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

NCT02789397 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: PRO26723
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Granulomatous and Lymphocytic Interstitial Lung Disease

Keywords

Granulomatous and lymphocytic interstitial lung disease (GLIILD); common variable immunodeficiency; Rituximab; Azathioprine; primary immunodeficiency; GLIILD; CVID

Outcome Measures

Primary Outcomes (1)

• 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.

  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 forced expiratory volume (FEV1) and forced vital capacity (FVC). Carbon monoxide diffusion capacity will be performed to assess gas exchange.

  Baseline and 18 months

Secondary Outcomes (13)

• 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

• 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

• Incidence of lymphoma in patients treated with RTX/AZA or placebo over the time of enrollment in the study.

  24 months

Study Arms (2)

Rituximab (RTX) and Azathioprine (AZA)

ACTIVE COMPARATOR

Rituximab 375 mg/m2/dose IV over 4 hours first dose, IV over 2-3 hours each subsequent dose weekly for 4 weeks at enrollment and again at months 6 and 12. Azathioprine: Starting dose of azathioprine will be 50 mg and increased in 25 mg increments to a maximum dose of 150 mg or 2 mg/k/day (whichever is lowest) as tolerated. Azathioprine will be administered by mouth daily for 18 months.

Drug: Rituximab (RTX) and Azathioprine (AZA)

Placebo

PLACEBO COMPARATOR

IV placebo will be administered on the same schedule as Rituximab. Oral placebo will be administered by mouth daily for 18 months.

Drug: Placebos

Interventions

Rituximab (RTX) and Azathioprine (AZA) DRUG

Rituximab 375 mg/m2/dose IV over 4 hours first dose, IV over 2-3 hours each subsequent dose weekly for 4 weeks at enrollment and again at months 6 and 12 for the active comparator arm Rituximab (RTX) and Azathioprine (AZA).

Also known as: Truxima

Rituximab (RTX) and Azathioprine (AZA)

Placebos DRUG

IV placebo will be administered on the same schedule as Rituximab and oral placebo will be administered by mouth daily for 18 months.

Also known as: Saline

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age:
• Patients must be 18 years of age or older.
• Diagnosis:
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Medical College of Wisconsin: lead

Related Publications (1)

• Zdziarski P, Gamian A. Lymphoid Interstitial Pneumonia in Common Variable Immune Deficiency - Case Report With Disease Monitoring in Various Therapeutic Options: Pleiotropic Effects of Rituximab Regimens. Front Pharmacol. 2019 Jan 18;9:1559. doi: 10.3389/fphar.2018.01559. eCollection 2018.

  PMID: 30713498 DERIVED

MeSH Terms

Conditions

Common Variable Immunodeficiency; Primary Immunodeficiency Diseases

Interventions

Rituximab; resiniferatoxin; Azathioprine; Sodium Chloride

Condition Hierarchy (Ancestors)

Immunologic Deficiency Syndromes; Immune System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Thionucleosides; Sulfur Compounds; Organic Chemicals; Mercaptopurine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• John M Routes, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chief

Study Record Dates

• First Submitted: May 16, 2016
• First Posted: June 3, 2016
• Study Start: May 2, 2016
• Primary Completion: March 6, 2018
• Study Completion: March 6, 2018
• Last Updated: March 10, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share