Abatacept for the Treatment of Common Variable Immunodeficiency With Interstitial Lung Disease (ABCVILD)

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.

Randomized, blinded/placebo-controlled clinical trial in pediatric and adult subjects ≥50 kg (cohort 1), with an additional cohort (#2) of pediatric subjects <50 kg tested as a single arm, receiving open-label abatacept

Pediatric subjects weighing <50 kg will be placed in an single arm with abatacept with dosing based on weight. Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through weekly 26. Pediatric dosing: Abatacept subcutaneous every week: 10-25 kg: 50 mg; 25-50 kg: 87.5 mg; >50 kg: 125 mg Adult dosing: Abatacept: 125 mg subcutaneous every week

Pediatric subjects weighing ≥50kg and adult subjects will enter a double blinded, randomization in a 1:2 ratio of subjects to the abatacept treatment group (arm 1) or to the placebo group (arm 2) treated weekly through weekly 26. The composition of the placebo is the same as the active study drug without the abatacept. To maintain the blind, injection volumes will be the same as the active treatment.

Abatacept is a selective costimulation modulator, inhibiting T lymphocyte activation by binding to CD80 and CD86, thereby blocking interaction with CD28. Orencia solution supplied in a prefilled syringe should be refrigerated at 2C to 8C (36F to 46F). Orencia should not be used beyond the expiration date on the prefilled syringe. The product should be protected from light by storing in the original package until time of use. The prefilled syringe should not be frozen.

The composition of the placebo for Orencia is the same as the active study drug without the abatacept. The placebo will be packaged and labeled as described above for the Orencia prefilled syringes. To maintain the blind, injection volumes will be the same as the active treatment.

Proportion of subjects achieving a significant response (defined as >30 percent change in lung tissue disease burden by GLILD) on HRCT after 6 months of abatacept therapy.

PedsQL Generic Core Scales: items are reversed scored and linearly transformed to a 0-100 scale, so that higher scores indicate better HRQOL. Range of 0-2300 for ages above 4, range of 0-2100 for 4 years old

King's Interstitial Lung Disease: scoring ranges from 0-100 where a higher score denotes better health

Inclusion Criteria: Diagnosis of CVID according to the international consensus document (ICON) Age 4 years or above Serum IgG at least 2 standard deviations below the age adjusted normal Decreased serum IgA and/or serum IgM Abnormal specific antibody response to immunization Exclusion of secondary immunodeficiency On replacement immunoglobulin for at least 6 months and willing to maintain throughout study Granulomatous-lymphocytic interstitial lung disease with a lymphocytic component diagnosed by lung biopsy prior to study entry, wedge biopsy preferred. 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. Signed written informed consent Willing to allow storage of biological specimens for future use in medical research. 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. 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: History of hypersensitivity to abatacept or any of its components Has received any lymphocyte depleting agents including anti-CD20 monoclonal antibodies, alemtuzumab, ATG in the preceding 6 months 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 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 History of HIV infection (positive PCR) Chronic untreated hepatitis B or C (positive PCR) Active tuberculosis (TB) by positive QuantiFERON gold. If history of latent TB, then must supply evidence of completing treatment. Persistent Epstein-Barr Virus (EBV) load ≥ 1,000 units/mL blood checked twice at least 1 month apart Other uncontrolled infections Live vaccine given within 6 weeks of the start of the trial Malignancy or treated for malignancy within the past year Currently pregnant or breast feeding Life expectancy less than 1 month Subjects unwilling to self-administer or have a parent/caregiver self-administer subcutaneous injections at home Other conditions that the investigators feel contraindicate participation in the study