Ambulatory IPF
Conditions
Keywords
Lung, Fibrosis
Brief summary
Recent research studies have suggested that proteins called antibodies that are produced by the immune system might be involved in the lung damage of idiopathic pulmonary fibrosis (IPF). Antibodies produced by the immune system normal help to fight infections by attacking bacteria and viruses without harming our own tissues. In patients with IPF, there is evidence that certain antibodies (called autoantibodies) attack the lung and contributes to the injury and scarring that occurs in IPF. Our recent studies have found that many IPF patients appear to have excessive autoantibody levels in blood and lungs that might make their disease worse. Rituximab is a medication approved by the Food and Drug Administration (FDA) for the treatment of autoantibody diseases such as rheumatoid arthritis. Rituximab works by destroying B cells, a type of white blood cell, called a B-lymphocyte, which produce autoantibodies. In this research study, rituximab will be given into a vein to reduce the autoantibody levels that we believe might be contributing to the lung damage in IPF. This study is being conducted to determine if rituximab provides beneficial effects for IPF patients by decreasing further lung injury.
Detailed description
This is a double-blinded, Phase II trial in which 58 ambulatory IPF patients at any of four medical centers (University of Pittsburgh, University of Chicago, Geisinger Medical Center, and Temple University) will be randomized equally to 1. placebo or 2. two doses of rituximab 1 gm i.v., with a 14 day interval inbetween doses. Subjects will be followed for 9 months.
Interventions
DRUGRituximab
i.v. rituximab given on two occasions 14 days apart.
DRUGPlacebo
Subjects randomized to placebo will receive two i.v. doses of 5% dextrose in water (D5W) in the same schedule as the rituximab subjects. The D5W and rituximab preparations will be indistinguishable.
Sponsors
National Institutes of Health (NIH)
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
Ambulatory patients with a diagnosis of IPF, not established \>5 years from the enrollment date, that fulfills American Thoracic Society (ATS)/European Thoracic Society (ETS) Consensus Criteria. Ability and willingness to give informed consent. Presence of autoantibodies against Hepatoma-2 (HEp-2) cells, the assay for the primary endpoint. Age 50-85 y.o.
Exclusion criteria
Diagnoses of current infection, proven or suspected by participating physicians based upon their clinical assessments. Presence of active hepatitis B or C, or HIV infection. Presence of positive CONVENTIONAL autoimmune serologic tests, e.g., Antinuclear Antibodies (ANA), Rheumatoid Factor (RF), Anti-Ro, Anti-LA, Anti-Ribonucleoprotein Antibodies (RNP), Anti-Jo-1. History of reaction to murine-derived products or any of the trial medications, or prior exposures to human-murine chimeric antibodies. Malignancy, excluding basal or squamous cell skin cancer and low-risk prostate cancer, defined as stage T1 or T2a with Prostate-Specific Antigen (PSA) less than 10 ng/dl. Unwillingness to complete post-treatment surveillance for 9 months. Diagnosis of major morbidities (aside from IPF) expected to interfere with subjects' study participation for 9 months. Treatment for \>5 days within the preceding month with \>10 mg. prednisone (or equivalent corticosteroid) or any treatment during the preceding month with a potent cellular immunosuppressant (e.g., cyclophosphamide, methotrexate, mycophenolate, azathioprine, calcineurin inhibitors, etc.). Uncontrolled diabetes or hypertension that preclude safe treatment with methylprednisolone. Concurrent participation in other experimental trials. Pregnancy or unwillingness to use contraception during the duration of the study among female participants with child-bearing potential. Ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) \<70% of predicted values.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Autoantibodies to Human Epidermoid (HEp)-2 Cells | baseline to 9 months | Titers of anti-HEp-2 autoantibodies, by indirect immunofluorescence assays (IFA) over 9 months, month 9 reported. Titers represent the highest dilution of patient plasma wherein the autoantibodies can be detected. Higher titers denote greater autoantibody concentrations. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Forced Vital Capacity (FVC) | baseline thru 9 months | FVC values over the observation period will be measured by spirometry, month 9 reported. |
| Number of Adverse Events (AE) | during the 9 months of observation | AE in the two treatment arms will be compared. Serious adverse events, as defined by national toxicity scale. |
| Number of Acute Exacerbations | during the study duration of 9 months | The number of acute exacerbations, defined using consensus criteria (new/worsened hypoxemia and dyspnea, with characteristic radiographic changes within the last 30 days). |
| Changes in Anti-Heat Shock Protein 70 (HSP70) Autoantibodies | baseline to 9 months | Changes of anti-HSP70 plasma concentrations as determined by ELISA, month 9 reported. The result is expressed as optical density (OD) units. The greater the number; the more autoantibody. |
| Transplant-Free Survival | during 9 months of observation | Actuarial transplant-free survival in the two arms, calculated by actuarial methods (Kaplan-Meier). These result in percent survival denoted as means and +/- standard error (these are detailed in the outcome table below). |
| Hospitalizations | during 9 months of observation | The number of hospitalizations in the two arms will be compared. |
| Absolute Survival Percentage | during 9 months of observation | Absolute survival in the two arms calculated by actuarial methods (Kaplan-Meier). These result in percent survival denoted as means and +/- standard error (these are detailed in the outcome table below). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo These subjects will receive i.v. placebo (5% dextrose in water) administered identically to the rituximab.
Placebo: Subjects randomized to placebo will receive two i.v. doses of 5% dextrose in water (D5W) in the same schedule as the rituximab subjects. The D5W and rituximab preparations will be indistinguishable. | 28 |
| Rituximab Rituximab i.v. given on two occasions, with 14 days between doses.
Rituximab: i.v. rituximab given on two occasions 14 days apart. | 30 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Transplant | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Rituximab |
|---|---|---|---|
| Age, Continuous | 70 years STANDARD_DEVIATION 7 | 69 years STANDARD_DEVIATION 7 | 68 years STANDARD_DEVIATION 7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 58 Participants | 30 Participants |
| Region of Enrollment United States | 28 participants | 58 participants | 30 participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 23 Participants | 46 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 28 | 2 / 30 |
| other Total, other adverse events | 21 / 28 | 24 / 30 |
| serious Total, serious adverse events | 5 / 28 | 9 / 30 |
Outcome results
Primary
Autoantibodies to Human Epidermoid (HEp)-2 Cells
Titers of anti-HEp-2 autoantibodies, by indirect immunofluorescence assays (IFA) over 9 months, month 9 reported. Titers represent the highest dilution of patient plasma wherein the autoantibodies can be detected. Higher titers denote greater autoantibody concentrations.
Time frame: baseline to 9 months
Population: 7 not analyzed: 4 deaths, 2 transplants, 1 dropout
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Autoantibodies to Human Epidermoid (HEp)-2 Cells | 288 titer | Standard Error 63 |
| Rituximab | Autoantibodies to Human Epidermoid (HEp)-2 Cells | 177 titer | Standard Error 29 |
Secondary
Absolute Survival Percentage
Absolute survival in the two arms calculated by actuarial methods (Kaplan-Meier). These result in percent survival denoted as means and +/- standard error (these are detailed in the outcome table below).
Time frame: during 9 months of observation
Population: 1 dropout (censored event)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Survival Percentage | 93 percent of participants | Standard Error 5 |
| Rituximab | Absolute Survival Percentage | 93 percent of participants | Standard Error 5 |
Secondary
Changes in Anti-Heat Shock Protein 70 (HSP70) Autoantibodies
Changes of anti-HSP70 plasma concentrations as determined by ELISA, month 9 reported. The result is expressed as optical density (OD) units. The greater the number; the more autoantibody.
Time frame: baseline to 9 months
Population: 7 not analyzed: 4 deaths, 2 transplants, 1 dropout
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Anti-Heat Shock Protein 70 (HSP70) Autoantibodies | 1.0 OD units | Standard Error 0.13 |
| Rituximab | Changes in Anti-Heat Shock Protein 70 (HSP70) Autoantibodies | 0.83 OD units | Standard Error 0.08 |
Secondary
Changes in Forced Vital Capacity (FVC)
FVC values over the observation period will be measured by spirometry, month 9 reported.
Time frame: baseline thru 9 months
Population: 7 not analyzed: 4 deaths, 2 transplants, 1 dropout
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Changes in Forced Vital Capacity (FVC) | 2.6 liters | Standard Error 0.14 |
| Rituximab | Changes in Forced Vital Capacity (FVC) | 2.5 liters | Standard Error 0.16 |
Secondary
Hospitalizations
The number of hospitalizations in the two arms will be compared.
Time frame: during 9 months of observation
Population: incomplete data on 1 dropout
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hospitalizations | 6 number of admissions |
| Rituximab | Hospitalizations | 12 number of admissions |
Secondary
Number of Acute Exacerbations
The number of acute exacerbations, defined using consensus criteria (new/worsened hypoxemia and dyspnea, with characteristic radiographic changes within the last 30 days).
Time frame: during the study duration of 9 months
Population: Data from 7 incomplete: 4 deaths, 2 transplants, 1 dropout
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Acute Exacerbations | 1 acute exacerbations |
| Rituximab | Number of Acute Exacerbations | 2 acute exacerbations |
Secondary
Number of Adverse Events (AE)
AE in the two treatment arms will be compared. Serious adverse events, as defined by national toxicity scale.
Time frame: during the 9 months of observation
Population: Data not complete in 7 due to 4 deaths, 2 transplants, 1 dropout
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Adverse Events (AE) | 7 serious adverse events |
| Rituximab | Number of Adverse Events (AE) | 12 serious adverse events |
Secondary
Transplant-Free Survival
Actuarial transplant-free survival in the two arms, calculated by actuarial methods (Kaplan-Meier). These result in percent survival denoted as means and +/- standard error (these are detailed in the outcome table below).
Time frame: during 9 months of observation
Population: 1 dropout
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Transplant-Free Survival | 89 percentage of participants | Standard Error 6 |
| Rituximab | Transplant-Free Survival | 90 percentage of participants | Standard Error 6 |