Clinical Trial: 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)

Study Status: Withdrawn
Recruit Status: Withdrawn
Study Type: Interventional

Official Title: 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 Com

Brief Summary: This phase II study will assess the effect of a treatment combination of Rituximab and azathioprine in patients with Granulomatous and Lymphocytic Interstitial Lung Disease (GLILD) compared to placebo, based on change in lung function at 18 months compared to baseline. The researchers will also assess if the drugs improved quality of life.

Detailed Summary:

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). Rituxim
Sponsor: Medical College of Wisconsin

Current Primary Outcome: The effect of treatment with RTX/AZA in patients with GLILD compared to placebo, based on change in forced vital capacity (FVC) at 18 months compared to baseline. [ Time Frame: Baseline and 18 months ]

Pulmonary Function Tests (PFTs) will be performed to measure lung volumes and airflow for evidence of restrictive and obstructive lung disease. PFTs are used to measure lung volumes and airflow for evidence of restrictive and obstructive lung disease. Measurements will be obtained by standard techniques following guidelines outlined by the American Thoracic Society. Spirometry, during screening, needs to be done pre- and post-bronchodilator. All subsequent spirometry is done post-bronchodilator. Diffusion capacity for carbon monoxide is always done post-bronchodilator. Spirometry will be performed to access the FEV1 and FVC. Carbon monoxide diffusion capacity will be performed to assess gas exchange.


Original Primary Outcome: The effect of treatment with RTX/AZA in patients with GLILD compared to placebo, based on change in forced vital capacity (FVC) at 18 months compared to baseline. [ Time Frame: Baseline, six months, 12 months and 24 months ]

Pulmonary Function Tests (PFTs) will be performed to measure lung volumes and airflow for evidence of restrictive and obstructive lung disease. PFTs are used to measure lung volumes and airflow for evidence of restrictive and obstructive lung disease. Measurements will be obtained by standard techniques following guidelines outlined by the American Thoracic Society. Spirometry, during screening, needs to be done pre- and post-bronchodilator. All subsequent spirometry is done post-bronchodilator. Diffusion capacity for carbon monoxide is always done post-bronchodilator. Spirometry will be performed to access the FEV1 and FVC. Carbon monoxide diffusion capacity will be performed to assess gas exchange.


Current Secondary Outcome:

  • The effect of treatment with RTX/AZA relative to placebo on the changes over time in high-resolution CT scans of the chest. [ Time Frame: Baseline, six months, 12 months, 18 months, 24 months ]
    Non-contrast, low dose HRCT scans of the chest will be performed at the intervals and analyzed. Studies will be performed on high-end scanners (64 or above detector rows) capable of producing thin section (1-1.25mm) lung algorithm scans.
  • Correlate changes in pulmonary function (FVC, FEV1, DLco) with extent of pulmonary fibrosis obtained on open lung biopsy. [ Time Frame: 24 months ]
    Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). Histopathologic abnormalities of lung tissue will be determined by open lung biopsy.
  • Correlate changes in pulmonary function (FVC, FEV1, DLco) with high-resolution CT scan scores over time in the two randomized groups of patients. [ Time Frame: 24 months ]
    Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). These will be compared with high-resolution CT scan scores.
  • Changes in FVC and HRCT of the chest (maintained for 6 months after completion of therapy in both randomized groups) [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
    Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). High-resolution CT scans will be performed.
  • Incidence of lymphoma in patients treated with RTX/AZA or placebo over the time of enrollment in the study. [ Time Frame: 24 months ]
    Patients will be monitored with physical examinations, laboratory tests (CBC, auto diff, ALT, bilirubin, serum creatinine, platelets, comprehensive lyphocyte phenotype and cell sort).
  • Changes in quality of life in the two randomized groups of patients as measured by SGRQ total score. [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
    Quality of life will be measured by the St. George's Respiratory Questionnaire, a pulmonary disease specific questionnaire measuring self-reported dyspnea symptoms and their relationship to activities of daily living and psychological functioning.
  • Changes in quality of life in the two randomized groups of patients as measured by Karnofsky Performance Status Scale (KPS). [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
    Karnofsky Performance Status Scale (KPS) will be performed at 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. [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
    The 6-minute Walking Test will performed at baseline, six months, 12 months, 18 months and 24 months.
  • Dysregulated molecular pathway determined by performing whole transcriptome sequencing. [ Time Frame: 24 Months ]
    This will be done by performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue.
  • 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. [ Time Frame: 24 Months ]
    This will be done by performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue. and
  • Peripheral blood biomarkers as indicators of GLILD disease activity. [ Time Frame: 24 Months ]
    The research team will examine blood specimens and evaluate HLA-DR negative and positive T cells.
  • Presence of bacterial (16S rRNA), fungal (Internal Transcribed Spacer region/ITS) and viral sequences (unbiased high-throughput sequencing) in the lungs of GLILD patients. [ Time Frame: 24 Months ]
    This will be done by screening lung biopsies from patients with GLILD, idiopathic pulmonary fibrosis, pulmonary sarcoidosis, or no known pulmonary disease.
  • Prevalence and abundance of bacterial, fungal and viral sequences. [ Time Frame: 24 Months ]
    This will be measured with quantitative PCR analysis of lung tissues obtained from patients with GLILD, idiopathic pulmonary f

    Original Secondary Outcome:

    • The effect of treatment with RTX/AZA relative to placebo on the changes over time in high-resolution CT scans of the chest. [ Time Frame: 19 months ]
      Non-contrast, low dose HRCT scans of the chest will be performed at the intervals and analyzed. Studies will be performed on high-end scanners (64 or above detector rows) capable of producing thin section (1-1.25mm) lung algorithm scans.
    • Correlate changes in pulmonary function (FVC, FEV1, DLco) with extent of pulmonary fibrosis obtained on open lung biopsy. [ Time Frame: 24 months ]
      Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). Histopathologic abnormalities of lung tissue will be determined by open lung biopsy.
    • Correlate changes in pulmonary function (FVC, FEV1, DLco) with high-resolution CT scan scores over time in the two randomized groups of patients. [ Time Frame: 24 months ]
      Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). These will be compared with high-resolution CT scan scores.
    • Changes in FVC and HRCT of the chest (maintained for 6 months after completion of therapy in both randomized groups) [ Time Frame: Seven Months ]
      Pulmonary Function Tests (PFTs) will measure forced vital capacity, forced expiratory volume in one second, diffusing capacity of the lungs for carbon monoxide (DLCO) (e.g., DLco will be measured by the single-breath technique using a 10-second breath hold). High-resolution CT scans will be performed.
    • Determine the incidence of lymphoma in patients treated with RTX/AZA or placebo over the time of enrollment in the study. [ Time Frame: 24 months ]
      Patients will be monitored with physical examinations, laboratory tests (CBC, auto diff, ALT, bilirubin, serum creatinine, platelets, comprehensive lyphocyte phenotype and cell sort).
    • Changes in quality of life in the two randomized groups of patients as measured by SGRQ total score. [ Time Frame: 24 Months ]
      Quality of life will be measured by the St. George's Respiratory Questionnaire, a pulmonary disease specific questionnaire measuring self-reported dyspnea symptoms and their relationship to activities of daily living and psychological functioning.
    • Changes in quality of life in the two randomized groups of patients as measured by Karnofsky Performance Status Scale (KPS). [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
      Karnofsky Performance Status Scale (KPS) will be performed at 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. [ Time Frame: Baseline, six months, 12 months, 18 months and 24 months ]
      The 6-minute Walking Test will performed at baseline, six months, 12 months, 18 months and 24 months.
    • Dysregulated molecular pathway determined by performing whole transcriptome sequenting. [ Time Frame: 24 Months ]
      This will be done by performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue.
    • Lung transcriptome predicts response to RTX/AZA therapy (performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue). [ Time Frame: 24 Months ]

      This will be done by performing whole transcriptome sequencing on GLILD, IPD, sarcoidosis and normal lung tissue.

      and confirm that lung transcriptome predicts response to RTX/AZA therapy.

    • Peripheral blood biomarkers as indicators of GLILD disease activity. [ Time Frame: 24 Months ]
      The research team will examine blood specimens and evaluate HLA-DR negative and positive T cells.
    • Presence of bacterial (16S rRNA), fungal (Internal Transcribed Spacer region/ITS) and viral sequences (unbiased high-throughput sequencing) in the lungs of GLILD patients. [ Time Frame: 24 Months ]
      This will be done by screening lung biopsies from patients with GLILD, idiopathic pulmonary fibrosis, pulmonary sarcoidosis, or no known pulmonary disease.
    • Prevalence and abundance of bacterial, fungal and viral sequences. [ Time Frame: 24 Months ]
      This will be measured with quantitative PCR analysis of lung tissues obtained from patients with GLILD, idiopathic pulmonary fibrosis, pulmonary sarco

      Information By: Medical College of Wisconsin

      Dates:
      Date Received: May 16, 2016
      Date Started: July 2016
      Date Completion: July 2022
      Last Updated: May 9, 2017
      Last Verified: May 2017