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Rituximab in Rheumatoid Arthritis Lung Disease

Primary Purpose

Rheumatoid Arthritis, Interstitial Pneumonia

Status

Completed

Phase

Phase 3

Locations

United States

Study Type

Interventional

Intervention

Rituximab

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring Rheumatoid Arthritis, Interstitial Pneumonia, Rheumatology, Rituximab

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Diagnosis of RA according to the revised 1987 American Rheumatism Association criteria
Absence of clinical features suggesting infection, neoplasm, sarcoidosis, interstitial lung disease other than UIP or NSIP, other collagen vascular disease, or exposure to known fibrogenic drugs or environmental factors
Diagnosis of progressive interstitial pneumonia of UIP or NSIP subtype, based on the following criteria
1. Clinical symptoms consistent with interstitial lung disease with onset between 3 months and 36 months prior to screening.
2. Worsening as demonstrated by any one of the following within the past year:
  - > 10% decrease in Forced Vital Capacity (FVC)
  - increasing infiltrates on chest X-ray or High Resolution Computed Tomography (HRCT), or worsening dyspnea at rest or on exertion
3. Diagnosis of UIP or NSIP by either of the following:
  - Open or video-assisted thoracic surgery (VATS) lung biopsy showing definite or probable UIP or NSIP
  - HRCT scan showing definite or probable UIP or NSIP AND abnormal pulmonary function tests (reduced FVC or decreased diffusing capacity of carbon monoxide (DLco) or impaired gas exchange at rest or with exercise) AND insidious onset of otherwise unexplained dyspnea or exertion and bibasilar, inspiratory crackles on auscultation
4. FVC > 50% of predicted value at Screening
5. DLco >30% of predicted value at Screening

5. No change of disease-modifying anti-rheumatic drug (DMARD) treatment within the last 3 months

Exclusion Criteria:

History of clinically significant environmental or drug exposure known to cause pulmonary fibrosis.
Forced expiratory volume in one second (FEV1) FEV1/FVC ratio < 0.6 at screening (pre- or post-bronchodilator).
Residual volume > 120% predicted at Screening
Evidence of active infection
Any pulmonary condition other than UIP/NSIP, which, in the opinion of the site principal investigator, is likely to result in the death of the patient within the next year
History of unstable or deteriorating cardiac or neurologic disease
Pregnancy or lactation
Treatment with cyclophosphamide, cyclosporine, interferon gamma or beta, anti-tumor necrosis factor therapy, anti-interleukin 1 (IL1) therapy or with endothelin receptor blockers within the last 8 weeks; experimental therapy for rheumatoid arthritis
Creatinine > 1.5 X upper limit of normal range (ULN) at Screening
Hematology outside of specified limits: white blood cell (WBC) < 2,500/mm^3 or absolute neutrophil count (ANC) < 1500
Hematocrit < 27% or > 59%, platelets < 100,000/mm^3 at screening
Positive hepatitis B or C serology
Any medical condition, which in the opinion of the site principal investigator, may be adversely affected by the participation in this study
History of recurrent significant infection or history of recurrent bacterial infections
Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
Abnormal neurological examination reflective of central nervous disease, including paresis, cognitive impairment and problems with coordination
Current enrollment in another clinical trial
Fever (>99.5º F)
History of previous rituximab administration
Receipt of any vaccine, particularly live viral vaccines, within 4 weeks of first study dose
Decreased Immunoglobulin G (IgG) and Immunoglobulin M (IgM) levels (below lower limit of normal range)
Present or past malignancy
History of severe allergic or anaphylactic reaction to administration of humanized or murine monoclonal antibodies
Positive human immunodeficiency virus (HIV) serology

Sites / Locations

Brigham and Women's Hospital
Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

open label, all subjects will receive rituximab

Outcomes

Primary Outcome Measures

Change in Diffusion Capacity for Carbon Monoxide (DLco) From Baseline to 48 Weeks

DLco is one pulmonary function measure. For DLco, worsening was defined as decrease of at least 15% and improvement was defined as increase of at least 15%.

Change in Forced Vital Capacity (FVC) From Baseline to 48 Weeks

FVC is one measure of pulmonary function. For FVC, worsening was defined as decrease of at least 10% and improvement was defined as increase of at least 10%.

Secondary Outcome Measures

Change in Lung Fibrosis Score as Observed on High Resolution Computerized Tomography (HRCT) Scans, From Baseline to 48 Weeks

Three serial HRCT scans of each patient were scored independently and simultaneously by two core radiologists, who were blinded to the sequence in which three scans were obtained (at screening, 24 and 48 weeks). The HRCT scoring sheet scored different domains of abnormality such as, linear opacities, consolidation, ground-glass density, etc. Radiographers reported composite impression based on scoring according to worsening, no worsening or improvement of relevant domains.

Assessment of RA Disease Activity Scores as Measured by the DAS28 Score at Baseline and 48 Weeks

The DAS28 score is a measure of RA disease activity calculated using variables such as swollen joint count, the Erythrocyte Sedimentation Rate (ESR) and patient reported assessment of health. Using this data, the DAS28 calculation provides a number on a scale from 0-10 indicating the current activity of a patient's RA. A DAS28 score above 5.1 means high disease activity whereas a DAS28 below 3.2 indicates low disease activity. Remission is achieved by a DAS28 score lower than 2.6.

Change in RA Disease Activity From Baseline to 48 Weeks Using the DAS28 Score.

Percentage of Change in Health Associated Quality of Life From Baseline to 48 Weeks

The percentage change from baseline to week 48 in a participant's perception of the impact of health on his or her quality of life was collected on the Health Assessment Questionnaire (HAQ). The HAQ measures a person's ability to function with arthritis. The questionnaire is divided into 8 categories (Dressing and Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip and Activities) which include several questions for each category. The category score is determined by the highest score of the set of questions for each category. The disability score is determined by adding the scores for all categories and dividing by 8. The disability scale ranges from 0 (best - without any difficulty) to 3 (worst - unable to do much).

Full Information

NCT ID

NCT00578565

First Posted

December 19, 2007

Last Updated

September 25, 2012

Sponsor

Eric Matteson

Collaborators

Genentech, Inc., National Center for Research Resources (NCRR)

1. Study Identification

Unique Protocol Identification Number

NCT00578565

Brief Title

Rituximab in Rheumatoid Arthritis Lung Disease

Official Title

Rituximab for the Treatment of Rheumatoid Arthritis-Associated Interstitial Pneumonia: A Pilot Study

Study Type

Interventional

2. Study Status

Record Verification Date

September 2012

Overall Recruitment Status

Completed

Study Start Date

May 2007 (undefined)

Primary Completion Date

June 2011 (Actual)

Study Completion Date

June 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Eric Matteson

Collaborators

Genentech, Inc., National Center for Research Resources (NCRR)

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

This study will examine the course of patients with progressive rheumatoid arthritis associated interstitial lung disease (RA-ILD) treated with rituximab for safety and progression-free survival at 48 weeks. Safety of rituximab therapy in this disease will be assessed through patient history, physical exams and laboratory parameters. Twelve male/or female patient with RA-associated lung disease (6 of each nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) histological subtype) will be enrolled The study involves 12 visits over 48 weeks Rituximab will be administered intravenously at Day 1 and Day 15 with repeat dosing at six months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis, Interstitial Pneumonia

Keywords

Rheumatoid Arthritis, Interstitial Pneumonia, Rheumatology, Rituximab

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

open label, all subjects will receive rituximab

Intervention Type

Drug

Intervention Name(s)

Rituximab

Other Intervention Name(s)

Rituxan, MabThera

Intervention Description

Rituximab 1000 mg. I.V.on each days 1 and 15 with repeat dosing at 6 months.

Primary Outcome Measure Information:

Title

Change in Diffusion Capacity for Carbon Monoxide (DLco) From Baseline to 48 Weeks

Description

DLco is one pulmonary function measure. For DLco, worsening was defined as decrease of at least 15% and improvement was defined as increase of at least 15%.

Time Frame

baseline, 48 weeks

Title

Change in Forced Vital Capacity (FVC) From Baseline to 48 Weeks

Description

FVC is one measure of pulmonary function. For FVC, worsening was defined as decrease of at least 10% and improvement was defined as increase of at least 10%.

Time Frame

baseline, 48 weeks

Secondary Outcome Measure Information:

Title

Change in Lung Fibrosis Score as Observed on High Resolution Computerized Tomography (HRCT) Scans, From Baseline to 48 Weeks

Description

Time Frame

baseline, 48 weeks

Title

Assessment of RA Disease Activity Scores as Measured by the DAS28 Score at Baseline and 48 Weeks

Description

Time Frame

baseline, 48 weeks

Title

Change in RA Disease Activity From Baseline to 48 Weeks Using the DAS28 Score.

Description

Time Frame

baseline, 48 weeks

Title

Percentage of Change in Health Associated Quality of Life From Baseline to 48 Weeks

Description

Time Frame

baseline, 48 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Diagnosis of RA according to the revised 1987 American Rheumatism Association criteria Absence of clinical features suggesting infection, neoplasm, sarcoidosis, interstitial lung disease other than UIP or NSIP, other collagen vascular disease, or exposure to known fibrogenic drugs or environmental factors Diagnosis of progressive interstitial pneumonia of UIP or NSIP subtype, based on the following criteria Clinical symptoms consistent with interstitial lung disease with onset between 3 months and 36 months prior to screening. Worsening as demonstrated by any one of the following within the past year: > 10% decrease in Forced Vital Capacity (FVC) increasing infiltrates on chest X-ray or High Resolution Computed Tomography (HRCT), or worsening dyspnea at rest or on exertion Diagnosis of UIP or NSIP by either of the following: Open or video-assisted thoracic surgery (VATS) lung biopsy showing definite or probable UIP or NSIP HRCT scan showing definite or probable UIP or NSIP AND abnormal pulmonary function tests (reduced FVC or decreased diffusing capacity of carbon monoxide (DLco) or impaired gas exchange at rest or with exercise) AND insidious onset of otherwise unexplained dyspnea or exertion and bibasilar, inspiratory crackles on auscultation FVC > 50% of predicted value at Screening DLco >30% of predicted value at Screening 5. No change of disease-modifying anti-rheumatic drug (DMARD) treatment within the last 3 months Exclusion Criteria: History of clinically significant environmental or drug exposure known to cause pulmonary fibrosis. Forced expiratory volume in one second (FEV1) FEV1/FVC ratio < 0.6 at screening (pre- or post-bronchodilator). Residual volume > 120% predicted at Screening Evidence of active infection Any pulmonary condition other than UIP/NSIP, which, in the opinion of the site principal investigator, is likely to result in the death of the patient within the next year History of unstable or deteriorating cardiac or neurologic disease Pregnancy or lactation Treatment with cyclophosphamide, cyclosporine, interferon gamma or beta, anti-tumor necrosis factor therapy, anti-interleukin 1 (IL1) therapy or with endothelin receptor blockers within the last 8 weeks; experimental therapy for rheumatoid arthritis Creatinine > 1.5 X upper limit of normal range (ULN) at Screening Hematology outside of specified limits: white blood cell (WBC) < 2,500/mm^3 or absolute neutrophil count (ANC) < 1500 Hematocrit < 27% or > 59%, platelets < 100,000/mm^3 at screening Positive hepatitis B or C serology Any medical condition, which in the opinion of the site principal investigator, may be adversely affected by the participation in this study History of recurrent significant infection or history of recurrent bacterial infections Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening Abnormal neurological examination reflective of central nervous disease, including paresis, cognitive impairment and problems with coordination Current enrollment in another clinical trial Fever (>99.5º F) History of previous rituximab administration Receipt of any vaccine, particularly live viral vaccines, within 4 weeks of first study dose Decreased Immunoglobulin G (IgG) and Immunoglobulin M (IgM) levels (below lower limit of normal range) Present or past malignancy History of severe allergic or anaphylactic reaction to administration of humanized or murine monoclonal antibodies Positive human immunodeficiency virus (HIV) serology

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Eric L Matteson, M.D., M.P.H.

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

Facility Information:

Facility Name

Brigham and Women's Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

12. IPD Sharing Statement

Links:

URL

http://clinicaltrials.mayo.edu

Description

Mayo Clinic Clinical Trials

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Rituximab in Rheumatoid Arthritis Lung Disease

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