Interstitial Lung Disease, Scleroderma
Conditions
Keywords
Systemic Sclerosis, Mycophenolate Mofetil, Cyclophosphamide, High Resolution Computerized Tomography, Pulmonary Function, Dyspnea, Health Related Quality of Life
Brief summary
Scleroderma is a rare, long-term autoimmune disease in which normal tissue is replaced with dense, thick fibrous tissue. Normally, the immune system helps defend the body against disease and infection. In people with scleroderma, the immune system triggers fibroblast cells to produce too much of the protein collagen. The extra collagen becomes deposited in the skin and organs, causing hardening and thickening that is similar to the scarring process. Although scleroderma most often affects the skin, it also can affect other parts of the body, including the lungs, and in its most severe forms scleroderma can be life-threatening. Scleroderma-related interstitial lung disease is one example of a life-threatening scleroderma condition. In people with symptomatic scleroderma-related interstitial lung disease, scarring occurs in the delicate lung tissue, compromising lung function. The purpose of this study is to determine whether people with symptomatic scleroderma-related interstitial lung disease experience more respiratory benefits from treatment with a 2-year course of mycophenolate mofetil or treatment with a 1-year course of oral cyclophosphamide.
Detailed description
Interstitial lung disease describes a condition in which the lung tissue has become scarred or inflamed. Interstitial lung disease caused by scleroderma, specifically seen as progressive pulmonary fibrosis, occurs in approximately 40 percent of patients with scleroderma and has emerged as the leading overall cause of death. In a previous study, the Scleroderma Lung Study I (SLS I), investigators evaluated a 1-year cyclophosphamide (CYC) treatment for people with scleroderma-related interstitial lung disease. The study results demonstrated statistically significant improvements in forced vital capacity, total lung capacity, dyspnea, Rodnan skin scores, and several measures of quality of life. However, when patients were followed for another year after completing their CYC therapy, the beneficial effects of CYC waned and were no longer significant by the 24-month follow-up. Preliminary information suggests that an alternative immunosuppressive medication, mycophenolate mofetil (MMF), may be effective in treating this disease, be given for longer periods, and result in fewer side effects. This study, the Scleroderma Lung Study II (SLS II), will compare the safety and efficacy of a 2-year treatment with MMF versus a 1-year treatment with CYC. Specifically, investigators will determine whether MMF produces similar or better improvements in lung capacity and fewer side effects throughout the entire 2-year period. Participation will include about 21 study visits over a 2-year period. Eligible participants will be randomly assigned to receive either MMF twice daily for 2 years or CYC once daily for 1 year, followed by placebo for 1 year. Blood and urine samples will be collected every 2 weeks for the first 2 months and then once a month for the remainder of the study. Every 3 months, participants will attend study visits that will include pulmonary function tests, blood and urine sampling, a physical exam, and questionnaires about current health and medications. At the final study visit, participants will also undergo a high resolution computerized tomography (HRCT) scan and possibly a punch biopsy.
Interventions
DRUGMycophenolate mofetil
24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated
DRUGCyclophosphamide
12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated
DRUGPlacebo
12 months of placebo will be delivered to participants in the Cyclophosphamide arm during the second year in order to maintain the blind with the Mycophenolate arm, which receives drug for the entire 2 years.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Hoffmann-La Roche
Michael Roth
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The presence of either limited (cutaneous thickening distal but not proximal to elbows and knees, with or without facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees, often involving the chest or abdomen) scleroderma, as determined by American College of Rheumatology criteria * Dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index) * FVC less than or equal to 80 percent of predicted value at screening and less than or equal to 85 percent predicted at baseline * Onset of the first non-Raynaud manifestation of SSc within the prior 84 months * Presence of any ground glass opacification on thoracic high resolution computerized tomography (HRCT) * Repeat FVC at the baseline visit (Visit 2) within 10 percent of the FVC measured at screening and less than or equal to 85 percent predicted.
Exclusion criteria
* FVC less than 45 percent of predicted value at either screening or baseline * Carbon monoxide diffusing capacity (DLCO) (HBg-corrected) less than 30 percent of predicted value and less than 40 percent of predicted when documentation of pulmonary artery pressures by echocardiogram, right heart catheterization or magnetic resonance imaging identifies clinically significant pulmonary hypertension. All participants with a DLCO less than 40 percent predicted must have documentation of pulmonary artery pressures in order to be considered for inclusion. * FEV1/FVC ratio less than 65 percent at either screening or baseline * Clinically significant abnormalities on HRCT not attributable to scleroderma * Diagnosis of clinically significant resting pulmonary hypertension requiring treatment, as ascertained before study evaluation or as part of a standard of care clinical assessment performed outside of the study protocol * Persistent unexplained hematuria (more than 10 red blood cells per high-power field \[RBCs/hpf\]) * History of persistent leukopenia (white blood cell count less than 4000) or thrombocytopenia (platelet count less than 150,000) * Clinically significant anemia (less than 10g/dl) * Baseline liver function test (LFTs) or bilirubin more than 1.5 times the upper limit of normal, other than that due to Gilbert's disease * Concomitant and present use of captopril * Serum creatinine more than 2.0mg/dL * Uncontrolled congestive heart failure * Pregnancy (documented by urine pregnancy test) and/or breast feeding * Prior use of oral CYC or MMF for more than 8 weeks or the receipt of more than two intravenous doses of CYC in the past * Use of CYC and/or MMF in the 30 days before random assignment * Active infection (lung or elsewhere) whose management would be compromised by CYC or MMF * Other serious concomitant medical illness (e.g., cancer), chronic debilitating illness (other than scleroderma), or unreliability or drug abuse that might compromise the patient's participation in the study * Current use, or use within the 30 days prior to random assignment, of prednisone (or equivalent) in doses of more than 10 mg/day * If of child bearing potential (a female participant \<55 years of age who has not been postmenopausal for \> 5 years and who has not had a hysterectomy and/or oophorectomy), failure to employ two reliable means of contraception (which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception). * Use of contraindicated medications; more information on this criterion can be found in the study protocol * Smoking of cigars, pipes, or cigarettes in the 6 months before study entry * Use of medications with putative disease-modifying properties within the past month (e.g., D-penicillamine, azathioprine, methotrexate, Potaba)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24 | The primary outcome is the course over time from baseline to 24 months for the FVC %-predicted. The FVC %-predicted represents the adjusted volume of air (adjusted as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity) that can be forcibly exhaled from the lungs after taking the deepest breath possible. The FVC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of lung involvement and disease severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24 | The DLCO is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLCO %-predicted represents the DLCO expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The DLCO %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity. |
| Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Measured at baseline and Month 24 | Imaging of the whole lung (WL) is performed using a volumetric high resolution computerized tomography (HRCT) scan, which is then analyzed using a computer algorithm to determine the percentage of overall pixels exhibiting features characteristic for quantitative lung fibrosis (QLF). Higher percentages for QLF-WL therefore represent greater involvement by lung fibrosis. |
| Transitional Dyspnea Index Score | Measured at Months 6, 12, 18, and 24 | Change in breathlessness was assessed using the Transitional Dyspnea Index, which compares current symptoms to those at baseline. Total score ranges from - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. |
| Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Measured at study entry and Months 6, 12, 18, and 24 | The TLC represents the total volume of air within the lung after taking the deepest breath possible and the TLC %-predicted represents the TLC expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The TLC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity. |
| Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24 | Skin thickness is quantified using the modified Rodnan measurement method (mRSS), with a scale that ranges from 0 (no skin involvement) to a maximum of 51. The reported skin score is determined by a clinical assessment of skin thickness, which is performed by a trained reader, and represents the sum of individual assessments that are made in each of 17 body areas. Each area is given a score in the range of 0-3 (0 = normal; 1= mild thickness; 2 = moderate; 3 = severe thickness). A higher score represents more severe skin involvement. |
| Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Measured throughout the 2-year study | — |
| Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Continuous assessment from randomization to 24 months | The number of participants who remained in the study at the listed time points are reported |
| Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24 | The HAQ-DI asks questions related to 8 activity domains (dressing, arising, eating, walking, hygiene, reach, grip, and common daily activities) with the patient's capacity to carry out each activity scored from 0 to 3. Scores across all domains are averaged and a higher score represents greater disability. |
Countries
United States
Participant flow
Recruitment details
Recruitment was carried out between September 28, 2009, and January 14, 2013, at 14 University Medical Centers within the United States.
Participants by arm
| Arm | Count |
|---|---|
| Mycophenolate Arm Participants will receive oral mycophenolate mofetil for 2 years.
Mycophenolate mofetil: 24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated | 69 |
| Cyclophosphamide Arm Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.
Cyclophosphamide: 12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated
Placebo: 12 months of placebo will be delivered to participants in the Cyclophosphamide arm during the second year in order to maintain the blind with the Mycophenolate arm, which receives drug for the entire 2 years. | 73 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 15 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Defined Treatment Failure | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Non-compliance | 3 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 9 |
Baseline characteristics
| Characteristic | Mycophenolate Arm | Cyclophosphamide Arm | Total |
|---|---|---|---|
| Age, Continuous | 52.6 years STANDARD_DEVIATION 9.7 | 52.0 years STANDARD_DEVIATION 9.8 | 52.3 years STANDARD_DEVIATION 9.7 |
| ANA(+) | 61 Participants | 66 Participants | 127 Participants |
| Centromere(+) | 1 Participants | 2 Participants | 3 Participants |
| Diffuse cutaneous scleroderma | 43 Participants | 40 Participants | 83 Participants |
| Duration of scleroderma | 2.6 years STANDARD_DEVIATION 1.7 | 2.5 years STANDARD_DEVIATION 1.8 | 2.6 years STANDARD_DEVIATION 1.8 |
| FEV1/FVC %-predicted | 81.0 Percent of predicted normal value STANDARD_DEVIATION 5.5 | 83.3 Percent of predicted normal value STANDARD_DEVIATION 5.6 | 82.6 Percent of predicted normal value STANDARD_DEVIATION 5.6 |
| FVC %-predicted | 66.5 Percent of predicted normal value STANDARD_DEVIATION 9.1 | 66.5 Percent of predicted normal value STANDARD_DEVIATION 8.3 | 66.5 Percent of predicted normal value STANDARD_DEVIATION 9.9 |
| HAQ disability index | 0.7 Score STANDARD_DEVIATION 0.6 | 0.7 Score STANDARD_DEVIATION 0.7 | 0.7 Score STANDARD_DEVIATION 0.7 |
| Limited cutaneous scleroderma | 26 Participants | 33 Participants | 59 Participants |
| Mahler Dyspnea Index, mean focal score | 7.3 Score STANDARD_DEVIATION 2.1 | 7.1 Score STANDARD_DEVIATION 2.3 | 7.2 Score STANDARD_DEVIATION 2.2 |
| modified-Rodnan Skin Score | 15.3 Score STANDARD_DEVIATION 10.4 | 14.0 Score STANDARD_DEVIATION 10.6 | 14.7 Score STANDARD_DEVIATION 10.5 |
| Quantitative extent of lung fibrosis on HRCT, for lobe of maximum involvement | 23.0 Score STANDARD_DEVIATION 20.2 | 22.6 Score STANDARD_DEVIATION 19.3 | 22.8 Score STANDARD_DEVIATION 19.6 |
| Quantitative extent of lung fibrosis on HRCT, for whole lung | 8.3 Score STANDARD_DEVIATION 6.9 | 8.9 Score STANDARD_DEVIATION 7 | 8.6 Score STANDARD_DEVIATION 6.9 |
| Quantitative extent of total insterstitial lung disease on HRCT, for lobe of maximum involvement | 50.0 Score STANDARD_DEVIATION 20.9 | 52.3 Score STANDARD_DEVIATION 19.9 | 51.2 Score STANDARD_DEVIATION 20.3 |
| Quantitative extent of total insterstitial lung disease on HRCT, for whole lung | 27.2 Score STANDARD_DEVIATION 13.2 | 31.6 Score STANDARD_DEVIATION 14.4 | 29.5 Score STANDARD_DEVIATION 14 |
| RNA Polymerase(+) | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Female | 48 Participants | 57 Participants | 105 Participants |
| Sex: Female, Male Male | 21 Participants | 16 Participants | 37 Participants |
| SF-36 Mental component | 49.1 Score STANDARD_DEVIATION 7.9 | 49.8 Score STANDARD_DEVIATION 10 | 49.4 Score STANDARD_DEVIATION 9 |
| SF-36 Physical component | 36.0 Score STANDARD_DEVIATION 10 | 35.6 Score STANDARD_DEVIATION 9.8 | 35.8 Score STANDARD_DEVIATION 9.9 |
| Single-Breath Diffusing Capacity | 60.9 Percent of predicted normal value STANDARD_DEVIATION 11.8 | 61.0 Percent of predicted normal value STANDARD_DEVIATION 13.7 | 60.9 Percent of predicted normal value STANDARD_DEVIATION 12.8 |
| Topoisomerase-1(+) | 29 Participants | 32 Participants | 61 Participants |
| Total Lung Capacity | 66.3 Percent of predicted normal value STANDARD_DEVIATION 10 | 65.5 Percent of predicted normal value STANDARD_DEVIATION 12 | 65.8 Percent of predicted normal value STANDARD_DEVIATION 11.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 69 | 71 / 73 |
| serious Total, serious adverse events | 27 / 69 | 22 / 73 |
Outcome results
Primary
Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
The primary outcome is the course over time from baseline to 24 months for the FVC %-predicted. The FVC %-predicted represents the adjusted volume of air (adjusted as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity) that can be forcibly exhaled from the lungs after taking the deepest breath possible. The FVC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of lung involvement and disease severity.
Time frame: Measured at study Baseline and Months 3, 6, 12, 15, 18, 21, and 24
Population: Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 66.52 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 9 | 68.11 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 69.65 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 68.43 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 15 | 69.84 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 3 | 66.22 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 70.57 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 21 | 70.87 FVC %-pred |
| Mycophenolate Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 68.02 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 21 | 72.55 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 70.15 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 66.52 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 3 | 67.03 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 67.86 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 9 | 69.42 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 15 | 71.94 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 72.57 FVC %-pred |
| Cyclophosphamide Arm | Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 69.86 FVC %-pred |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in the FVC %-predicted. Covariates were %-predicted FVC, HRCT-defined extent of lung fibrosis in the lobe of maximum involvement, and terms for time-trend, treatment and treatment-time trend interactions.p-value: 0.24Mixed Models Analysis
Comparison: The inferential joint model, as described for the primary analysis, was used to estimate the change from baseline to 24 months for the FVC %-predicted for each treatment arm independently.p-value: <0.05Mixed Models Analysis
Comparison: Based on the absolute difference between the value of FVC %-predicted at baseline and at 24 months for each subject who returned for a 24-month assessment, a frequency distributions was prepared, stratified by treatment arm, to assess the relative distribution of subjects who either had improvements or worsening in the FVC %-predicted.p-value: 0.55Fisher Exact
Secondary
Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT)
Imaging of the whole lung (WL) is performed using a volumetric high resolution computerized tomography (HRCT) scan, which is then analyzed using a computer algorithm to determine the percentage of overall pixels exhibiting features characteristic for quantitative lung fibrosis (QLF). Higher percentages for QLF-WL therefore represent greater involvement by lung fibrosis.
Time frame: Measured at baseline and Month 24
Population: Analysis was carried out in the subset of subjects that had measurable HRCT scans at both study entry and 24 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Baseline | 8.25 % of lung exhibiting QLF |
| Mycophenolate Arm | Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Month 24 | 7.99 % of lung exhibiting QLF |
| Cyclophosphamide Arm | Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Baseline | 8.91 % of lung exhibiting QLF |
| Cyclophosphamide Arm | Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT) | Month 24 | 8.48 % of lung exhibiting QLF |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in the Quantitative Lung Fibrosis Score for the whole lung (QLF-WL).p-value: >0.05Mixed Models Analysis
Secondary
Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI)
The HAQ-DI asks questions related to 8 activity domains (dressing, arising, eating, walking, hygiene, reach, grip, and common daily activities) with the patient's capacity to carry out each activity scored from 0 to 3. Scores across all domains are averaged and a higher score represents greater disability.
Time frame: Measured at study entry and Months 3, 6, 9, 12, 15, 18, 21, and 24
Population: The analysis population contains all of those with data available at the defined time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 3 | 0.83 HAQ-DI Total Score | Standard Deviation 0.72 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 15 | 0.58 HAQ-DI Total Score | Standard Deviation 0.62 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 9 | 0.66 HAQ-DI Total Score | Standard Deviation 0.66 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 18 | 0.55 HAQ-DI Total Score | Standard Deviation 0.55 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 6 | 0.75 HAQ-DI Total Score | Standard Deviation 0.71 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 21 | 0.65 HAQ-DI Total Score | Standard Deviation 0.65 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 12 | 0.64 HAQ-DI Total Score | Standard Deviation 0.67 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 24 | 0.62 HAQ-DI Total Score | Standard Deviation 0.69 |
| Mycophenolate Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline | 0.71 HAQ-DI Total Score | Standard Deviation 0.62 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 24 | 0.57 HAQ-DI Total Score | Standard Deviation 0.68 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Baseline | 0.74 HAQ-DI Total Score | Standard Deviation 0.73 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 3 | 0.64 HAQ-DI Total Score | Standard Deviation 0.67 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 6 | 0.58 HAQ-DI Total Score | Standard Deviation 0.65 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 9 | 0.65 HAQ-DI Total Score | Standard Deviation 0.62 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 12 | 0.56 HAQ-DI Total Score | Standard Deviation 0.6 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 15 | 0.62 HAQ-DI Total Score | Standard Deviation 0.63 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 18 | 0.55 HAQ-DI Total Score | Standard Deviation 0.66 |
| Cyclophosphamide Arm | Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI) | Month 21 | 0.48 HAQ-DI Total Score | Standard Deviation 0.53 |
Secondary
Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
The DLCO is a pulmonary function test that measures the capacity for the lung to carry out gas exchange between the inhaled breath and the pulmonary capillary blood vessels and the DLCO %-predicted represents the DLCO expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The DLCO %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity.
Time frame: Measured at study entry and Months 3, 6, 12, 15, 18, 21, and 24
Population: Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 55.32 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 3 | 53.38 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 15 | 57.77 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 53.99 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 56.62 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 21 | 55.47 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 54.86 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 55.31 DLCO %-pred |
| Mycophenolate Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 9 | 54.13 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 52.90 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 9 | 51.55 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 55.9 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 54.05 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 3 | 51.92 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 50.87 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 53.12 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 15 | 53.62 DLCO %-pred |
| Cyclophosphamide Arm | Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 21 | 54.26 DLCO %-pred |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in the DLCO %-predicted.p-value: <0.001Mixed Models Analysis
Comparison: The inferential joint model, as described for the primary analysis, was used to estimate the change from baseline to 24 months for the DLCO %-predicted for each treatment arm independently.p-value: >0.05Mixed Models Analysis
Secondary
Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS)
Skin thickness is quantified using the modified Rodnan measurement method (mRSS), with a scale that ranges from 0 (no skin involvement) to a maximum of 51. The reported skin score is determined by a clinical assessment of skin thickness, which is performed by a trained reader, and represents the sum of individual assessments that are made in each of 17 body areas. Each area is given a score in the range of 0-3 (0 = normal; 1= mild thickness; 2 = moderate; 3 = severe thickness). A higher score represents more severe skin involvement.
Time frame: Measured at baseline and Months 3, 6, 9, 12, 15, 18, 21, and 24
Population: Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Baseline | 15.32 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 15 | 12.43 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 12 | 12.45 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 18 | 11.98 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 3 | 16.03 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 21 | 11.22 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 6 | 14.37 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 24 | 11.40 mRSS score |
| Mycophenolate Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 9 | 14.33 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 24 | 7.87 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 12 | 9.47 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Baseline | 14.04 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 6 | 11.95 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 9 | 10.61 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 15 | 9.80 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 18 | 9.87 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 21 | 8.50 mRSS score |
| Cyclophosphamide Arm | Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS) | Month 3 | 12.85 mRSS score |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in modified Rodnan Skin Score (mRSS).p-value: >0.05Mixed Models Analysis
Comparison: The inferential joint model, as described for the primary analysis, was used to estimate the change from baseline to 24 months for the modified Rodnan Skin Score for each treatment arm independently.p-value: <0.05Mixed Models Analysis
Comparison: Based on the absolute difference between the value of the mRSS at baseline and at 24 months for each subject who returned for a 24-month assessment, a frequency distributions was prepared, stratified by treatment arm, to assess the relative distribution of subjects who either had improvements or worsening in the mRSS.p-value: >0.05Fisher Exact
Secondary
Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure.
The number of participants who remained in the study at the listed time points are reported
Time frame: Continuous assessment from randomization to 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 9 | 55 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 3 | 66 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 12 | 52 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Baseline | 69 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 15 | 52 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 21 | 49 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 6 | 58 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 24 | 49 Participants |
| Mycophenolate Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 18 | 49 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 24 | 38 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 18 | 42 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Baseline | 73 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 3 | 64 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 6 | 56 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 9 | 51 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 12 | 46 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 21 | 39 Participants |
| Cyclophosphamide Arm | Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure. | Month 15 | 44 Participants |
Comparison: A log-rank test was utilized to assess differences between the MMF and CYC treatment arms with respect to the time to withdrawal from study drug or meeting protocol-defined criteria for treatment failure.p-value: 0.019Log Rank
Secondary
Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
The TLC represents the total volume of air within the lung after taking the deepest breath possible and the TLC %-predicted represents the TLC expressed as a percentage of the expected normal valued based on the participant's age, height, gender and ethnicity. The TLC %-predicted is reduced in patients with interstitial lung disease and is used as a measure of disease severity.
Time frame: Measured at study entry and Months 6, 12, 18, and 24
Population: Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 67.84 TLC %-pred |
| Mycophenolate Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 68.50 TLC %-pred |
| Mycophenolate Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 66.16 TLC %-pred |
| Mycophenolate Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 68.24 TLC %-pred |
| Mycophenolate Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 67.31 TLC %-pred |
| Cyclophosphamide Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 24 | 66.97 TLC %-pred |
| Cyclophosphamide Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 6 | 67.39 TLC %-pred |
| Cyclophosphamide Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 12 | 68.25 TLC %-pred |
| Cyclophosphamide Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Month 18 | 69.63 TLC %-pred |
| Cyclophosphamide Arm | Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value | Baseline | 65.49 TLC %-pred |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in the TLC %-predicted.p-value: >0.05Mixed Models Analysis
Secondary
Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death
Time frame: Measured throughout the 2-year study
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Neutropenia (<1.0x10^3 neutrophils/microliter) | 3 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Pneumonia | 5 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Thrombocytopenia (<100x10^3 platelets/microliter) | 0 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | SAE-Total | 27 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Anemia (Hgb <10 g/dl) | 8 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | SAE-related to treatment | 3 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Hematuria (>10 RBC/high power field) | 3 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Deaths | 5 Participants |
| Mycophenolate Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Leukopenia (<2.5x10^3 WBC/microliter) | 4 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Deaths | 11 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Leukopenia (<2.5x10^3 WBC/microliter) | 30 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Neutropenia (<1.0x10^3 neutrophils/microliter) | 7 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Anemia (Hgb <10 g/dl) | 13 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Thrombocytopenia (<100x10^3 platelets/microliter) | 4 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Hematuria (>10 RBC/high power field) | 2 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | Pneumonia | 4 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | SAE-Total | 22 Participants |
| Cyclophosphamide Arm | Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death | SAE-related to treatment | 7 Participants |
Comparison: Fisher's Exact Test was utilized to compare the number of participants with a protocol-defined adverse event of interest, SAE or death between the MMF and CYC treatment arms.p-value: <0.05Fisher Exact
Secondary
Transitional Dyspnea Index Score
Change in breathlessness was assessed using the Transitional Dyspnea Index, which compares current symptoms to those at baseline. Total score ranges from - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea.
Time frame: Measured at Months 6, 12, 18, and 24
Population: Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mycophenolate Arm | Transitional Dyspnea Index Score | Month 6 | 0.74 Transitional Dyspnea Index Score |
| Mycophenolate Arm | Transitional Dyspnea Index Score | Month 18 | 0.91 Transitional Dyspnea Index Score |
| Mycophenolate Arm | Transitional Dyspnea Index Score | Month 12 | 1.17 Transitional Dyspnea Index Score |
| Mycophenolate Arm | Transitional Dyspnea Index Score | Month 24 | 1.86 Transitional Dyspnea Index Score |
| Cyclophosphamide Arm | Transitional Dyspnea Index Score | Month 12 | 1.23 Transitional Dyspnea Index Score |
| Cyclophosphamide Arm | Transitional Dyspnea Index Score | Month 6 | 0.31 Transitional Dyspnea Index Score |
| Cyclophosphamide Arm | Transitional Dyspnea Index Score | Month 24 | 2.09 Transitional Dyspnea Index Score |
| Cyclophosphamide Arm | Transitional Dyspnea Index Score | Month 18 | 1.78 Transitional Dyspnea Index Score |
Comparison: A modified intention-to-treat inferential joint model combined a mixed-effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data due to study dropout, treatment failure, or death, to assess the course over time, from baseline to 24 months, for the change in dyspnea as measured by the Transitional Dyspnea Index Score.p-value: >0.05Mixed Models Analysis
Comparison: The inferential joint model, as described for the primary analysis, was used to estimate the change from baseline to 24 months for dyspnea using the Transitional Dyspnea Index Score for each treatment arm independently.p-value: <0.05Mixed Models Analysis