Interstitial Lung Disease, Myositis
Conditions
Keywords
ILD
Brief summary
A randomized, controlled pilot trial to evaluate the efficacy and safety of subcutaneous Abatacept in treating interstitial lung disease associated with the anti-synthetase syndrome.
Detailed description
This is a proof of concept study to evaluate the efficacy, safety and tolerability of abatacept in Syn-ILD in a multi-center randomized, placebo-controlled 6-month (24-week) pilot study.
Interventions
DRUGAbatacept
Abatacept 125mg subcutaneous weekly
OTHERPlacebo
Placebo
Sponsors
Bristol-Myers Squibb
Rohit Aggarwal, MD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Only the site pharmacist is unblinded.
Intervention model description
A 1:1 randomization scheme for abatacept 125 mg vs. placebo as a weekly subcutaneous (SQ) injection for 24 weeks.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years. 2. Anti-synthetase syndrome defined as the patient possessing 1 antisynthetase autoantibody (Jo-1, PL-12, PL-7, KS, OJ, EJ, Zo) in the presence of autoimmune ILD. 3. ILD defined by radiographic (HRCT chest) findings of reticulation, honeycombing or ground glass opacities (GGO) without another plausible explanation. HRCT chest defining ILD for inclusion criteria, should be within last 1 year done as SOC. 4. Active ILD (see Section 4.2). 5. Baseline FVC a) % \<80% b) FVC 80-100% with \> = 10% decline in FVC in last 12 months as minimal threshold of ILD severity (PFT done within last 3 months is acceptable for inclusion criteria determination) 6. SOC immunosuppressive therapy (IS) therapy: 1. Steroids (prednisone or other forms of steroid in equivalent doses) OR one of the other immunosuppressive agent (either Mycophenolate (MMF) or Azathioprine (AZA) OR a combination of steroid and an immunosuppressive agent. MMF (maximum of 3 gm/day) or azathioprine (maximum of 200 mg/day).Goal is to start the trial drug (or placebo) soon after starting SOC (MMF/AZA/Steroids) and their doses are stable. Note that patients on steroids alone as well as not on steroids can be enrolled in the trial as well. 2. Desired dose of the SOC therapy should be reached 4 weeks prior to first study visit (Visit 1). No dose changes are allowed 4 weeks prior to first study visit. 3. Dose of concomitant therapy (SOC) cannot be changed during the 24 weeks of the trial unless safety/toxicity issues supervene. 4. If on steroid, the steroid dose must be stable for 2 weeks prior to Visit 1. 7. No other concomitant IS medications including methotrexate, cyclosporine, intravenous immunoglobulin (IVIG), tacrolimus, cyclophosphamide or tofacitinib. 8. No concomitant biologic agents (i.e. rituximab, anti-tumor necrosis factor (TNF) agents, tocilizumab). 9. Additional IS therapy: Patient cannot begin any new IS therapy or new steroid taper for the 24-week study period, except if severe clinical worsening (flare up) of the disease requiring rescue therapy occurs (i.e. documentation of worsening of PFT/HRCT and patient and physician determination of worsening). See section of rescue medication below for details. 10. If the enrolling physician is planning to discontinue current IS agent or steroid before clinical trial, then following washout period is required prior to Visit 1. Medication Washout Period methotrexate 4 weeks Other IS agent (e.g. azathioprine, cyclosporine, tacrolimus, leflunomide, mycophenolate mofetil) 4 weeks IVIg or cyclophosphamide 3 months rituximab 6 months infliximab or adalimumab 8 weeks glucocorticoids 2 weeks etanercept 2 weeks anakinra 1 week pirfenidone 4 weeks 11. Men and women of reproductive potential must agree to use an acceptable method of birth control during the trial period. 12. Subject has provided written informed consent.
Exclusion criteria
A patient will be excluded if any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| % Predicted Forced Vital Capacity (FVC) Absolute Change | 24 Weeks | The primary outcome criteria for efficacy will be the absolute change of % predicted FVC from the baseline visit to week 24 between the 2 treatment arms (SOC/placebo vs. SOC/Abatacept). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression Free Survival | 48 weeks | The first occurrence of any of the following: death or lung transplantation or decline in % predicted FVC ≥ 10% or decline in % predicted FVC ≥ 5% with a decline in % predicted DLCO ≥ 15% |
| Comparison of Change in Patient Reported Dyspnea Scores (University of California San Diego Shortness of Breath Questionnaire) | 24 weeks | Measured by University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (range 0-120, higher score is worsening dyspnea). |
| Time to Improvement in % Predicted FVC ≥10% | 48 weeks | Comparison of percent predicted FVC results from pulmonary function tests from baseline to week 48. Improvement is defined as a % predicted FVC change ≥10% |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled from four clinical sites between June 2017 through May 2021.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subcutaneous placebo injection weekly for 24 weeks.
Placebo: Placebo | 11 |
| Abatacept Subcutaneous injection of abatacept 125 mg weekly for 24 weeks. 24 week optional follow up phase all subjects receive abatacept 125 mg weekly.
Abatacept: Abatacept 125mg subcutaneous weekly | 9 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open Label Extension | Adverse Event | 1 | 0 |
| Open Label Extension | Death | 0 | 1 |
| Open Label Extension | Lack of Efficacy | 1 | 0 |
| Randomized, Placebo-controlled | Lack of Efficacy | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Abatacept | Total |
|---|---|---|---|
| Age, Continuous | 55.95 years STANDARD_DEVIATION 6.87 | 51.56 years STANDARD_DEVIATION 10.69 | 53.98 years STANDARD_DEVIATION 8.83 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 9 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Forced Vital Capacity (FVC) % | 61.0 % | 66.0 % | 63.5 % |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 2 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 | 10 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 1 / 20 |
| other Total, other adverse events | 5 / 11 | 6 / 20 |
| serious Total, serious adverse events | 0 / 11 | 3 / 20 |
Outcome results
Primary
% Predicted Forced Vital Capacity (FVC) Absolute Change
The primary outcome criteria for efficacy will be the absolute change of % predicted FVC from the baseline visit to week 24 between the 2 treatment arms (SOC/placebo vs. SOC/Abatacept).
Time frame: 24 Weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | % Predicted Forced Vital Capacity (FVC) Absolute Change | -1.70 % predicted FVC |
| Abatacept | % Predicted Forced Vital Capacity (FVC) Absolute Change | -2.05 % predicted FVC |
Comparison: The null hypothesis for the change outcomes is µABT - µPlacebo = 0.p-value: <0.0595% CI: [-9.36, 4.26]Mixed Models Analysis
Secondary
Comparison of Change in Patient Reported Dyspnea Scores (University of California San Diego Shortness of Breath Questionnaire)
Measured by University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) (range 0-120, higher score is worsening dyspnea).
Time frame: 24 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Comparison of Change in Patient Reported Dyspnea Scores (University of California San Diego Shortness of Breath Questionnaire) | -4.59 score on a scale |
| Abatacept | Comparison of Change in Patient Reported Dyspnea Scores (University of California San Diego Shortness of Breath Questionnaire) | 3.20 score on a scale |
Comparison: The null hypothesis for the change outcomes is µABT - µPlacebo = 0.p-value: <0.0595% CI: [-8.8, 23.83]Mixed Models Analysis
Secondary
Time to Improvement in % Predicted FVC ≥10%
Comparison of percent predicted FVC results from pulmonary function tests from baseline to week 48. Improvement is defined as a % predicted FVC change ≥10%
Time frame: 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Improvement in % Predicted FVC ≥10% | 17.86 weeks |
| Abatacept | Time to Improvement in % Predicted FVC ≥10% | 11.86 weeks |
Comparison: The null hypothesis for the time to event outcomes is exp(bABT) / exp(bPlacebo) = 1.p-value: <0.0595% CI: [0.04, 4.02]Regression, Cox
Secondary
Time to Progression Free Survival
The first occurrence of any of the following: death or lung transplantation or decline in % predicted FVC ≥ 10% or decline in % predicted FVC ≥ 5% with a decline in % predicted DLCO ≥ 15%
Time frame: 48 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Progression Free Survival | 27.71 Weeks |
| Abatacept | Time to Progression Free Survival | 16.86 Weeks |
Comparison: The null hypothesis for the time to event outcomes is exp(bABT) / exp(bPlacebo) = 1.p-value: <0.0595% CI: [0.16, 2.77]Regression, Cox