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Comparison of Therapeutic Regimens for Scleroderma Interstitial Lung Disease (The Scleroderma Lung Study II) (SLSII)

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ClinicalTrials.gov Identifier: NCT00883129
Recruitment Status : Completed
First Posted : April 17, 2009
Results First Posted : February 10, 2017
Last Update Posted : February 10, 2017
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Hoffmann-La Roche
Information provided by (Responsible Party):
Michael Roth, University of California, Los Angeles

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Scleroderma
Interstitial Lung Disease
Interventions Drug: Mycophenolate mofetil
Drug: Cyclophosphamide
Drug: Placebo
Enrollment 142
Recruitment Details Recruitment was carried out between September 28, 2009, and January 14, 2013, at 14 University Medical Centers within the United States.
Pre-assignment Details  
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description

Participants treated with 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

Participants treated with 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.

Period Title: Overall Study
Started 69 73
Completed 49 [1] 37 [2]
Not Completed 20 36
Reason Not Completed
Adverse Event             7             15
Withdrawal by Subject             8             9
Non-compliance             3             6
Lost to Follow-up             1             2
Death             1             2
Defined Treatment Failure             0             2
[1]
53 subjects provided a 24 month outcome, 4 of whom had prematurely withdrawn from drug treatment.
[2]
53 subjects provided a 24 month outcome, 16 of whom had prematurely withdrawn from drug treatment.
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm Total
Hide Arm/Group Description

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

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.

Total of all reporting groups
Overall Number of Baseline Participants 69 73 142
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 69 participants 73 participants 142 participants
52.6  (9.7) 52.0  (9.8) 52.3  (9.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 73 participants 142 participants
Female
48
  69.6%
57
  78.1%
105
  73.9%
Male
21
  30.4%
16
  21.9%
37
  26.1%
Duration of scleroderma   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 67 participants 72 participants 139 participants
2.6  (1.7) 2.5  (1.8) 2.6  (1.8)
[1]
Measure Analysis Population Description: Only participants with available data included
Limited cutaneous scleroderma  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 73 participants 142 participants
26
  37.7%
33
  45.2%
59
  41.5%
Diffuse cutaneous scleroderma  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 73 participants 142 participants
43
  62.3%
40
  54.8%
83
  58.5%
modified-Rodnan Skin Score   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 69 participants 73 participants 142 participants
15.3  (10.4) 14.0  (10.6) 14.7  (10.5)
[1]
Measure Description: Skin score may range 0-51, with higher scores indicating more severe thickening
FVC %-predicted  
Mean (Standard Deviation)
Unit of measure:  Percent of predicted normal value
Number Analyzed 69 participants 73 participants 142 participants
66.5  (9.1) 66.5  (8.3) 66.5  (9.9)
FEV1/FVC %-predicted  
Mean (Standard Deviation)
Unit of measure:  Percent of predicted normal value
Number Analyzed 69 participants 73 participants 142 participants
81.0  (5.5) 83.3  (5.6) 82.6  (5.6)
Total Lung Capacity  
Mean (Standard Deviation)
Unit of measure:  Percent of predicted normal value
Number Analyzed 69 participants 73 participants 142 participants
66.3  (10.0) 65.5  (12.0) 65.8  (11.1)
Single-Breath Diffusing Capacity  
Mean (Standard Deviation)
Unit of measure:  Percent of predicted normal value
Number Analyzed 69 participants 73 participants 142 participants
60.9  (11.8) 61.0  (13.7) 60.9  (12.8)
Mahler Dyspnea Index, mean focal score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 65 participants 68 participants 133 participants
7.3  (2.1) 7.1  (2.3) 7.2  (2.2)
[1]
Measure Description: Scores range 0-12, with lower scores indicating worse dyspnea
[2]
Measure Analysis Population Description: Only participants with available data included
SF-36 Physical component   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 69 participants 73 participants 142 participants
36.0  (10.0) 35.6  (9.8) 35.8  (9.9)
[1]
Measure Description: Score range 0-100, with lower scores indicating worse health status
SF-36 Mental component   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 69 participants 73 participants 142 participants
49.1  (7.9) 49.8  (10.0) 49.4  (9.0)
[1]
Measure Description: Score range 0-100, with lower scores indicating worse health status
HAQ disability index   [1] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 69 participants 73 participants 142 participants
0.7  (0.6) 0.7  (0.7) 0.7  (0.7)
[1]
Measure Description: Score range 0-3, with higher scores indicating greater disability
Quantitative extent of lung fibrosis on HRCT, for whole lung   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 66 participants 71 participants 137 participants
8.3  (6.9) 8.9  (7.0) 8.6  (6.9)
[1]
Measure Description: Score range 0 to 100, with higher score indicating greater lung involvement
[2]
Measure Analysis Population Description: Only participants with available data included
Quantitative extent of lung fibrosis on HRCT, for lobe of maximum involvement   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 66 participants 71 participants 137 participants
23.0  (20.2) 22.6  (19.3) 22.8  (19.6)
[1]
Measure Description: Score range 0 to 100, with higher score indicating greater lung involvement
[2]
Measure Analysis Population Description: Only participants with available data included
Quantitative extent of total insterstitial lung disease on HRCT, for whole lung   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 66 participants 71 participants 137 participants
27.2  (13.2) 31.6  (14.4) 29.5  (14.0)
[1]
Measure Description: Score range 0 to 100, with higher score indicating greater lung involvement
[2]
Measure Analysis Population Description: Only participants with available data included
Quantitative extent of total insterstitial lung disease on HRCT, for lobe of maximum involvement   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Score
Number Analyzed 66 participants 71 participants 137 participants
50.0  (20.9) 52.3  (19.9) 51.2  (20.3)
[1]
Measure Description: Score range 0 to 100, with higher score indicating greater lung involvement
[2]
Measure Analysis Population Description: Only participants with available data included
ANA(+)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 71 participants 134 participants
61
  96.8%
66
  93.0%
127
  94.8%
[1]
Measure Analysis Population Description: Only participants with available data included
Topoisomerase-1(+)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 71 participants 134 participants
29
  46.0%
32
  45.1%
61
  45.5%
[1]
Measure Analysis Population Description: Only participants with available data included
RNA Polymerase(+)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 71 participants 134 participants
9
  14.3%
9
  12.7%
18
  13.4%
[1]
Measure Analysis Population Description: Only participants with available data included
Centromere(+)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 63 participants 71 participants 134 participants
1
   1.6%
2
   2.8%
3
   2.2%
[1]
Measure Analysis Population Description: Only participants with available data included
1.Primary Outcome
Title Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: FVC %-pred
Baseline Number Analyzed 69 participants 73 participants
66.52
(64.55 to 68.49)
66.52
(64.22 to 68.82)
Month 3 Number Analyzed 69 participants 73 participants
66.22
(64.08 to 69.42)
67.03
(64.64 to 69.42)
Month 6 Number Analyzed 60 participants 56 participants
68.02
(65.55 to 70.49)
67.86
(65.27 to 70.45)
Month 9 Number Analyzed 54 participants 51 participants
68.11
(65.55 to 70.67)
69.42
(66.34 to 72.50)
Month 12 Number Analyzed 59 participants 51 participants
68.43
(65.48 to 71.38)
69.86
(66.82 to 72.90)
Month 15 Number Analyzed 51 participants 44 participants
69.84
(67.14 to 72.54)
71.94
(68.40 to 75.48)
Month 18 Number Analyzed 49 participants 46 participants
70.57
(67.57 to 73.57)
72.57
(69.53 to 75.61)
Month 21 Number Analyzed 47 participants 40 participants
70.87
(67.91 to 73.83)
72.55
(69.18 to 75.92)
Month 24 Number Analyzed 53 participants 51 participants
69.65
(66.53 to 72.77)
70.15
(66.88 to 73.42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.24
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.55
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Fisher Exact
Comments [Not Specified]
2.Secondary Outcome
Title Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: TLC %-pred
Baseline Number Analyzed 69 participants 73 participants
66.16
(63.74 to 68.58)
65.49
(62.72 to 68.26)
Month 6 Number Analyzed 60 participants 56 participants
67.84
(65.35 to 70.33)
67.39
(64.30 to 70.48)
Month 12 Number Analyzed 57 participants 54 participants
67.31
(64.45 to 70.17)
68.25
(64.93 to 71.57)
Month 18 Number Analyzed 49 participants 46 participants
68.50
(65.45 to 71.55)
69.63
(65.65 to 73.61)
Month 24 Number Analyzed 53 participants 51 participants
68.24
(64.99 to 71.49)
66.97
(63.42 to 70.52)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
3.Secondary Outcome
Title Single-breath Diffusing Capacity for Carbon Monoxide (DLCO), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: DLCO %-pred
Baseline Number Analyzed 69 participants 73 participants
53.99
(51.35 to 56.63)
54.05
(50.80 to 57.30)
Month 3 Number Analyzed 62 participants 64 participants
53.38
(50.48 to 56.28)
51.92
(48.34 to 55.50)
Month 6 Number Analyzed 60 participants 56 participants
54.86
(51.27 to 58.45)
50.87
(46.84 to 56.28)
Month 9 Number Analyzed 54 participants 50 participants
54.13
(50.50 to 57.76)
51.55
(47.09 to 56.01)
Month 12 Number Analyzed 58 participants 51 participants
55.32
(51.31 to 59.33)
53.12
(48.38 to 57.86)
Month 15 Number Analyzed 51 participants 44 participants
57.77
(54.20 to 61.34)
53.62
(48.29 to 58.95)
Month 18 Number Analyzed 49 participants 44 participants
56.62
(52.84 to 60.40)
55.9
(50.82 to 60.98)
Month 21 Number Analyzed 47 participants 40 participants
55.47
(51.39 to 59.55)
54.26
(49.29 to 59.23)
Month 24 Number Analyzed 52 participants 48 participants
55.31
(51.64 to 58.98)
52.90
(48.71 to 57.09)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
4.Secondary Outcome
Title Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Analysis was carried out in the subset of subjects that had measurable HRCT scans at both study entry and 24 months
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: % of lung exhibiting QLF
Baseline Number Analyzed 66 participants 71 participants
8.25
(6.58 to 9.92)
8.91
(7.26 to 10.56)
Month 24 Number Analyzed 51 participants 47 participants
7.99
(6.14 to 9.84)
8.48
(6.33 to 10.63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm
Comments 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).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
5.Secondary Outcome
Title Transitional Dyspnea Index Score
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: Transitional Dyspnea Index Score
Month 6 Number Analyzed 52 participants 50 participants
0.74
(-0.07 to 1.55)
0.31
(-0.43 to 1.05)
Month 12 Number Analyzed 49 participants 47 participants
1.17
(0.23 to 2.11)
1.23
(0.14 to 2.32)
Month 18 Number Analyzed 42 participants 35 participants
0.91
(-0.01 to 1.83)
1.78
(0.47 to 3.09)
Month 24 Number Analyzed 40 participants 39 participants
1.86
(0.62 to 3.10)
2.09
(0.80 to 3.38)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
6.Secondary Outcome
Title Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The analysis population contains all of those with data available at the defined time point.
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (Standard Deviation)
Unit of Measure: HAQ-DI Total Score
Baseline Number Analyzed 69 participants 73 participants
0.71  (0.62) 0.74  (0.73)
Month 3 Number Analyzed 66 participants 65 participants
0.83  (0.72) 0.64  (0.67)
Month 6 Number Analyzed 60 participants 58 participants
0.75  (0.71) 0.58  (0.65)
Month 9 Number Analyzed 54 participants 55 participants
0.66  (0.66) 0.65  (0.62)
Month 12 Number Analyzed 58 participants 55 participants
0.64  (0.67) 0.56  (0.60)
Month 15 Number Analyzed 51 participants 45 participants
0.58  (0.62) 0.62  (0.63)
Month 18 Number Analyzed 50 participants 47 participants
0.55  (0.55) 0.55  (0.66)
Month 21 Number Analyzed 49 participants 40 participants
0.65  (0.65) 0.48  (0.53)
Month 24 Number Analyzed 53 participants 53 participants
0.62  (0.69) 0.57  (0.68)
7.Secondary Outcome
Title Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Randomized participants with an acceptable baseline HRCT study (a pre-specified covariate) and at least one outcome measure
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Mean (95% Confidence Interval)
Unit of Measure: mRSS score
Baseline Number Analyzed 69 participants 73 participants
15.32
(12.85 to 17.79)
14.04
(11.58 to 16.50)
Month 3 Number Analyzed 65 participants 65 participants
16.03
(13.44 to 18.62)
12.85
(10.17 to 15.53)
Month 6 Number Analyzed 60 participants 58 participants
14.37
(11.75 to 16.99)
11.95
(9.27 to 14.63)
Month 9 Number Analyzed 54 participants 54 participants
14.33
(11.62 to 17.04)
10.61
(8.27 to 12.95)
Month 12 Number Analyzed 58 participants 55 participants
12.45
(10.05 to 14.85)
9.47
(7.35 to 11.59)
Month 15 Number Analyzed 51 participants 45 participants
12.43
(10.08 to 14.78)
9.80
(7.66 to 11.94)
Month 18 Number Analyzed 50 participants 47 participants
11.98
(9.48 to 14.48)
9.87
(7.60 to 12.14)
Month 21 Number Analyzed 49 participants 40 participants
11.22
(8.74 to 13.70)
8.50
(6.19 to 10.81)
Month 24 Number Analyzed 53 participants 53 participants
11.40
(8.91 to 13.89)
7.87
(5.85 to 9.89)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Fisher Exact
Comments [Not Specified]
8.Secondary Outcome
Title Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death
Hide Description [Not Specified]
Time Frame Measured throughout the 2-year study
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Measure Type: Count of Participants
Unit of Measure: Participants
Leukopenia (<2.5x10^3 WBC/microliter)
4
   5.8%
30
  41.1%
Neutropenia (<1.0x10^3 neutrophils/microliter)
3
   4.3%
7
   9.6%
Anemia (Hgb <10 g/dl)
8
  11.6%
13
  17.8%
Thrombocytopenia (<100x10^3 platelets/microliter)
0
   0.0%
4
   5.5%
Hematuria (>10 RBC/high power field)
3
   4.3%
2
   2.7%
Pneumonia
5
   7.2%
4
   5.5%
SAE-Total
27
  39.1%
22
  30.1%
SAE-related to treatment
3
   4.3%
7
   9.6%
Deaths
5
   7.2%
11
  15.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.05
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Fisher Exact
Comments The threshold for statistical significance was met only for the frequency of leukopenia and thrombocytopenia, but not for total SAE or death.
9.Secondary Outcome
Title Tolerability, as Assessed by the Time to Withdrawal From the Study Drug or Meeting Protocol-defined Criteria for Treatment Failure.
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description:

Participants treated with 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

Participants treated with 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.

Overall Number of Participants Analyzed 69 73
Measure Type: Count of Participants
Unit of Measure: Participants
Baseline
69
 100.0%
73
 100.0%
Month 3
66
  95.7%
64
  87.7%
Month 6
58
  84.1%
56
  76.7%
Month 9
55
  79.7%
51
  69.9%
Month 12
52
  75.4%
46
  63.0%
Month 15
52
  75.4%
44
  60.3%
Month 18
49
  71.0%
42
  57.5%
Month 21
49
  71.0%
39
  53.4%
Month 24
49
  71.0%
38
  52.1%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Mycophenolate Arm, Cyclophosphamide Arm
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.019
Comments The threshold for statistical significance was a P-Value of </=0.05.
Method Log Rank
Comments [Not Specified]
Time Frame Randomization to withdrawal from taking study drug or completion of the 24 month treatment protocol.
Adverse Event Reporting Description An organ system designation was developed for the study and applied in a systematic manner to all adverse event assessments
 
Arm/Group Title Mycophenolate Arm Cyclophosphamide Arm
Hide Arm/Group Description

Participants treated with 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

Participants treated with 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.

All-Cause Mortality
Mycophenolate Arm Cyclophosphamide Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Mycophenolate Arm Cyclophosphamide Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   27/69 (39.13%)   22/73 (30.14%) 
Blood and lymphatic system disorders     
Hematologic   1/69 (1.45%)  2/73 (2.74%) 
Cardiac disorders     
Cardiac   8/69 (11.59%)  8/73 (10.96%) 
Gastrointestinal disorders     
Gastrointestinal   2/69 (2.90%)  4/73 (5.48%) 
General disorders     
Weakness   0/69 (0.00%)  1/73 (1.37%) 
Infections and infestations     
Respiratory Infection   2/69 (2.90%)  7/73 (9.59%) 
Abscess   1/69 (1.45%)  0/73 (0.00%) 
Injury, poisoning and procedural complications     
Medication Reaction   1/69 (1.45%)  0/73 (0.00%) 
Injury   1/69 (1.45%)  0/73 (0.00%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal   4/69 (5.80%)  3/73 (4.11%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer   2/69 (2.90%)  1/73 (1.37%) 
Nervous system disorders     
Syncope and Seizure   2/69 (2.90%)  0/73 (0.00%) 
Renal and urinary disorders     
Renal and Bladder   1/69 (1.45%)  1/73 (1.37%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory Events   7/69 (10.14%)  5/73 (6.85%) 
Surgical and medical procedures     
Elective Surgery   2/69 (2.90%)  0/73 (0.00%) 
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Mycophenolate Arm Cyclophosphamide Arm
Affected / at Risk (%) Affected / at Risk (%)
Total   68/69 (98.55%)   71/73 (97.26%) 
Blood and lymphatic system disorders     
Blood and Lymphatic   20/69 (28.99%)  47/73 (64.38%) 
Cardiac disorders     
Cardiac   18/69 (26.09%)  21/73 (28.77%) 
Ear and labyrinth disorders     
Vision and hearing   2/69 (2.90%)  6/73 (8.22%) 
Gastrointestinal disorders     
Gastrointestinal   47/69 (68.12%)  40/73 (54.79%) 
General disorders     
General   31/69 (44.93%)  33/73 (45.21%) 
Hepatobiliary disorders     
Hepatobiliary   6/69 (8.70%)  4/73 (5.48%) 
Immune system disorders     
Immune disorder   2/69 (2.90%)  4/73 (5.48%) 
Infections and infestations     
Infections and Infestations   52/69 (75.36%)  57/73 (78.08%) 
Injury, poisoning and procedural complications     
Injury, Poisoning and Procedural   8/69 (11.59%)  10/73 (13.70%) 
Metabolism and nutrition disorders     
Metabolism and Nutrition   11/69 (15.94%)  22/73 (30.14%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal and Connective Tissue   34/69 (49.28%)  34/73 (46.58%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasm   4/69 (5.80%)  2/73 (2.74%) 
Nervous system disorders     
Nervous System   12/69 (17.39%)  9/73 (12.33%) 
Psychiatric disorders     
Psychiatric   10/69 (14.49%)  9/73 (12.33%) 
Renal and urinary disorders     
Renal and Urinary   26/69 (37.68%)  27/73 (36.99%) 
Reproductive system and breast disorders     
Reproductive and Breast   15/69 (21.74%)  12/73 (16.44%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory and Thoracic   46/69 (66.67%)  45/73 (61.64%) 
Skin and subcutaneous tissue disorders     
Skin and Subcutaneous Tissue   35/69 (50.72%)  43/73 (58.90%) 
Surgical and medical procedures     
Procedures   6/69 (8.70%)  5/73 (6.85%) 
Vascular disorders     
Vascular   19/69 (27.54%)  22/73 (30.14%) 
Indicates events were collected by systematic assessment
While the rate of premature withdrawal from taking study drug was significant, this was anticipated in the study design and addressed by the sample size and the use of the mixed model statistical analysis.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Donald P. Tashkin, M.D.
Organization: David Geffen School of Medicine at UCLA
Phone: 310-825-5316
Publications of Results:
Other Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Michael Roth, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT00883129     History of Changes
Other Study ID Numbers: 632
R01HL089901 ( U.S. NIH Grant/Contract )
R01HL089758 ( U.S. NIH Grant/Contract )
First Submitted: April 16, 2009
First Posted: April 17, 2009
Results First Submitted: November 6, 2016
Results First Posted: February 10, 2017
Last Update Posted: February 10, 2017