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

• Sponsor: Michael Roth (Other)
• Overall Status: Completed
• CT.gov ID: NCT00883129
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Hoffmann-La Roche (Industry)
• Enrollment: 142
• Locations: 14
• Arms: 2
• Duration (Months): 74
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Scleroderma; Interstitial Lung Disease	Drug: Mycophenolate mofetil; Drug: Cyclophosphamide; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Mycophenolate vs. Oral Cyclophosphamide in Scleroderma Interstitial Lung Disease (Scleroderma Lung Study II)
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Mycophenolate Arm Participants will receive oral mycophenolate mofetil for 2 years.	Drug: Mycophenolate mofetil; 24 months of oral mycophenolate mofetil, up to a maximal dose of 1.5 grams twice daily as tolerated; Other Names: CellCept
Experimental: Cyclophosphamide Arm Participants will receive oral cyclophosphamide for 1 year, followed by placebo for 1 year.	Drug: Cyclophosphamide; 12 months of oral cyclophosphamide, up to a maximal dose of 2 mg/kg daily as tolerated; Other Names: Cytoxan ; Drug: 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.; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death [Measured throughout the 2-year study]

8. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
2	University of California, San Francisco	San Francisco	California	United States	94143
3	National Jewish Health	Denver	Colorado	United States	80206
4	Georgetown University School of Medicine	Washington	District of Columbia	United States	20057
5	Feinberg School of Medicine, Northwestern University	Chicago	Illinois	United States	60611
6	University of Illinois at Chicago, College of Medicine	Chicago	Illinois	United States	60612
7	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21205
8	Boston University School of Medicine	Boston	Massachusetts	United States	02118
9	University of Michigan Medical School	Ann Arbor	Michigan	United States	48109
10	University of Minnesota	Minneapolis	Minnesota	United States	55454
11	University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08854
12	Medical University of South Carolina	Charleston	South Carolina	United States	29425
13	University of Texas Medical School at Houston	Houston	Texas	United States	77225
14	University of Utah	Salt Lake City	Utah	United States	84132

Sponsors and Collaborators

• Michael Roth
• National Heart, Lung, and Blood Institute (NHLBI)
• Hoffmann-La Roche

Investigators

• Principal Investigator: Donald P. Tashkin, MD, University of California, Los Angeles
• Principal Investigator: Robert M. Elashoff, PhD, UCLA School of Public Health
• Principal Investigator: Michael D. Roth, MD, University of California, Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

• Elashoff RM, Li G, Li N. A joint model for longitudinal measurements and survival data in the presence of multiple failure types. Biometrics. 2008 Sep;64(3):762-771. doi: 10.1111/j.1541-0420.2007.00952.x. Epub 2007 Dec 20.
• Elashoff RM, Li G, Li N. An approach to joint analysis of longitudinal measurements and competing risks failure time data. Stat Med. 2007 Jun 30;26(14):2813-35.
• Furst DE, Tseng CH, Clements PJ, Strange C, Tashkin DP, Roth MD, Khanna D, Li N, Elashoff R, Schraufnagel DE; Scleroderma Lung Study. Adverse events during the Scleroderma Lung Study. Am J Med. 2011 May;124(5):459-67. doi: 10.1016/j.amjmed.2010.12.009.
• Hant FN, Ludwicka-Bradley A, Wang HJ, Li N, Elashoff R, Tashkin DP, Silver RM; Scleroderma Lung Study Research Group. Surfactant protein D and KL-6 as serum biomarkers of interstitial lung disease in patients with scleroderma. J Rheumatol. 2009 Apr;36(4):773-80. doi: 10.3899/jrheum.080633. Epub 2009 Mar 13.
• Khanna D, Tseng CH, Farmani N, Steen V, Furst DE, Clements PJ, Roth MD, Goldin J, Elashoff R, Seibold JR, Saggar R, Tashkin DP. Clinical course of lung physiology in patients with scleroderma and interstitial lung disease: analysis of the Scleroderma Lung Study Placebo Group. Arthritis Rheum. 2011 Oct;63(10):3078-85. doi: 10.1002/art.30467.
• Kim HG, Tashkin DP, Clements PJ, Li G, Brown MS, Elashoff R, Gjertson DW, Abtin F, Lynch DA, Strollo DC, Goldin JG. A computer-aided diagnosis system for quantitative scoring of extent of lung fibrosis in scleroderma patients. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 62):S26-35. Epub 2010 Nov 3.
• Kim HJ, Brown MS, Elashoff R, Li G, Gjertson DW, Lynch DA, Strollo DC, Kleerup E, Chong D, Shah SK, Ahmad S, Abtin F, Tashkin DP, Goldin JG. Quantitative texture-based assessment of one-year changes in fibrotic reticular patterns on HRCT in scleroderma lung disease treated with oral cyclophosphamide. Eur Radiol. 2011 Dec;21(12):2455-65. doi: 10.1007/s00330-011-2223-2. Epub 2011 Sep 17.
• Kim HJ, Li G, Gjertson D, Elashoff R, Shah SK, Ochs R, Vasunilashorn F, Abtin F, Brown MS, Goldin JG. Classification of parenchymal abnormality in scleroderma lung using a novel approach to denoise images collected via a multicenter study. Acad Radiol. 2008 Aug;15(8):1004-16. doi: 10.1016/j.acra.2008.03.011.
• Li N, Elashoff RM, Li G. Robust joint modeling of longitudinal measurements and competing risks failure time data. Biom J. 2009 Feb;51(1):19-30. doi: 10.1002/bimj.200810491.
• Roth MD, Tseng CH, Clements PJ, Furst DE, Tashkin DP, Goldin JG, Khanna D, Kleerup EC, Li N, Elashoff D, Elashoff RM; Scleroderma Lung Study Research Group. Predicting treatment outcomes and responder subsets in scleroderma-related interstitial lung disease. Arthritis Rheum. 2011 Sep;63(9):2797-808. doi: 10.1002/art.30438.
• Theodore AC, Tseng CH, Li N, Elashoff RM, Tashkin DP. Correlation of cough with disease activity and treatment with cyclophosphamide in scleroderma interstitial lung disease: findings from the Scleroderma Lung Study. Chest. 2012 Sep;142(3):614-621. doi: 10.1378/chest.11-0801.

• Responsible Party: Michael Roth, Professor, Division of Pulmonary & Critical Care; Vice Chairman for Research Compliance, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00883129
• Other Study ID Numbers: 632; R01HL089901; R01HL089758
• First Posted: Apr 17, 2009
• Last Update Posted: Feb 10, 2017
• Last Verified: Feb 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Michael Roth, Professor, Division of Pulmonary & Critical Care; Vice Chairman for Research Compliance, University of California, Los Angeles: Systemic Sclerosis; Mycophenolate Mofetil; Cyclophosphamide; High Resolution Computerized Tomography; Pulmonary Function; Dyspnea; Health Related Quality of Life
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Interstitial; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized; Mycophenolic Acid; Cyclophosphamide

Study Results

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.

Arm/Group Title	Mycophenolate Arm	Cyclophosphamide Arm
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	37
NOT COMPLETED	20	36

Baseline Characteristics

Arm/Group Title	Mycophenolate Arm	Cyclophosphamide Arm	Total
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 Participants	69	73	142
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.6 (9.7)	52.0 (9.8)	52.3 (9.7)
Sex: Female, Male (Count of Participants)
Female	48 69.6%	57 78.1%	105 73.9%
Male	21 30.4%	16 21.9%	37 26.1%
Duration of scleroderma (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.6 (1.7)	2.5 (1.8)	2.6 (1.8)
Limited cutaneous scleroderma (Count of Participants)
Count of Participants [Participants]	26 37.7%	33 45.2%	59 41.5%
Diffuse cutaneous scleroderma (Count of Participants)
Count of Participants [Participants]	43 62.3%	40 54.8%	83 58.5%
modified-Rodnan Skin Score (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	15.3 (10.4)	14.0 (10.6)	14.7 (10.5)
FVC %-predicted (Percent of predicted normal value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of predicted normal value]	66.5 (9.1)	66.5 (8.3)	66.5 (9.9)
FEV1/FVC %-predicted (Percent of predicted normal value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of predicted normal value]	81.0 (5.5)	83.3 (5.6)	82.6 (5.6)
Total Lung Capacity (Percent of predicted normal value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of predicted normal value]	66.3 (10.0)	65.5 (12.0)	65.8 (11.1)
Single-Breath Diffusing Capacity (Percent of predicted normal value) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of predicted normal value]	60.9 (11.8)	61.0 (13.7)	60.9 (12.8)
Mahler Dyspnea Index, mean focal score (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	7.3 (2.1)	7.1 (2.3)	7.2 (2.2)
SF-36 Physical component (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	36.0 (10.0)	35.6 (9.8)	35.8 (9.9)
SF-36 Mental component (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	49.1 (7.9)	49.8 (10.0)	49.4 (9.0)
HAQ disability index (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	0.7 (0.6)	0.7 (0.7)	0.7 (0.7)
Quantitative extent of lung fibrosis on HRCT, for whole lung (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	8.3 (6.9)	8.9 (7.0)	8.6 (6.9)
Quantitative extent of lung fibrosis on HRCT, for lobe of maximum involvement (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	23.0 (20.2)	22.6 (19.3)	22.8 (19.6)
Quantitative extent of total insterstitial lung disease on HRCT, for whole lung (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	27.2 (13.2)	31.6 (14.4)	29.5 (14.0)
Quantitative extent of total insterstitial lung disease on HRCT, for lobe of maximum involvement (Score) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Score]	50.0 (20.9)	52.3 (19.9)	51.2 (20.3)
ANA(+) (Count of Participants)
Count of Participants [Participants]	61 88.4%	66 90.4%	127 89.4%
Topoisomerase-1(+) (Count of Participants)
Count of Participants [Participants]	29 42%	32 43.8%	61 43%
RNA Polymerase(+) (Count of Participants)
Count of Participants [Participants]	9 13%	9 12.3%	18 12.7%
Centromere(+) (Count of Participants)
Count of Participants [Participants]	1 1.4%	2 2.7%	3 2.1%

Outcome Measures

1. Primary Outcome

Title	Forced Vital Capacity (FVC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	66.52	66.52
Month 3	66.22	67.03
Month 6	68.02	67.86
Month 9	68.11	69.42
Month 12	68.43	69.86
Month 15	69.84	71.94
Month 18	70.57	72.57
Month 21	70.87	72.55
Month 24	69.65	70.15

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
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

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
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

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
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

2. Secondary Outcome

Title	Total Lung Capacity (TLC), as a Percent of the Age, Height, Gender, and Ethnicity Adjusted Predicted Value
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	66.16	65.49
Month 6	67.84	67.39
Month 12	67.31	68.25
Month 18	68.50	69.63
Month 24	68.24	66.97

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
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

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
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	53.99	54.05
Month 3	53.38	51.92
Month 6	54.86	50.87
Month 9	54.13	51.55
Month 12	55.32	53.12
Month 15	57.77	53.62
Month 18	56.62	55.9
Month 21	55.47	54.26
Month 24	55.31	52.90

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
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

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
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

4. Secondary Outcome

Title	Fibrosis Score, as Measured by Thoracic High Resolution Computerized Tomography (HRCT)
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	8.25	8.91
Month 24	7.99	8.48

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
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

5. Secondary Outcome

Title	Transitional Dyspnea Index Score
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Month 6	0.74	0.31
Month 12	1.17	1.23
Month 18	0.91	1.78
Month 24	1.86	2.09

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
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

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
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

6. Secondary Outcome

Title	Health-related Quality of Life as Measured by the Patient Responses to the Health Assessment Questionnaire Disability Index (HAQ-DI)
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	0.71 (0.62)	0.74 (0.73)
Month 3	0.83 (0.72)	0.64 (0.67)
Month 6	0.75 (0.71)	0.58 (0.65)
Month 9	0.66 (0.66)	0.65 (0.62)
Month 12	0.64 (0.67)	0.56 (0.60)
Month 15	0.58 (0.62)	0.62 (0.63)
Month 18	0.55 (0.55)	0.55 (0.66)
Month 21	0.65 (0.65)	0.48 (0.53)
Month 24	0.62 (0.69)	0.57 (0.68)

7. Secondary Outcome

Title	Skin Involvement, as Measured by the Modified Rodnam Skin Thickness Scores (mRSS)
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

Outcome Measure Data

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
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.
Measure Participants	69	73
Baseline	15.32	14.04
Month 3	16.03	12.85
Month 6	14.37	11.95
Month 9	14.33	10.61
Month 12	12.45	9.47
Month 15	12.43	9.80
Month 18	11.98	9.87
Month 21	11.22	8.50
Month 24	11.40	7.87

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
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

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
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

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
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

8. Secondary Outcome

Title	Toxicity, as Measured by Adverse Events, Serious Adverse Events, and Death
Time Frame	Measured throughout the 2-year study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mycophenolate Arm	Cyclophosphamide Arm
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.
Measure Participants	69	73
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%	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%

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
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.
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mycophenolate Arm	Cyclophosphamide Arm
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.
Measure Participants	69	73
Baseline	69 100%	73 100%
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%
Month 15	52 75.4%	44 60.3%
Month 18	49 71%	42 57.5%
Month 21	49 71%	39 53.4%
Month 24	49 71%	38 52.1%

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
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

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Mycophenolate Arm		Cyclophosphamide Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/69 (39.1%)		22/73 (30.1%)
Blood and lymphatic system disorders
Hematologic	1/69 (1.4%)		2/73 (2.7%)
Cardiac disorders
Cardiac	8/69 (11.6%)		8/73 (11%)
Gastrointestinal disorders
Gastrointestinal	2/69 (2.9%)		4/73 (5.5%)
General disorders
Weakness	0/69 (0%)		1/73 (1.4%)
Infections and infestations
Respiratory Infection	2/69 (2.9%)		7/73 (9.6%)
Abscess	1/69 (1.4%)		0/73 (0%)
Injury, poisoning and procedural complications
Medication Reaction	1/69 (1.4%)		0/73 (0%)
Injury	1/69 (1.4%)		0/73 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	4/69 (5.8%)		3/73 (4.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer	2/69 (2.9%)		1/73 (1.4%)
Nervous system disorders
Syncope and Seizure	2/69 (2.9%)		0/73 (0%)
Renal and urinary disorders
Renal and Bladder	1/69 (1.4%)		1/73 (1.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory Events	7/69 (10.1%)		5/73 (6.8%)
Surgical and medical procedures
Elective Surgery	2/69 (2.9%)		0/73 (0%)
Other (Not Including Serious) Adverse Events
	Mycophenolate Arm		Cyclophosphamide Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	68/69 (98.6%)		71/73 (97.3%)
Blood and lymphatic system disorders
Blood and Lymphatic	20/69 (29%)		47/73 (64.4%)
Cardiac disorders
Cardiac	18/69 (26.1%)		21/73 (28.8%)
Ear and labyrinth disorders
Vision and hearing	2/69 (2.9%)		6/73 (8.2%)
Gastrointestinal disorders
Gastrointestinal	47/69 (68.1%)		40/73 (54.8%)
General disorders
General	31/69 (44.9%)		33/73 (45.2%)
Hepatobiliary disorders
Hepatobiliary	6/69 (8.7%)		4/73 (5.5%)
Immune system disorders
Immune disorder	2/69 (2.9%)		4/73 (5.5%)
Infections and infestations
Infections and Infestations	52/69 (75.4%)		57/73 (78.1%)
Injury, poisoning and procedural complications
Injury, Poisoning and Procedural	8/69 (11.6%)		10/73 (13.7%)
Metabolism and nutrition disorders
Metabolism and Nutrition	11/69 (15.9%)		22/73 (30.1%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and Connective Tissue	34/69 (49.3%)		34/73 (46.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm	4/69 (5.8%)		2/73 (2.7%)
Nervous system disorders
Nervous System	12/69 (17.4%)		9/73 (12.3%)
Psychiatric disorders
Psychiatric	10/69 (14.5%)		9/73 (12.3%)
Renal and urinary disorders
Renal and Urinary	26/69 (37.7%)		27/73 (37%)
Reproductive system and breast disorders
Reproductive and Breast	15/69 (21.7%)		12/73 (16.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory and Thoracic	46/69 (66.7%)		45/73 (61.6%)
Skin and subcutaneous tissue disorders
Skin and Subcutaneous Tissue	35/69 (50.7%)		43/73 (58.9%)
Surgical and medical procedures
Procedures	6/69 (8.7%)		5/73 (6.8%)
Vascular disorders
Vascular	19/69 (27.5%)		22/73 (30.1%)

Limitations/Caveats

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.

More Information

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.