Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease in Patients With Common Variable Immunodeficiency

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.

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

Eligibility Criteria:
INCLUSION CRITERIA:

Age:

* Patients must be 18 years of age or older.

Diagnosis:

* Diagnosis of CVID in accordance with international criteria which includes: A) Serum immunoglobin G (IgG) at least 2 standard deviations below the age adjusted norm; B) Decreased serum immunoglobin A (IgA) and/or immunoglobin M (IgM); C) Age \> 4 years.; D) Abnormal specific antibody production in response to immunization; E) Exclusion of secondary causes of hypogammaglobulinemia.
* Diagnosis of GLILD based on histopathologic abnormalities of lung tissue obtained by open lung biopsy within 12 months of enrollment and confirmed by Pathology Core.

Performance Level:

* Karnofsky Performance Status (KPS) ≥ 50%

Prior Therapy:

* Patients must have fully recovered from the acute toxic effects of all prior therapy.
* Systemic steroids need to be completed at least 60 days from the time of enrollment.

Organ Function:

* Adequate Lung Function defined as:

  • FVC \> 60 % predicted and

  • DLco \> 35 % predicted
* Adequate Bone Marrow Function defined as:

  • Peripheral absolute neutrophil count (ANC) ≥ 750/mm3 and

  • Platelet count ≥ 50,000/mm3
* Adequate Hepatic Function as evidenced by:

  * Direct Bilirubin \< 1.5 x upper limit of normal (ULN) for age
  * Serum glutamic pyruvic transaminase (SGPT) (ALT) \< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.
* Adequate Renal Function as defined by a normal serum creatinine

Reproductive Function:

o Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed prior to enrollment.

* Female patients with infants must agree not to breastfeed their infants while on this study.
* Male and female patients of childbearing potential must agree to use an effective method of contraception approved by the investigator during the study.
* Sexually active females of childbearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device (UD), surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 6 months after the last dose of study therapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 6 months after the last dose of study therapy.

Regulatory Requirements

* All patients must sign a written informed consent.
* All institutional, FDA, and NIH requirements for human studies must be met.

EXCLUSION CRITERIA:

Infection:

* Patients with uncontrolled infection are not eligible.
* Patients with documented serious infection within 3 months of screening or opportunistic infection within 6 months of screening are not eligible.

Cardiac Function:

o Patients cannot be diagnosed with New York Heart Association (NYHA) Class III or IV congestive heart failure, ventricular arrhythmias, or uncontrolled hypertension.

Allergies:

o Known hypersensitivity to any of the components of RTX or AZA.

Current Therapy:

* Systemic immunosuppressive medications including steroids.
* Steroids can be used to prevent or to treat infusion-related RTX symptoms, but this should be used only prior to or immediately after the RTX infusion, and should not be continued beyond 3 days. The use of systemic steroids should be recorded.
* Inhaled steroids are acceptable.

Previous Therapy:

o Previous treatment with RTX or AZA for GLILD.

Pregnant Females:

o Pregnant females will not be allowed to participate in this study.

Hepatic Disease:

o Known cirrhosis and/or portal hypertension.

Hepatitis B or Hepatitis C Infection:

* All patients will be screened for Hepatitis B and C by polymerase chain reaction (PCR).
* Hepatitis C positive as determined by PCR.
* Hepatitis B Reactivation: Hepatitis B Reactivation is defined as Hepatitis B carrier patients with one of the following:

  * Positive hepatitis B e-antigen (HBe-Ag)
  * Quantitative hepatitis B Viral (HBV) DNA Load \> 10\^5 genomes/ml

Human Immunodeficiency Virus (HIV) 1 Positive:

o HIV 1 infection will be determined by PCR.

Homozygous Mutations:

o Patients with homozygous mutations of thiopurine methyltransferase (TPMT) will be excluded from the study.