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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02789397
• Date of registration: 16/05/2016
• Prospective Registration: No
• Primary sponsor: Medical College of Wisconsin
• Public title: Treatment of Granulomatous and Lymphocytic Interstitial Lung Disease in Patients With Common Variable Immunodeficiency
• Scientific 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 Common Variable Immunodeficiency (CVID)
• Date of first enrolment: May 2, 2016
• Target sample size: 0
• Recruitment status: Withdrawn
• URL: https://clinicaltrials.gov/show/NCT02789397
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator).
• Phase: Phase 2

Contacts

• Name: John M Routes, MD
• Affiliation: Medical College of Wisconsin

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Granulomatous and Lymphocytic Interstitial Lung Disease

Intervention(s)

Drug: Rituximab (RTX) and Azathioprine (AZA)

Drug: Placebos

Primary Outcome(s)

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]

Secondary Outcome(s)

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]

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]

Peripheral blood biomarkers as indicators of GLILD disease activity. [Time Frame: 24 Months]

Prevalence and abundance of bacterial, fungal and viral sequences. [Time Frame: 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]

Dysregulated molecular pathway determined by performing whole transcriptome sequencing. [Time Frame: 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. [Time Frame: 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. [Time Frame: 24 Months]

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]

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]

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]

Correlate changes in pulmonary function (FVC, FEV1, DLco) with extent of pulmonary fibrosis obtained on open lung biopsy. [Time Frame: 24 months]

Incidence of lymphoma in patients treated with RTX/AZA or placebo over the time of enrollment in the study. [Time Frame: 24 months]

Secondary ID(s)

PRO26723

Source(s) of Monetary Support

Please refer to primary and secondary sponsors