There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept has recently looked promising for the treatment of patients with complex CVID. This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric and adult subjects to determine the efficacy of abatacept compared to placebo for treatment of subjects with GLILD in the context of CVID.

Funding Source - FDA OOPD

There is no standard of care therapy for patients with granulomatous-lymphocytic interstitial lung disease (GLILD) seen in common variable immunodeficiency (CVID). Abatacept is a recombinant, human fusion protein of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and human IgG1 that blocks T cell activation by binding to CD80 and CD86, thereby blocking CD28 engagement- the "second signal" needed for T cell activation. Abatacept has recently looked promising for the treatment of patients with complex CVID.

This study is a multi-site, phase II, randomized, blinded/placebo-controlled clinical trial in pediatric subjects ≥50 kg and adult subjects (cohort 1), with an additional cohort (#2) of pediatric subjects <50 kg tested as a single arm, receiving open-label abatacept. Cohort 1 utilizes a 'delayed-start' design to obtain maximum statistical power from this cohort. Cohort 2 will be open label due to the lack of a suitable placebo for pediatric dose abatacept syringes. A total of 21-30 evaluable subjects will be treated in cohort 1 and 8 evaluable subjects in cohort 2.

Following the initial 12 months of treatment, patients will have the option of continuing abatacept for up to 3 years. Patients will have the option of continuing abatacept any time after the initial 12 months of treatment (does not have to be immediately). A separate consent form will be utilized to document a patient's decision to continue. Abatacept will be provided by BMS. Patients who decide to continue abatacept will be monitored for safety, including infections, approximately every 3 months.

Inclusion Criteria:

1. Diagnosis of CVID according to the international consensus document (ICON)

   1. Age 4 years or above
   2. Serum IgG at least 2 standard deviations below the age adjusted normal
   3. Decreased serum IgA and/or serum IgM
   4. Abnormal specific antibody response to immunization
   5. Exclusion of secondary immunodeficiency

2. On replacement immunoglobulin for at least 6 months and willing to maintain throughout study

3. Granulomatous-lymphocytic interstitial lung disease with a lymphocytic component diagnosed by lung biopsy prior to study entry, wedge biopsy preferred.

4. Persistence or worsening of interstitial lung disease measured on serial CT imaging of the lung at least 6 months apart, with the latest assessment within 3 months of study entry.

5. Signed written informed consent

6. Willing to allow storage of biological specimens for future use in medical research.

7. Female subjects of childbearing potential must agree to an effective form of birth control such as hormone based contraceptive, intrauterine device, condoms/barrier, surgically sterile partner, or abstinence.

8. Fertile, non-vasectomized males with a female partner of childbearing potential should use condoms throughout the study and for 3 months after the last dose

Exclusion Criteria:

1. History of hypersensitivity to abatacept or any of its components
2. Has received any lymphocyte depleting agents including anti-CD20 monoclonal antibodies, alemtuzumab, ATG in the preceding 6 months
3. Has received abatacept, cyclophosphamide, tumor necrosis factor inhibitors, or pulse steroids (defined as >15mg/kg/day of methylprednisone or corticosteroid equivalent) within the past 3 months
4. Have started or increased any of the following immune modulating drugs within 3 months of enrolling and 3 months from initial CT chest: azathioprine, cyclosporine, tacrolimus, mercaptopurine, methotrexate, mycophenolate mofetil, or sirolimus
5. History of HIV infection (positive PCR)
6. Chronic untreated hepatitis B or C (positive PCR)
7. Active tuberculosis (TB) by positive QuantiFERON gold. If history of latent TB, then must supply evidence of completing treatment.
8. Persistent Epstein-Barr Virus (EBV) load ≥ 1,000 units/mL blood checked twice at least 1 month apart
9. Other uncontrolled infections
10. Live vaccine given within 6 weeks of the start of the trial
11. Malignancy or treated for malignancy within the past year
12. Currently pregnant or breast feeding
13. Life expectancy less than 1 month
14. Subjects unwilling to self-administer or have a parent/caregiver self-administer subcutaneous injections at home
15. Other conditions that the investigators feel contraindicate participation in the study

Inclusion criteria for Extended Treatment Plan:

• Patients must have completed the abatacept for the treatment of Interstitial Lung Disease in Common Variable Immunodeficiency (ABCVILD) trial
• Patients must have demonstrated positive response to abatacept.
• Patients must provide informed consent to participate in the Extended Treatment Plan.

Exclusion criteria for Extended Treatment Plan:

• Patients who experienced SAEs during the original trial, and such SAEs were determined as related to treatment, or patients who in the opinion of the investigator would not benefit from the extended treatment option.