Rituximab for Anti-cytokine Autoantibody-Associated Diseases

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT01842386
First received: April 25, 2013
Last updated: October 16, 2014
Last verified: September 2014
  Purpose

Background:

  • Healthy people have white blood cells that protect them against bacteria, viruses, and fungi. However, some people have diseases which cause the body to make white blood cells that do not work properly. These white blood cells can attack the body s own proteins. These types of diseases are called anti-cytokine autoantibody-associated diseases. They can cause severe illnesses and even death. They are also difficult to treat with standard drugs.
  • Rituximab is a drug used to treat rheumatoid arthritis. It attacks white blood cells that do not work properly. Currently, it is not approved for treating anti-cytokine autoantibody-associated diseases. However, researchers think that it may be able to help treat people with these immune diseases.

Objectives:

- To see if rituximab is a safe and effective treatment for anti-cytokine autoantibody-associated diseases.

Eligibility:

  • Individuals at least 18 years of age who have anti-cytokine autoantibody-associated diseases.
  • Participants must also be enrolled in a related immune disorder study at the National Institutes of Health.

Design:

  • The study will last 24 months. Participants will take rituximab for 6 months and have follow-up visits for the remaining 18 months.
  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Other samples will be collected as needed if participants currently have an infection.
  • Participants will enter the hospital for 1 week at the start of treatment. They will have four doses of rituximab given 2 days apart. This first treatment will be monitored with frequent blood tests.
  • Over the next 6 months, participants will have four more doses of rituximab given about 1 month apart. Treatment will be monitored with frequent blood tests and sample collections as needed.
  • There will be four follow-up study visits at 3, 6, 12, and 18 months after the last dose of rituximab.

Condition Intervention Phase
Anticytokine Autoantibody-Associated Diseases
Disseminated Non-Tuberculous Mycobacteria
Chronic Mucocutaneous Candidiasis
Pulmonary Alveolar Proteinosis (PAP)
Drug: Rituximab/Rituxan
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Rituximab (Anti-CD20) for the Treatment of Subjects With Anticytokine Autoantibody-Associated Diseases

Resource links provided by NLM:


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

Primary Outcome Measures:
  • The evaluation of adverse events to determine the safety and tolerability of rituximab in subjects with anticytokine autoantibody-associated diseases who are refractory to conventional treatment. [ Time Frame: At the conclusion of the study or if a serious adverse event occurs during the course of the study that may be related to the study drug. ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Evaluation of changes in autoantibody titers in response to rituximab treatment. [ Time Frame: At the conclusion of the study or if a serious adverse event occurs during the course of the study that may be related to the study drug. ] [ Designated as safety issue: No ]
  • Assessment of the effects of rituximab on autoantibody-mediatedclinical disease. [ Time Frame: At the conclusion of the study or if a serious adverse event occurs during the course of the study that may be related to the study drug. ] [ Designated as safety issue: Yes ]
  • The measurement of both qualitative and quantitative differences in antibody composition and immune function after treatment with rituximab. [ Time Frame: At the conclusion of the study or if a serious adverse event occurs during the course of the study that may be related to the study drug. ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: February 2013
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single
This is a Phase 1, single-arm, open label study.
Drug: Rituximab/Rituxan
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody targeting the CD20 antigen expressed on the surface of normal and malignant B cells. It is an FDA-approved drug for the treatment of rheumatoid arthritis and non-Hodgkin's Lymphoma. We have received permission from the FDA to use rituximab for this study.

Detailed Description:

Anticytokine autoantibodies are an important and emerging cause of disease. Anticytokine autoantibody-associated diseases include disseminated nontuberculous mycobacterial infection caused by anti-interferon- >= autoantibodies, severe mucocutaneous candidiasis caused by anti-interleukin-17 autoantibodies, and pulmonary alveolar proteinosis caused by anti-granulocyte macrophage colony stimulating factor autoantibodies. Many subjects undergoing treatments related to these diseases fail to respond or develop toxicity to long term therapy. Rituximab, an anti-CD20 monoclonal antibody that targets antibody-producing B cells, has been used successfully to treat autoimmune diseases (e.g., rheumatoid arthritis), as well as syndromes caused by pathogenic anticytokine autoantibodies (e.g., myasthenia gravis and pemphigus vulgaris). This is a phase I, single arm, open-label study evaluating the safety and clinical response to rituximab treatment in subjects (greater than or equal to 18 years of age; n=20) with anticytokine autoantibody-associated diseases who are intolerant or refractory to conventional treatment. Rituximab will be administered as intravenous infusions of 1 gram on days 1 and 15, and subsequently if indicated up to once a month for 5 months (plus or minue 5 days for each visit) starting on approximately day 42. Follow-up visits will occur within 3, 6, 9, 12, 15, and 18 months (plus or minus 2 weeks for each visit) after the last infusion. Subjects will be maintained on a background of appropriate therapy for their respective diseases. The safety and clinical response to rituximab will be assessed by clinical and laboratory parameters while subjects are receiving rituximab, and for an additional year and a half after completion of treatment.

  Eligibility

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

Subjects (greater than or equal to 18 years of age) are eligible if they meet the following criteria:

  1. Currently enrolled in one of the following protocols: 95-I-0066, 07-I-0033, 01-I-0202, or 93-I-0119.
  2. Presence of anticytokine autoantibodies in serum or plasma, along with the anticipated clinical consequences of the identified anticytokine autoantibody including, but not limited to:

    • Anti-IFN- >= autoantibodies and disseminated NTM.
    • Anti-IL-17 autoantibodies and CMC.
    • Anti-GM-CSF autoantibodies and PAP or cryptococcosis.
  3. Progression of anticytokine autoantibody-associated diseases despite conventional therapy, including, but not limited to:

    • Antimycobacterials for disseminated NTM.
    • Antifungals for mucocutaneous candidiasis or cryptococcosis.
    • Subcutaneous or inhaled GM-CSF and/or whole lung lavage for PAP.
  4. For ongoing autoantibody-associated infection, stable, optimized antibiotic regimen for at least 1 month prior to initiation of rituximab and ability to continue these antibiotics throughout treatment with rituximab.
  5. Willingness to comply with study medication, visits, and procedures, as deemed necessary by the study investigator.
  6. Willingness to have samples stored for future research and genetic testing.
  7. Willingness to be hospitalized for the inpatient visits (initial doese on day 1 and day 15 will occur in the inpatient unit.
  8. Negative serum pregnancy test result for women of childbearing potential.

    • Women of childbearing potential and men are eligible if they agree to postpone conception for 18 months following rituximab therapy. They must agree to use 2 adequate methods of contraception, such as:
    • Hormonal contraception.
    • Male or female condoms with or without a spermicide, diaphragm or cervical cap with a spermicide, or intrauterine device.
    • Sterilization of either partner.

EXCLUSION CRITERIA:

Subjects who meet the following criteria are not eligible to enter the study:

  1. HIV seropositivity.
  2. Active underlying malignancy, except thymoma and basal and squamous cell carcinoma.
  3. Immunomodulatory or immunosuppressive therapy, including:

    • Corticosteroids at a dose equivalent to greater than or equal to 15 mg of prednisone/day at any time during the month immediately prior to enrollment.
    • History of using biologic agents or any other systemic immune-suppressive or immunomodulatory agents within the past year.
  4. Use of another investigational study agent within 8 weeks of enrollment.
  5. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of the study medication.
  6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies.
  7. Evidence of significant uncontrolled concomitant diseases, such as cardiovascular disease, or nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders.
  8. Diagnosis of an unrelated underlying immunodeficiency.
  9. Hepatitis B (subjects with hepatitis C are eligible to enter the study).
  10. Live vaccines within 1 month prior to receiving the study drug.
  11. Unsuitable participation as judged by the principal investigator.
  12. History of cancer, including solid tumors and hematologic malignancies (except basal cell or squamous cell carcinoma of the skin that have been excised and cured and thymoma).
  13. History of alcohol, drug, or chemical abuse within 6 months prior to screening.
  14. Poor peripheral venous access.
  15. Intolerance or contraindications to oral or IV corticosteroids.
  16. Screening laboratory values:

    • Serum creatinine > 1.4 mg/dL for women and > 1.6 mg/dL for men.
    • Platelet count < 100,000/ L.
    • Absolute neutrophil count < 1500 cells/ L.
    • IgG < 5.65 times 10(-2) mg/dL or IgM < 0.55 times 10(-2) mg/dL.
  17. Breastfeeding.
  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: NCT01842386

Contacts
Contact: Pamela A Welch, R.N. (301) 402-0449 welchp@mail.nih.gov
Contact: Christa S Zerbe, M.D. (301) 594-5932 zerbech@niaid.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Christa S Zerbe, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT01842386     History of Changes
Other Study ID Numbers: 130082, 13-I-0082
Study First Received: April 25, 2013
Last Updated: October 16, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Anti-CD20
Anticytokine Autoanitbody-Associated Disease
Rituximab

Additional relevant MeSH terms:
Mycobacterium Infections
Candidiasis
Candidiasis, Chronic Mucocutaneous
Pulmonary Alveolar Proteinosis
Actinomycetales Infections
Bacterial Infections
Dermatomycoses
Gram-Positive Bacterial Infections
Infection
Lung Diseases
Mycoses
Respiratory Tract Diseases
Skin Diseases
Skin Diseases, Infectious
Autoantibodies
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014