A Phase 1 Evaluation of the Safety of Belimumab in People With Idiopathic CD4 Lymphopenia and Autoantibodies (Phoebe)

  • STATUS
    Recruiting
  • End date
    Dec 29, 2023
  • participants needed
    20
  • sponsor
    National Institute of Allergy and Infectious Diseases (NIAID)
Updated on 21 September 2022

Summary

Background

People with Idiopathic CD4 lymphopenia (ICL) have lower numbers of a type of white blood cell called CD4 cells. White blood cells fight against infections. Low levels of CD4 cells may make a person more likely to get sick. There are no approved treatments for ICL. Researchers think a drug called belimumab may be able to help in specific situations.

Objective

To see if belimumab is safe for people with ICL.

Eligibility

People ages 18-70 who have ICL and are participating in NIH protocol 09-I-0102 (EPIC)

Design

Participants will be screened with:

Medical and medication history

Physical exam

Questionnaire about mental health and depression

Blood and urine tests

Participants will have a baseline visit. This will include some repeats of the screening tests. They may also have leukapheresis: Blood will be taken from a needle in one arm and passed through a machine that separates out the white blood cells. The rest of the blood will be returned through a needle in the other arm.

Participants will receive 8 doses of belimumab through IV: A needle will insert a thin plastic tube into an arm vein. Belimumab will be given through the IV line. The first 3 doses will be given every 2 weeks. The other 5 will be given once every 4 weeks. Participants will have a physical exam and blood and urine tests at each dosing visit. They will be monitored for up to 4 hours after the infusion.

Participants will have 3 follow-up visits, at around 8, 16, and 24 weeks after the last dose of belimumab. They will have a physical exam and blood and urine tests. Once they finish this protocol and they will continue to be followed under 09-I-0102 (EPIC study).

...

Description

Idiopathic CD4 lymphopenia (ICL) is characterized by persistent low CD4 counts, frequently in combination with CD8, natural killer, or B cell lymphopenia. It is considered a heterogeneous disorder with manifestations that can include autoimmunity, invasive fungal infections or infections with human papillomavirus, and malignancies typically related to infections. The exact etiology of ICL remains unclear and there is no specific treatment.

Recent data from our group revealed a high prevalence of antilymphocyte antibodies in many of the ICL patients evaluated. The targets of these antibodies remain unknown and are being investigated. On some occasions, these antibodies have the ability to cause antibody-dependent cytotoxicity or complement activation, both mechanisms that can cause cell death. Although it is unclear if these antibodies are the cause (or perhaps more likely the effect) of lymphopenia, it is plausible they play a significant pathogenic role and at a minimum may be hampering lymphocyte compensatory mechanisms for expansion and improved survival.

The immune deficiency and the unclear role of autoantibodies preclude aggressive immunosuppressive treatment (eg, corticosteroids) for ICL. Therefore, a rational approach to treatment is belimumab, a monoclonal antibody that targets Blys (also call BAFF for B-cell activating factor), expressed on activated B cells and plasma cells. Belimumab is approved by the United States Food and Drug Administration (FDA) for patients with systemic lupus erythematosus (SLE) who have evidence of autoantibodies and has shown efficacy in both reducing symptoms and leading to a modest decrease in autoantibodies.

In this open-label prospective single-arm study, ICL patients with laboratory evidence of antilymphocyte antibodies will be recruited. Belimumab will be administered by intravenous infusion for 6 months with an extended follow-up of an additional 6 months. Administration of the study drug will follow the SLE scheme of 10 mg/kg at study entry, 2 weeks, 4 weeks, and monthly thereafter (8 doses total). Three additional visits approximately every 2 months will complete the 52-week study. Clinical safety evaluations with immunologic and serologic testing will be performed at all study visits.

This protocol will assess the safety of belimumab in ICL and also help in better understanding the role of autoantibodies in ICL pathogenesis. This knowledge could substantially improve rationale and design of novel therapeutic interventions in ICL.

Details
Condition Idiopathic CD4 Lymphopenia
Treatment belimumab, Belimubab
Clinical Study IdentifierNCT04097561
SponsorNational Institute of Allergy and Infectious Diseases (NIAID)
Last Modified on21 September 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Individuals must meet all of the following criteria to be eligible for study
participation
Aged 18-70 years
Enrolled in study 09-I-0102
Has a documented diagnosis of ICL, defined as the following
CD4 count < 300 cells/microliter in at least 2 separate measurements 6 weeks apart at any point in the past, AND
CD4 count < 300 cells/microliter within previous 90 days
Evidence for autoantibody positivity (eg, ANA or in the research flow method looking
Female participants of childbearing potential must agree to use adequate contraception when engaging in sexual activities that can result in pregnancy, beginning at day 0 (or day 30 for hormonal contraception) until 4 months after the last dose of belimumab
for antilymphocyte antibodies)
Acceptable methods of contraception include the following
Hormonal contraception
Male or female condom
Diaphragm or cervical cap with a spermicide
Intrauterine device
Able to provide informed consent
Willing to allow samples to be stored for future research

Exclusion Criteria

Individuals meeting any of the following criteria will be excluded from study
participation
Prior receipt of belimumab for any reason
Allergy to any component of belimumab formulation
HIV infection or other recognized congenital or acquired immunodeficiency
Untreated hepatitis B or C (acute or chronic)
Current moderate or severe acute illness (eg, febrile illness, seizure, myocardial
infarction, cerebrovascular accident, pulmonary embolism) or progressive serious
Active tuberculosis infection
infection related to ICL that, in the opinion of the principal investigator, would
Serum creatinine > 1.5 times the upper limit of normal (ULN)
make the participant unsuitable for the study. Pre-existing infections that have been
Hemoglobin < 8 g/dL
Alanine transaminase or aspartate transaminase > 2 times ULN
stable both clinically and with laboratory (eg, cryptococcal antigen titer or
histoplasma antigen level) and radiographic evaluations on maintenance therapy over at
Serum IgG < 400 mg/L
least a year will be eligible
Severe depression. Psychiatry may be consulted prior to final eligibility decision
Receipt of any vaccination within the past 30 days
Pregnant
Breastfeeding
Current use of systemic glucocorticosteroids, with the exception of corticosteroid
nasal spray or inhaler and topical steroids
Any cancer diagnosis or autoimmune condition requiring systemic chemotherapy or
immunomodulant-affecting antibody responses (eg, rituximab, ibrutinib), IV or SC Ig
supplementation, radiation therapy, or any such treatment within the previous 6
months. Apremilast, Plaquenil, or nonsteroidal anti-inflammatory drugs will not be
exclusionary
Infections (recently acquired or exacerbation of a chronic infection) that required
new medications for management within the past 60 days
Any behavioral or substance use issue that would compromise appropriate follow up and
participation in this study
Concomitant diagnosis of SLE will not be exclusionary. Although SLE can be associated with
lymphopenia, patients with lupus and extreme lymphopenia in the absence of cytotoxic or
immunosuppressive medications and history of unusual infections will be eligible if they
are participants of study 09-I-0102
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