Rituximab in Rheumatoid Arthritis Lung Disease

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00578565

Enrollment

Registered

2007-12-21

Start date

2007-05-31

Completion date

2011-06-30

Last updated

2012-10-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Interstitial Pneumonia, Rheumatoid Arthritis

Keywords

Rheumatoid Arthritis, Interstitial Pneumonia, Rheumatology, Rituximab

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.

Interventions

DRUGRituximab

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

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

Inclusion criteria

1. Diagnosis of RA according to the revised 1987 American Rheumatism Association criteria 2. 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 3. 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

1. History of clinically significant environmental or drug exposure known to cause pulmonary fibrosis. 2. Forced expiratory volume in one second (FEV1) FEV1/FVC ratio \< 0.6 at screening (pre- or post-bronchodilator). 3. Residual volume \> 120% predicted at Screening 4. Evidence of active infection 5. 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 6. History of unstable or deteriorating cardiac or neurologic disease 7. Pregnancy or lactation 8. 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 9. Creatinine \> 1.5 X upper limit of normal range (ULN) at Screening 10. Hematology outside of specified limits: white blood cell (WBC) \< 2,500/mm\^3 or absolute neutrophil count (ANC) \< 1500 11. Hematocrit \< 27% or \> 59%, platelets \< 100,000/mm\^3 at screening 12. Positive hepatitis B or C serology 13. Any medical condition, which in the opinion of the site principal investigator, may be adversely affected by the participation in this study 14. History of recurrent significant infection or history of recurrent bacterial infections 15. 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 16. Abnormal neurological examination reflective of central nervous disease, including paresis, cognitive impairment and problems with coordination 17. Current enrollment in another clinical trial 18. Fever (\>99.5º F) 19. History of previous rituximab administration 20. Receipt of any vaccine, particularly live viral vaccines, within 4 weeks of first study dose 21. Decreased Immunoglobulin G (IgG) and Immunoglobulin M (IgM) levels (below lower limit of normal range) 22. Present or past malignancy 23. History of severe allergic or anaphylactic reaction to administration of humanized or murine monoclonal antibodies 24. Positive human immunodeficiency virus (HIV) serology

Design outcomes

Primary

Measure	Time frame	Description
Change in Diffusion Capacity for Carbon Monoxide (DLco) From Baseline to 48 Weeks	baseline, 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	baseline, 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

Measure	Time frame	Description
Change in Lung Fibrosis Score as Observed on High Resolution Computerized Tomography (HRCT) Scans, From Baseline to 48 Weeks	baseline, 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	baseline, 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.	baseline, 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.
Percentage of Change in Health Associated Quality of Life From Baseline to 48 Weeks	baseline, 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).

Countries

United States

Participant flow

Recruitment details

Participants were recruited from Mayo Clinic and Brigham and Women's rheumatology outpatient clinics.

Participants by arm

Arm	Count
Rituximab open label, all subjects will receive Rituximab 1000 mg. I.V.on each days 1 and 15 with repeat dosing at 6 months	10
Total	10

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	3

Baseline characteristics

Characteristic	Rituximab
Age Continuous	64.7 years
Duration of Interstitial Lung Disease (ILD)	3.2 Years
Duration of Rheumatoid Arthritis (RA)	13.8 Years
Histological subtypes of RA-ILD Nonspecific Interstitial Pneumonia (NSIP)	6 participants
Histological subtypes of RA-ILD Usual Interstitial Pneumonia (UIP)	4 participants
Region of Enrollment United States	10 participants
Sex: Female, Male Female	6 Participants
Sex: Female, Male Male	4 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	1 / 10
serious Total, serious adverse events	2 / 10

Outcome results

Primary

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%.

Time frame: baseline, 48 weeks