Clinical Trial to Assess the Efficacy of Rituximab and Azathioprine in the Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) in Adult Patients With Common Variable Immunodeficiency (CVID)

Brief Summary

Detailed Description

BACKGROUND Common Variable Immunodeficiency (CVID) is one of the most clinically important primary immunodeficiencies due to its frequency, serious complications, and long-term costs of therapy. A form of lung disease known as granulomatous and lymphocytic interstitial lung disease (GLILD) occurs in 10-15% of patients with CVID. The causes of GLILD are unknown; no long-term study has defined the natural course of GLILD; and no clinical trials have been done to define the best possible treatment for this condition. As a result, currently there is no proven standard of care for the treatment of GLILD. The best treatment for individuals with GLILD is not currently known. Some doctors believe that GLILD does not always continue to get worse and patients should only be treated unless this happens. Other doctors believe GLILD is always progressive and should be treated early to prevent more problems later. There is compelling evidence to support that treatment using rituximab (RTX) in conjunction with azathioprine (AZA), may improve the lung function and abnormalities seen on high resolution CT (HRCT) scans of the chest. STUDY GROUPS Patients in this study will either receive a placebo or a combination of Rituximab and azathioprine. These drugs are approved by the US Food and Drug Administration for other conditions, but not yet for this disease. Because no one knows which of the treatments is best, patients will be "randomized" into one of the two study groups. Randomization means that you are put into a group by chance. TREATMENT Eligible patients will be randomized to receive either 18 months of Rituximab and Azathioprine (20 patients) or placebo (20 patients). Rituximab will be administered intravenously (IV) weekly for four consecutive weeks at enrollment and months 6 and 12. IV placebo will be administered on the same schedule as Rituximab. Azathioprine or oral placebo will be administered by mouth daily for 18 months. SUMMARY OF STUDY PROCEDURES -Month 1, 6, 12 Patients will be required to travel to a study site weekly for four consecutive weeks at enrollment and at 6 and 12 months to receive study infusions. At each of these visits, patients will be given: * Your study infusions * Physical exams with vital signs * Blood tests to check your organ function Every six months (Enrollment, 6, 12 \& 18 months) while receiving study treatment, patients will be asked to complete the following study tests: * Lung Function testing * High resolution CT of the chest * Quality of Life Questionnaire, 6-min walk distance test and Karnofsky performance scale. * Blood for research - approximately 10 teaspoons of blood will be collected Monthly Labs Following the first month of study treatment, patients will be required to visit their local clinic/hospital for a blood draw to monitor their lab values twice monthly for the second and third months of treatment, then monthly. Final Study Visit The final study visit will take place at Month 24 after start of study treatment. Patients will also have the following tests done: * Physical exams with vital signs * Lung Function testing * High resolution CT of the chest * Quality of Life Questionnaire, 6-min walk distance test and Karnofsky performance scale. * Blood for research - approximately 10 teaspoons of blood will be collected

Primary Outcomes

Secondary Outcomes

• The effect of treatment with RTX/AZA relative to placebo on the changes over time in high-resolution CT scans of the chest.(Baseline, six months, 12 months, 18 months, 24 months)
• Changes in quality of life in the two randomized groups of patients as measured by Karnofsky Performance Status Scale (KPS).(Baseline, six months, 12 months, 18 months and 24 months)
• Prevalence and abundance of bacterial, fungal and viral sequences.(24 Months)
• Presence of bacterial (16S rRNA), fungal (Internal Transcribed Spacer region/ITS) and viral sequences (unbiased high-throughput sequencing) in the lungs of GLILD patients.(24 Months)
• Incidence of lymphoma in patients treated with RTX/AZA or placebo over the time of enrollment in the study.(24 months)
• Changes in quality of life in the two randomized groups of patients as measured by SGRQ total score.(Baseline, six months, 12 months, 18 months and 24 months)
• Dysregulated molecular pathway determined by performing whole transcriptome sequencing.(24 Months)
• Lung transcriptome predicts response to RTX/AZA therapy (performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue) and confirm that lung transcriptome predicts response to RTX/AZA therapy.(24 Months)
• Peripheral blood biomarkers as indicators of GLILD disease activity.(24 Months)
• Correlate changes in pulmonary function (FVC, FEV1, DLco) with extent of pulmonary fibrosis obtained on open lung biopsy.(24 months)
• Correlate changes in pulmonary function (FVC, FEV1, DLco) with high-resolution CT scan scores over time in the two randomized groups of patients.(24 months)
• Changes in FVC and HRCT of the chest (maintained for 6 months after completion of therapy in both randomized groups)(Baseline, six months, 12 months, 18 months and 24 months)
• Changes in quality of life in the two randomized groups of patients as measured by 6-minute Walking Test.(Baseline, six months, 12 months, 18 months and 24 months)