clear" or a decrease
 in EASI value >=50% and >=75 % without the use of disallowed therapy as defined in the
 protocol at each scheduled visit will be presented.

 The EASI at Visit 3-11 will be compared to EASI at baseline/Day1 using a paired t-test.
 The threshold for significant changes will be p<0,05.

 APPENDIX 1: ECZEMA AREA AND SEVERITY INDEX (EASI) The EASI assigns proportionate body
 surface areas to the head and neck [10%], trunk [30%], upper extremities [20%] and lower
 extremities [40%] for children aged 7 and above. This is roughly consistent with the
 rule of nine. The numbers are modified when used with children under the age of 7: head
 and neck [20%], trunk [30%], upper extremities [20%] and lower extremities [30%]. The
 area of involvement (affected by inflammation, not including dry skin) of each of the
 four body regions is represented by a numeric coded value [0 - 6] as below (the
 investigator is required to record the percent area on the CRF).

 Table 1. EASI: Area of involvement Area Involvement 0 1 2 3 4 5 6 no eruption < 10% 10%
 - 29% 30% - 49% 50% - 69% 70% - 89% 90% - 100%

 The head, trunk, upper limbs and lower limbs are assessed separately for erythema (E),
 infiltration/papulation (I), excoriation (Ex) and lichenification (L). The average
 degree of severity of each sign in each of the four body parts, is assigned a score of
 0-3 indicating none (0), mild (1), moderate (2) and severe (3) expression of the
 clinical sign. Half steps are allowed.

 Further practical details to aid the assessment are:

 The lower extremities region includes the buttocks. The trunk region includes the
 internal/medial axillae and groin. The head/neck region comprises the face and the
 anterior and posterior neck. The upper extremities region includes the hands and
 external axillae.

 The definitions of the scoring signs of EASI are given below:

 Table 2. Scoring signs of EASI Erythema (E) 0 None

 1 Mild Faintly detectable erythema: very light pink 2 Moderate Dull red, clearly
 distinguishable 3 Severe Deep / dark red Infiltration / Papulation (I) 0 None

 1. Mild Barely perceptible elevation

 2. Moderate Clearly perceptible elevation but not extensive

 3. Severe Marked and extensive elevation Excoriations (Ex)

 0 None

 1 Mild Scant evidence of excoriations with no signs of deeper skin damage (erosion, crust) 2
 Moderate Several linear marks of skin with some showing evidence of deeper skin injury
 (erosion, crust) 3 Severe Many erosive or crusty lesions Lichenification (L) 0 None

 1. Mild Slight thickening of the skin discernible only by touch and with skin markings
 minimally exaggerated

 2. Moderate Definite thickening of the skin with skin markings exaggerated so that they
 form a visible criss-cross pattern

 3. Severe Thickened indurated skin with skin markings visibly portraying an exaggerated
 criss-cross pattern

 The EASI will then be calculated according to the following formula:

 Table 3 . EASI: Calculation of score for ages 7 years and above Head/Neck (E + I + Ex + L) x
 Area(1) x 0.1 Trunk (E + I + Ex + L) x Area(1) x 0.3 Upper limbs (E + I + Ex + L) x Area(1) x
 0.2 Lower limbs (E + I + Ex + L) x Area(1) x 0.4 EASI = sum of the above four body areas

 1. Where Area is defined on a Seven Point Ordinal Scale, as shown in the table 3-3.

 Dermatologists Signature: _______________________________ date (dd/MMM/yyyy): ____/____/_____

 APPENDIX 2: PHYSICIAN GLOBAL ASSESSMENT OF EFFICACY

 Please mark the box based on the patient's condition at the time of this visit.

 Clear Almost Clear Mild Moderate Severe Very Severe

 1 0 2 0 3 0 4 0 50 6 0

 Very Severe = severe erythema and severe papulation infiltration with oozing/crusting

 Severe = severe erythema and severe papulation infiltration

 Moderate = moderate erythema and moderate papulation infiltration

 Mild = mild erythema and mild papulation infiltration

 Almost Clear = just perceptible erythema and just perceptible papulation infiltration

 Clear = No inflammatory signs of AD

 APPENDIX 3: PRURITUS SEVERITY SCORE IN AVERAGE ABOUT THE LAST WEEK

 Severe Moderate Mild Absent

 1. 0 2 0 3 0 4 0

 Severe = Intense itching with severe sleep disturbance Moderate = Moderate itching with some
 sleep disturbance Mild = mild itching without sleep disturbance Absent = no itching
Inclusion Criteria:

 -  Must give written informed consent.

 -  Must be at least 18 years of age.

 -  Must have been diagnosed with atopic dermatitis fulfilling the diagnostic criteria of
 Hanfin and Rajka and having active inflammation.

 -  Must have a severity score of 6-9 according to Langeland and Rajka.

 -  Must have a PGA of "severe" or "very severe" and a pruritus score of "moderate" or
 "severe" at baseline.

 Exclusion Criteria:

 -  Patients with other skin diseases that might interfere with the evaluation of AD.

 -  Patients with severe diseases of other organ systems (e.g. cardiovascular, liver,
 kidney, psychiatric, neurologic) that might put the patient on risk during the study
 or might interfere with the evaluations (in the opinion of the investigator).

 -  Patient older than 65 years.

 -  Systemic treatment for atopic dermatitis (e. g. corticosteroids, cyclosporine,
 mycophenolat-mofetil, interferon-gamma, UVB, UVA, PUVA) or systemic treatment with
 immunosuppressive/immunomodulating substances (e.g. azathioprin, methotrexate,
 biologics or hyposensitization -therapy) within 28 days prior to baseline.

 -  Local treatment for atopic dermatitis with pimecrolimus/tacrolimus, steroids > class
 III, instable use of steroids class <III, emollients or local antiseptics/antibiotics
 within 14 days prior to day 1.

 -  Serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g.,
 pneumonia, septicemia) within 3 months prior to the first dose of Rituximab.

 -  History of recurrent clinically significant infection.

 -  Congenital or acquired immunodeficiency syndrome.

 -  History of or a new diagnosis or treatment of an invasive malignancy within 5 years of
 enrollment. Patients with a history of treated squamous cell and/or basal cell
 carcinomas limited to the skin are not excluded.

 -  For female patients, unless postmenopausal or surgically sterile, unwillingness to
 practice effective contraception, as defined by the investigator, during the study.
 The rhythm method is not to be used as the sole method of contraception. Female
 patients considering becoming pregnant while in the study are excluded.

 -  Female patients who are currently pregnant or breast-feeding.

 -  Current enrollment in any other investigational drug study.

 -  Previous participation in this study or previous studies with Rituximab.