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Rituximab for Anti-cytokine Autoantibody-Associated Diseases

Primary Purpose

Pulmonary Alveolar Proteinosis (PAP), Severe Mucocutaneous Candidiasis

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Alveolar Proteinosis (PAP) focused on measuring Pulmonary Alveolar Proteinosis, Autoantibodies, Mucocutaneous Candidiasis, Anti-Granulocyte, Macrophage

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • 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.

Sites / Locations

  • National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Rituximab

Arm Description

Adults (=18 years of age) with anticytokine autoantibodyassociated diseases who are refractory to conventional treatment and who test negative for the human immunodeficiency virus (HIV)

Outcomes

Primary Outcome Measures

safe and tolerable administration of rituximab in subjects with anticytokine autoantibody-associated diseases who are refractory to conventional treatment
safe and tolerable administration of rituximab in subjects with anticytokine autoantibody-associated diseases who are refractory to conventional treatment

Secondary Outcome Measures

Full Information

First Posted
April 25, 2013
Last Updated
September 22, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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1. Study Identification

Unique Protocol Identification Number
NCT01842386
Brief Title
Rituximab for Anti-cytokine Autoantibody-Associated Diseases
Official Title
Rituximab (Anti-CD20) for the Treatment of Subjects With Anticytokine Autoantibody-Associated Diseases
Study Type
Interventional

2. Study Status

Record Verification Date
January 31, 2023
Overall Recruitment Status
Completed
Study Start Date
April 29, 2014 (Actual)
Primary Completion Date
May 6, 2021 (Actual)
Study Completion Date
May 6, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
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.
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. Patients may be retreated at the discretion of the Principal Investigator.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Alveolar Proteinosis (PAP), Severe Mucocutaneous Candidiasis
Keywords
Pulmonary Alveolar Proteinosis, Autoantibodies, Mucocutaneous Candidiasis, Anti-Granulocyte, Macrophage

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rituximab
Arm Type
Experimental
Arm Description
Adults (=18 years of age) with anticytokine autoantibodyassociated diseases who are refractory to conventional treatment and who test negative for the human immunodeficiency virus (HIV)
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Subjects will receive intravenous (IV) infusions of rituximab 1 gram on days 1 and 15, and subsequently if indicated up to once a month for 5 months (+/-5 days for each visit) starting approximately on day 42. Subjects whose infections respond positively to the treatment but then relapse may be offered additional treatment.
Primary Outcome Measure Information:
Title
safe and tolerable administration of rituximab in subjects with anticytokine autoantibody-associated diseases who are refractory to conventional treatment
Description
safe and tolerable administration of rituximab in subjects with anticytokine autoantibody-associated diseases who are refractory to conventional treatment
Time Frame
at study end

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Subjects (greater than or equal to 18 years of age) are eligible if they meet the following criteria: Currently enrolled in one of the following protocols: 95-I-0066, 07-I-0033, 01-I-0202, or 93-I-0119. 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. 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. 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. Willingness to comply with study medication, visits, and procedures, as deemed necessary by the study investigator. Willingness to have samples stored for future research and genetic testing. Willingness to be hospitalized for the inpatient visits (initial doese on day 1 and day 15 will occur in the inpatient unit. 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: HIV seropositivity. Active underlying malignancy, except thymoma and basal and squamous cell carcinoma. 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. Use of another investigational study agent within 8 weeks of enrollment. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of the study medication. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Evidence of significant uncontrolled concomitant diseases, such as cardiovascular disease, or nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal disorders. Diagnosis of an unrelated underlying immunodeficiency. Hepatitis B (subjects with hepatitis C are eligible to enter the study). Live vaccines within 1 month prior to receiving the study drug. Unsuitable participation as judged by the principal investigator. 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). History of alcohol, drug, or chemical abuse within 6 months prior to screening. Poor peripheral venous access. Intolerance or contraindications to oral or IV corticosteroids. 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. Breastfeeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christa S Zerbe, M.D.
Organizational Affiliation
National Institute of Allergy and Infectious Diseases (NIAID)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2013-I-0082.html
Description
NIH Clinical Center Detailed Web Page

Learn more about this trial

Rituximab for Anti-cytokine Autoantibody-Associated Diseases

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