SCOT: Scleroderma: Cyclophosphamide or Transplantation

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00114530
• Collaborator: Rho Federal Systems Division, Inc. (Industry)
• Enrollment: 75
• Locations: 17
• Arms: 2
• Duration (Months): 130
• Patients Per Site: 4.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

SCOT is a clinical research study designed for people with severe forms of scleroderma. SCOT stands for Scleroderma: Cyclophosphamide Or Transplantation. The SCOT study will compare the potential benefits of stem cell transplant and high-dose monthly cyclophosphamide (Cytoxan) in the treatment of scleroderma.

Condition or Disease	Intervention/Treatment	Phase
Scleroderma, Systemic; Sclerosis; Autoimmune Disease	Biological: mHSCT; Drug: cyclophosphamide	Phase 2/Phase 3

Detailed Description

Severe systemic sclerosis (SSc) is a serious autoimmune disorder in which a person's own immune cells attack organs in the body. SSc affects the skin, joints, lungs, heart, intestinal tract, and kidneys, and half of the patients with the most severe organ involvement die within 5 years. Treatment for SSc usually includes supportive care or immunosuppressive drugs (drugs to suppress the immune system). As the immune cells are believed to be causing the disease, researchers are looking for new therapies that either slow down or stop this process, while not being too toxic.

The main purpose of this study is to determine the safety and effectiveness of high-dose immunosuppressive therapy followed by reinfusion (transplantation) of the participant's own autologous (self) peripheral blood stem cells (PBSCs) compared to treatment with monthly (for 12 months) intravenous doses of cyclophosphamide (Cytoxan) therapy for the treatment of severe systemic sclerosis (SSc). These treatments are being given in order to determine if they will slow down or stop SSc from becoming more severe, and if they can reverse the effects of the disease. The researchers are evaluating the effects of the two treatments on serious organ damage and survival related to SSc, while also looking at the side effects of the two treatments.

This trial also includes three optional mechanistic sub-studies open to a subset of participants enrolled in the SCOT trial:

1. Pharmacokinetics of 4-hydroxycyclophosphamide in Patients Receiving Cyclophosphamide for the SCOT trial (Originally listed separately as DAIT SCSSc-01-01, NCT00848614). The purpose of this study is to determine the plasma concentration and exposure time required for cyclophosphamide to produce optimal immunosuppressive activity with minimal toxicity in participants with severe systemic sclerosis.

2. Vascular Progenitor Cells and the Pathogenesis of Systemic Sclerosis(Originally listed separately as DAIT SCSSc-01-02, NCT00871221). The purpose of this study is to measure and characterize the circulating endothelial progenitor cells from the blood of 30 participants and also to determine the extent of vascular cell apoptosis and proliferation in cutaneous microvasculature in these participants before and after the receipt of the two SCOT treatment regimens.

3. Molecular Analysis of T Cell Immune Recovery for the SCOT Trial(Originally listed separately as DAIT SCSSc-01-03, NCT00872508). The purpose of this study is [1] to describe the condition of peripheral T cell reactivity and repertoire diversity in SSc patients and evaluate evidence for potential defects prior to randomization, [2] to gain a better understanding of the impact of cyclophosphamide (Cytoxan) and high-dose immunosuppressive therapy with autologous stem cell transplantation on thymopoiesis, and [3] to describe the kinetics and breadth of T cell immune recovery in SSc patients treated with these interventions.

Study Design

• Study Type: Interventional
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Phase II Multicenter Study of High-Dose Immunosuppressive Therapy Using Total Body Irradiation, Cyclophosphamide, ATGAM, and Autologous Transplantation With Auto-CD34+HPC Versus Intravenous Pulse Cyclophosphamide for the Treatment of Severe Systemic Sclerosis (SCSSc-01)
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: mHSCT Myeloablative Hematopoietic Stem Cell Transplant (mHSCT) Participants will first have hematopoietic stem cells removed from their blood. They then will receive high doses of chemotherapy and radiation to eliminate their developed and presumably abnormal immune system, followed by autologous stem cell transplantation to reintroduce the purified stem cells to re-establish their immune system.	Biological: mHSCT; Hematopoietic progenitors were mobilized with G-CSF. After leukapheresis and CD34+ cell enrichment, the autologous product was cryopreserved. Fractionated TBI (800 cGy), CY (120 mg/kg) and equine antithymocyte globulin (90 mg/kg) were administered as previously reported (References provided in citation section of this ClinicalTrials.gov record: PubMed ID: 17452515 citation and 2.) PubMed ID: 12176878 citation).; Other Names: Myeloablative Hematopoietic Stem Cell Transplant
Experimental: cyclophosphamide Cyclophosphamide (CY) Participants will receive high doses of intravenous cyclophosphamide. The dose being used in this study is about 50% higher than that commonly used by most physicians to treat many other autoimmune diseases. Administration of 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).	Drug: cyclophosphamide; An initial intravenous dose of 500 mg/m^2 was followed by 11 infusions of 750 mg/m^2 with mesna given for bladder protection.; Other Names: cytoxan CY

Outcome Measures

Primary Outcome Measures

1. Global Rank Composite Score (GRCS) (Month 54, ITT) [54 Months Post-Randomization]

   The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

Secondary Outcome Measures

1. Global Rank Composite Score (GRCS) (Month 54, PP) [54 Months Post-Randomization]

   The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

2. Global Rank Composite Score (GRCS) (Month 48, ITT) [48 Months Post-Randomization]

   The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

3. Global Rank Composite Score (GRCS) (Month 48, PP) [48 Months Post-Randomization]

   The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).

4. Event-Free Survival (EFS) (Month 54, ITT) [54 Months Post-Randomization]

   Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in diffusion in liters of carbon monoxide (DLCO) % predicted or >20% in forced vital capacity (FVC) % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 54 post-randomization.

5. Event-Free Survival (EFS) (Month 54, PP) [54 Months Post-Randomization]

   Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 54 post-randomization.

6. Event-Free Survival (EFS) (Month 48, ITT) [48 Months Post-Randomization]

   Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 48 post-randomization.

7. Event-Free Survival (EFS) (Month 48, PP) [48 Months Post-Randomization]

   Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 48 post-randomization.

8. Treatment-Related Mortality (Month 54, ITT) [54 Months Post-Randomization]

   Death, occurring at any time between randomization and Month 54 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.

9. Treatment-Related Mortality (Month 54, PP) [54 Months Post-Randomization]

   Death, occurring at any time between randomization and Month 54 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.

10. Treatment-Related Mortality (Month 48, ITT) [48 Months Post-Randomization]

    Death, occurring at any time between randomization and Month 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.

11. Treatment-Related Mortality (Month 48, PP) [48 Months Post-Randomization]

    Death, occurring at any time between randomization and Month 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.

12. All-Cause Mortality (Month 54, ITT) [54 Months Post-Randomization]

    Any death, regardless of relationship to treatment, between randomization and Month 54 post-randomization.

13. All-Cause Mortality (Month 54, PP) [54 Months Post-Randomization]

    Any death, regardless of relationship to treatment, between randomization and Month 54 post-randomization.

14. All-Cause Mortality (Month 48, ITT) [48 Months Post-Randomization]

    Any death, regardless of relationship to treatment, between randomization and Month 48 post-randomization.

15. All-Cause Mortality (Month 48, PP) [48 Months Post-Randomization]

    Any death, regardless of relationship to treatment, between randomization and Month 48 post-randomization.

16. Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (ITT) [54 Months Post-Randomization]

    HAQ-DI is a self-reported questionnaire of functionality that includes questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities). The final score ranges from 0 to 3, where a higher HAQ-DI score indicates a worse outcome. Analysis was based on an ordinal response variable, defined as follows: a decrease of >0.4 from baseline in the HAQ-DI score was considered disease improvement, an increase of >0.4 was considered disease worsening, and any change less than 0.4 was considered "no change." Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

17. Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (PP) [54 Months Post-Randomization]

    HAQ-DI is a self-reported questionnaire of functionality that includes questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities). The final score ranges from 0 to 3, where a higher HAQ-DI score indicates a worse outcome. Analysis was based on an ordinal response variable, defined as follows: a decrease of >0.4 from baseline in the HAQ-DI score was considered disease improvement, an increase of >0.4 was considered disease worsening, and any change less than 0.4 was considered "no change." Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

18. Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (ITT) [54 Months Post-Randomization]

    The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component was transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. Analysis was based on ordinal response, defined as follows for each component: a >= 10 point increase indicated disease improvement, a >= 10 point decrease indicated disease worsening, and a change <10 points indicated "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

19. Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (PP) [54 Months Post-Randomization]

    The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component was transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. Analysis was based on ordinal response, defined as follows for each component: a >= 10 point increase indicated disease improvement, a >= 10 point decrease indicated disease worsening, and a change <10 points indicated "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

20. Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (ITT) [54 Months Post-Randomization]

    Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was <13 or >17 gm/dL, and altitude (Calgary site only). Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >15% in DLCO % Predicted indicated disease improvement, a decrease of >15% indicated disease worsening, and a change of <=15% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

21. Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (PP) [54 Months Post-Randomization]

    Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was <13 or >17 gm/dL, and altitude (Calgary site only). Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >15% in DLCO % Predicted indicated disease improvement, a decrease of >15% indicated disease worsening, and a change of <=15% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

22. Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (ITT) [54 Months Post-Randomization]

    Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards. Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >10% in FVC % Predicted indicated disease improvement, a decrease of >10% indicated disease worsening, and a change of <=10% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

23. Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (PP) [54 Months Post-Randomization]

    Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards. Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >10% in FVC % Predicted indicated disease improvement, a decrease of >10% indicated disease worsening, and a change of <=10% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

24. Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (ITT) [54 Months Post-Randomization]

    The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity. Analysis was based on an ordinal response variable, defined as follows: if the baseline mRSS was <=20, a decrease >=5 points from baseline indicated disease improvement and an increase >= 5 points indicated disease worsening; if the baseline mRSS was >20, then a decrease of >25% indicated disease improvement and an increase of >25% indicated disease worsening. Participants who do not meet the disease criteria outlined above were considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

25. Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (PP) [54 Months Post-Randomization]

    The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity. Analysis was based on an ordinal response variable, defined as follows: if the baseline mRSS was <=20, a decrease >=5 points from baseline indicated disease improvement and an increase >= 5 points indicated disease worsening; if the baseline mRSS was >20, then a decrease of >25% indicated disease improvement and an increase of >25% indicated disease worsening. Participants who do not meet the disease criteria outlined above were considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.

26. New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (ITT) [54 Months Post-Randomization]

    Any events that met the criteria outlined below or were reported as adverse events between randomization and Month 54 post-randomization are summarized. 1) Development of new or worsening arrhythmias that require medical treatment for >= 3 months or require ablative therapy or pacemaker insertion. (Note that for a participant who has medically controlled arrhythmia at randomization, worsening was defined as breakthrough episodes severe enough to prompt change in medication, an increase in the dose of a medication, or addition of a new medication to maintain control of the arrhythmia.) 2) Congestive heart failure (CHF) requiring clinical treatment for >= 3 months develops. 3) Clinically significant pericardial effusion (excess fluid around the heart) that required pericardial window.

27. New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (PP) [54 Months Post-Randomization]

    Any events that met the criteria outlined below or were reported as adverse events between randomization and Month 54 post-randomization are summarized. 1) Development of new or worsening arrhythmias that require medical treatment for >= 3 months or require ablative therapy or pacemaker insertion. (Note that for a participant who has medically controlled arrhythmia at randomization, worsening will be defined as breakthrough episodes severe enough to prompt change in medication, an increase in the dose of a medication or addition of a new medication to maintain control of the arrhythmia.) 2) Congestive heart failure (CHF) requiring clinical treatment for >= 3 months develops. 3) Clinically significant pericardial effusion (excess fluid around the heart) that required pericardial window.

28. New or Worsening Pulmonary Hypertension (ITT) [54 Months Post-Randomization]

    Any pulmonary arterial hypertension (PAH) events that occurred between randomization and Month 54 post-randomization were summarized. Development of PAH occurred if the participant met the following criteria, where the measurement value(s) could not be explained by other causes such as congestive heart failure or pulmonary emboli: 1) a post-baseline peak systolic pulmonary artery pressure > 55 mmHg by echocardiogram or 2) a mean pulmonary artery pressure > 30 mmHg at rest measured by right heart catheterization. If the post-baseline peak systolic pulmonary artery pressure was between 40 to 55 mmHg by echocardiogram, a right heart catheterization was done to confirm a diagnosis of pulmonary artery hypertension. The endpoint was met if the mean pulmonary artery pressure was > 30 mmHg at rest by right heart catheterization. Additionally, any adverse event reported as PAH was included in the analysis.

29. New or Worsening Pulmonary Hypertension (PP) [54 Months Post-Randomization]

    Any pulmonary arterial hypertension (PAH) events that occurred between randomization and Month 54 post-randomization were summarized. Development of PAH occurred if the participant met the following criteria, where the measurement value(s) could not be explained by other causes such as congestive heart failure or pulmonary emboli: 1) a post-baseline peak systolic pulmonary artery pressure > 55 mmHg by echocardiogram or 2) a mean pulmonary artery pressure > 30 mmHg at rest measured by right heart catheterization. If the post-baseline peak systolic pulmonary artery pressure was between 40 to 55 mmHg by echocardiogram, a right heart catheterization would be done to confirm a diagnosis of pulmonary artery hypertension. The endpoint was met if the mean pulmonary artery pressure was > 30 mmHg at rest by right heart catheterization. Additionally, any adverse event reported as PAH was included in the analysis.

30. Occurrence of Scleroderma Renal Crisis (ITT) [54 Months Post-Randomization]

    Documented scleroderma renal crisis (hypertensive or non-hypertensive) occurring from randomization to Month 54 post-randomization was summarized. A hypertensive scleroderma renal crisis occurred if a participant obtained both of the following: New-onset hypertension, defined as systolic blood pressure (SBP) >= 140 mmHg, diastolic blood pressure (DBP) >= 90 mmHg, a rise in SBP >= 30 mmHg compared to baseline, or a rise in DBP >= 20 mmHg compared to baseline, and one of the following features: 1) increase of >= 50 % above baseline in serum creatinine, 2) proteinuria (>= 2+ by dipstick confirmed by protein:creatinine ratio > 2.5), 3) hematuria (>= 2+ by dipstick or > 10 RBCs/HPF, without menstruation), 4) thrombocytopenia (< 100,000 plts/mm3), or 5) hemolysis (determined by blood smear or increased reticulocyte count). Additionally, any adverse event reported as a scleroderma renal crisis was included in the analysis.

31. Occurrence of Scleroderma Renal Crisis (PP) [54 Months Post-Randomization]

    Documented scleroderma renal crisis (hypertensive or non-hypertensive) occurring from randomization to Month 54 post-randomization was summarized. A hypertensive scleroderma renal crisis occurred if a participant obtained both of the following: New-onset hypertension, defined as systolic blood pressure (SBP) >= 140 mmHg, diastolic blood pressure (DBP) >= 90 mmHg, a rise in SBP >= 30 mmHg compared to baseline, or a rise in DBP >= 20 mmHg compared to baseline, and one of the following features: 1) increase of >= 50 % above baseline in serum creatinine, 2) proteinuria (>= 2+ by dipstick confirmed by protein:creatinine ratio > 2.5), 3) hematuria (>= 2+ by dipstick or > 10 RBCs/HPF, without menstruation), 4) thrombocytopenia (< 100,000 plts/mm3), or 5) hemolysis (determined by blood smear or increased reticulocyte count). Additionally, any adverse event reported as a scleroderma renal crisis was included in the analysis.

32. Documented Myositis (ITT) [54 Months Post-Randomization]

    Number of participants who experienced any event of myositis that occurred from randomization to Month 54 post-randomization. Documented myositis occurred if the participant had 1) elevated creatine phosphokinase (CPK), electromyography, and/or biopsy and 2) required > 30 mg per day prednisone for over 1 month or another therapy such as methotrexate (MTX) for treatment of myositis. Additionally, any adverse event reported as myositis was included in the analysis.

33. Documented Myositis (PP) [54 Months Post-Randomization]

    Number of participants who experienced any event of myositis that occurred from randomization to Month 54 post-randomization. Documented myositis occurred if the participant had 1) elevated creatine phosphokinase (CPK), electromyography, and/or biopsy and 2) required > 30 mg per day prednisone for over 1 month or another therapy such as methotrexate (MTX) for treatment of myositis. Additionally, any adverse event reported as myositis was included in the analysis.

34. Initiating Use of Disease-Modifying Antirheumatic Drugs (DMARDs) by Month 54 (ITT) [54 Months Post-Randomization]

    Initiation of disease-modifying antirheumatic drugs (DMARDs). Participants were not expected to receive additional disease-modifying therapy for systemic sclerosis (SSc) in the absence of disease progression. In general, this includes the administration of any therapy clearly given for the purpose of treating the underlying SSc. It does not include concomitant treatments permitted in the protocol, such as use of methotrexate (15 g or less), anti-malarials, or minocycline for arthritis only. Systemic corticosteroids given at > 10 mg/day (prednisone or prednisone equivalent), without clearly defined non-SSc indications, and methotrexate given for non-arthritis indications are examples of qualifying DMARDs.

35. Initiating Use of Disease-Modifying Antirheumatic Drugs by Month 54 (DMARDs) (PP) [54 Months Post-Randomization]

    Initiation of disease-modifying antirheumatic drugs (DMARDs). Participants were not expected to receive additional disease-modifying therapy for systemic sclerosis (SSc) in the absence of disease progression. In general, this includes the administration of any therapy clearly given for the purpose of treating the underlying SSc. It does not include concomitant treatments permitted in the protocol, such as use of methotrexate (15 g or less), anti-malarials, or minocycline for arthritis only. Systemic corticosteroids given at > 10 mg/day (prednisone or prednisone equivalent), without clearly defined non-SSc indications, and methotrexate given for non-arthritis indications are examples of qualifying DMARDs.

36. Regimen-Related Toxicities [Randomization through end of study follow-up (up to Month 72 post-randomization)]

    Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy.

37. Number of Subjects With Regimen-Related Toxicities [Randomization through end of study follow-up (up to Month 72 post-randomization).]

    Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy.

38. Infectious Complications [Randomization through end of study follow-up (up to Month 72 post-randomization).]

    Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.

39. Number of Subjects With Infectious Complications [Randomization through end of study follow-up (up to Month 72 post-randomization).]

    Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.

40. Time to Absolute Neutrophil Count Engraftment [28 days post-transplant]

    Time to absolute neutrophil count (ANC) engraftment is defined as the number of days post-transplant until required levels of ANC are attained (for the mHSCT arm only). If engraftment did not occur within 28 days post-transplant, then the variable was set to 28 days. ANC engraftment required an ANC of > 500 cells/microliter, maintained for 3 consecutive days.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Severe systemic sclerosis (SSc) as defined by the American College of Rheumatology (ACR);

• SSc, including extensive skin and internal organ involvement involving either the lungs or the kidneys, that threatens participant's life; and

• Willingness to use accepted methods of contraception for at least 15 months after starting study treatment.

Exclusion Criteria:

• Lung, heart, liver, or kidney impairment that would interfere with the study or compromise participant's survival;

• Active blood vessel dilation in the stomach (Active Gastric Antral Vascular Ectasia/GAVE, also known as "watermelon stomach"). Patients found to have this disorder at study screening can receive treatment outside the study and then be re-screened. For more information about this study criterion, refer to the study protocol.

• Previous treatment with cyclophosphamide, as defined by: a) prior IV cyclophosphamide administration for more than 6 months OR a total cumulative IV dose greater than 3 g/m^2; b) prior oral cyclophosphamide administration for more than 4 months, regardless of dose; or c) combination of prior oral and IV cyclophosphamide administration for more than 6 months, independent of dose.

• Steroid therapy at doses of greater than 10 mg/day, or more than 2 pulses for concurrent illnesses within prior 12 months;

• Unwillingness or inability to discontinue certain disease-modifying antirheumatic drugs (DMARDs) for the treatment of SSc;

• Presence of clinically significant rheumatic diseases other than scleroderma requiring significant immunosuppression;

• Any active uncontrolled infection that would interfere with high-dose therapy or pulse cyclophosphamide regimens:

• Hepatitis B virus infected

• Hepatitis C virus infected or

• HIV infected.

• Blood abnormalities;

• Diagnosis of cancer within 2 years prior to study entry. Participants with adequately treated squamous cell skin cancer, basal cell carcinoma, and carcinoma in situ are not excluded.

• Other comorbid illnesses with an estimated life expectancy of less than 5 years;

• Defective formation of bone marrow cells (myelodysplasia);

• Uncontrolled hypertension;

• History of hypersensitivity to murine or Escherichia coli (e.g., E. coli) proteins; History of noncompliance with prior medical care;

• History of substance abuse within 5 years prior to study entry; or

• Pregnancy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010-3000
2	UCLA Medical School	Los Angeles	California	United States	90095-1670
3	University of Kentucky	Lexington	Kentucky	United States	40536-0284
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Boston University School of Medicine	Boston	Massachusetts	United States	02118
6	University of Michigan	Ann Arbor	Michigan	United States	48109
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Duke University Medical Center	Durham	North Carolina	United States	27709
9	University of Toledo Health Science Campus	Toledo	Ohio	United States	43606
10	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261
11	Medical University of South Carolina	Charleston	South Carolina	United States	29425
12	University of Texas-Houston Medical School	Houston	Texas	United States	77030
13	MD Anderson Cancer Center	Houston	Texas	United States	77230
14	Fred Hutchinson Cancer Research Center (FHCRC)	Seattle	Washington	United States	98109
15	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
16	University of Calgary	Calgary	Alberta	Canada
17	Dr. Markland Medical Professional Corporation	Saskatoon	Saskatchewan	Canada	S7K OH6

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Rho Federal Systems Division, Inc.

Investigators

• Study Chair: Keith M. Sullivan, MD, Duke University
• Study Chair: Daniel E. Furst, MD, University of California, Los Angeles Rheumatology
• Study Chair: Peter A. McSweeney, MD, Presbyterian/St. Luke's Medical Center:Rocky Mountain Cancer Center
• Principal Investigator: Leslie J. Crofford, MD, University of Kentucky, Women's Health Program: Rheumatology
• Principal Investigator: Maureen D. Mayes, MD, MPH, University of Texas - Houston Health Science Center
• Principal Investigator: Richard A. Nash, MD, Fred Hutchinson Cancer Research

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Scleroderma: Cyclophosphamide or Transplantation (SCOT) Study

Publications

• Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin JD, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener MH, Seibold JR, Sullivan KM, Furst DE. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. Blood. 2007 Aug 15;110(4):1388-96. Epub 2007 Apr 23.
• Sullivan KM, Shah A, Sarantopoulos S, Furst DE. Review: Hematopoietic Stem Cell Transplantation for Scleroderma: Effective Immunomodulatory Therapy for Patients With Pulmonary Involvement. Arthritis Rheumatol. 2016 Oct;68(10):2361-71. doi: 10.1002/art.39748. Review.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00114530
• Other Study ID Numbers: DAIT SCSSc-01; NIAID CRMS ID#: 20133; NCT00472277; NCT00545038; NCT00848614; NCT00871221; NCT00872508
• First Posted: Jun 16, 2005
• Last Update Posted: Jun 2, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): systemic sclerosis; hematopoietic stem cell transplant; clinical trial; global rank composite score
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Autoimmune Diseases; Sclerosis; Cyclophosphamide

Study Results

Participant Flow

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Period Title: Overall Study
STARTED	36	39
COMPLETED	27	19
NOT COMPLETED	9	20

Baseline Characteristics

Arm/Group Title	mHSCT	Cyclophosphamide	Total
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).	Total of all reporting groups
Overall Participants	36	39	75
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	35 97.2%	38 97.4%	73 97.3%
>=65 years	1 2.8%	1 2.6%	2 2.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.9 (10.90)	46.9 (10.43)	45.9 (10.63)
Sex: Female, Male (Count of Participants)
Female	19 52.8%	29 74.4%	48 64%
Male	17 47.2%	10 25.6%	27 36%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 8.3%	5 12.8%	8 10.7%
Not Hispanic or Latino	32 88.9%	34 87.2%	66 88%
Unknown or Not Reported	1 2.8%	0 0%	1 1.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 5.6%	1 2.6%	3 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 5.6%	4 10.3%	6 8%
White	29 80.6%	31 79.5%	60 80%
More than one race	2 5.6%	3 7.7%	5 6.7%
Unknown or Not Reported	1 2.8%	0 0%	1 1.3%
Region of Enrollment (participants) [Number]
Canada	1 2.8%	2 5.1%	3 4%
United States	35 97.2%	37 94.9%	72 96%
Health Assessment Questionnaire - Disability Index (HAQ-DI) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	1.2 (0.65)	1.4 (0.86)	1.3 (0.77)
Short Form 36 Health Survey (SF-36) (units on a scale) [Mean (Standard Deviation) ]
Physical Component Score	29.5 (9.20)	28.9 (9.46)	29.2 (9.27)
Mental Component Score	44.7 (10.70)	44.6 (9.86)	44.6 (10.21)
Diffusion in Liters of Carbon Monoxide (DLCO) (Percent-Predicted) (Percent predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent predicted]	53.9 (7.63)	52.7 (8.19)	53.3 (7.90)
Forced Vital Capacity (FVC) (Percent-Predicted) (percent predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted]	74.5 (14.77)	73.8 (16.98)	74.2 (15.86)
Modified Rodnan Skin Score (mRSS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	28.5 (8.72)	30.8 (10.55)	29.7 (9.72)
Disease-Modifying Anti-Rheumatic Drug (DMARD) Use Within 6 Months of Randomization (Count of Participants)
Count of Participants [Participants]	26 72.2%	25 64.1%	51 68%
Disease-Modifying Anti-Rheumatic Drug (DMARD) Use (Count of Participants)
Count of Participants [Participants]	27 75%	32 82.1%	59 78.7%

Outcome Measures

1. Primary Outcome

Title	Global Rank Composite Score (GRCS) (Month 54, ITT)
Description	The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Median (Full Range) [Sum of subject-pair comparison scores]	17.0	-6.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	A Data and Safety Monitoring Board reviewed 4 pre-specified futility analyses that included an ability to stop for efficacy with p<0.0001, leaving alpha equal to 0.0496 for the primary ITT analysis of the GRCS at 54 months post-randomization.
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Global Rank Composite Score (GRCS) (Month 54, PP)
Description	The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Median (Full Range) [Sum of subject-pair comparison scores]	16	-11.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Global Rank Composite Score (GRCS) (Month 48, ITT)
Description	The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Median (Full Range) [Sum of subject-pair comparison scores]	20.0	-8.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Global Rank Composite Score (GRCS) (Month 48, PP)
Description	The GRCS is an analytic tool that accounts for multiple disease manifestations simultaneously. It does not measure clinical disease activity or severity but reflects how participants compared to one another based on a hierarchy of ordered outcomes: death, event-free survival (EFS), forced vital capacity (FVC), Health Assessment Questionnaire - Disability Index (HAQ-DI), and Modified Rodnan Skin Score (mRSS). Participants alive ranked higher than those who died; those who survived event-free ranked higher than EFS failures. EFS failure included death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted ), renal failure (chronic dialysis > 6 month or renal transplant), or cardiac failure (clinical congestive heart failure or left ventricular ejection fraction <30%). The lowest 3 GRCS components are ordinal; improvement, stability, or worsening from baseline (±10% change in FVC % predicted, ±0.4 change in HAQ-DI, ±25% change in mRSS).
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Median (Full Range) [Sum of subject-pair comparison scores]	17.0	-13.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Event-Free Survival (EFS) (Month 54, ITT)
Description	Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in diffusion in liters of carbon monoxide (DLCO) % predicted or >20% in forced vital capacity (FVC) % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 54 post-randomization.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
EFS Failure	10 27.8%	20 51.3%
Survived Event Free	26 72.2%	19 48.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of EFS at Month 54.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of Kaplan-Meier curves for EFS through Month 72
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments
	Method	Log Rank
	Comments

6. Secondary Outcome

Title	Event-Free Survival (EFS) (Month 54, PP)
Description	Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 54 post-randomization.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
EFS Failure	7 19.4%	17 43.6%
Survived Event Free	26 72.2%	17 43.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of EFS at Month 54.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of Kaplan-Meier curves for EFS through Month 72
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Log Rank
	Comments

7. Secondary Outcome

Title	Event-Free Survival (EFS) (Month 48, ITT)
Description	Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 48 post-randomization.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
EFS Failure	10 27.8%	20 51.3%
Survived Event Free	26 72.2%	19 48.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Event-Free Survival (EFS) (Month 48, PP)
Description	Event-free survival (EFS) is defined as survival without significant organ damage or death. EFS failure includes any one of the following: death, respiratory failure (decrease from baseline of >30% in DLCO % predicted or >20% in FVC % predicted, documented on at least 2 successive occasions at least 1 month apart), renal failure (requiring chronic dialysis > 6 months or transplantation), or the occurrence of cardiomyopathy (clinical congestive heart failure or left ventricular ejection fraction <30%, documented on at least 2 successive occasions at least 1 month apart). EFS failures include participants who failed any component of the EFS definition between randomization and Month 48 post-randomization.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
EFS Failure	7 19.4%	17 43.6%
Survived Event Free	26 72.2%	17 43.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Treatment-Related Mortality (Month 54, ITT)
Description	Death, occurring at any time between randomization and Month 54 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	Fisher Exact
	Comments

10. Secondary Outcome

Title	Treatment-Related Mortality (Month 54, PP)
Description	Death, occurring at any time between randomization and Month 54 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Fisher Exact
	Comments

11. Secondary Outcome

Title	Treatment-Related Mortality (Month 48, ITT)
Description	Death, occurring at any time between randomization and Month 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments
	Method	Fisher Exact
	Comments

12. Secondary Outcome

Title	Treatment-Related Mortality (Month 48, PP)
Description	Death, occurring at any time between randomization and Month 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.49
	Comments
	Method	Fisher Exact
	Comments

13. Secondary Outcome

Title	All-Cause Mortality (Month 54, ITT)
Description	Any death, regardless of relationship to treatment, between randomization and Month 54 post-randomization.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	6 16.7%	11 28.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of overall survival at Month 54.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of Kaplan-Meier curves for overall survival through Month 72.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Log Rank
	Comments

14. Secondary Outcome

Title	All-Cause Mortality (Month 54, PP)
Description	Any death, regardless of relationship to treatment, between randomization and Month 54 post-randomization.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	3 8.3%	8 20.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT
	Comments	Treatment arm comparisons of overall survival at Month 54.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Treatment arm comparisons of Kaplan-Meier curves for overall survival through Month 72.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Log Rank
	Comments

15. Secondary Outcome

Title	All-Cause Mortality (Month 48, ITT)
Description	Any death, regardless of relationship to treatment, between randomization and Month 48 post-randomization.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	6 16.7%	11 28.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Fisher Exact
	Comments

16. Secondary Outcome

Title	All-Cause Mortality (Month 48, PP)
Description	Any death, regardless of relationship to treatment, between randomization and Month 48 post-randomization.
Time Frame	48 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	3 8.3%	8 20.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Fisher Exact
	Comments

17. Secondary Outcome

Title	Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (ITT)
Description	HAQ-DI is a self-reported questionnaire of functionality that includes questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities). The final score ranges from 0 to 3, where a higher HAQ-DI score indicates a worse outcome. Analysis was based on an ordinal response variable, defined as follows: a decrease of >0.4 from baseline in the HAQ-DI score was considered disease improvement, an increase of >0.4 was considered disease worsening, and any change less than 0.4 was considered "no change." Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	19	10	20
Improvement	17 47.2%	6 15.4%	2 2.7%	0 NaN
No Change	8 22.2%	11 28.2%	5 6.7%	11 NaN
Worsening	1 2.8%	2 5.1%	3 4%	9 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

18. Secondary Outcome

Title	Change From Baseline to Month 54 in Health Assessment Questionnaire - Disability Index (HAQ-DI) (PP)
Description	HAQ-DI is a self-reported questionnaire of functionality that includes questions in 8 domains (dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities). The final score ranges from 0 to 3, where a higher HAQ-DI score indicates a worse outcome. Analysis was based on an ordinal response variable, defined as follows: a decrease of >0.4 from baseline in the HAQ-DI score was considered disease improvement, an increase of >0.4 was considered disease worsening, and any change less than 0.4 was considered "no change." Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	17	7	17
Improvement	17 47.2%	6 15.4%	2 2.7%	0 NaN
No Change	8 22.2%	10 25.6%	5 6.7%	9 NaN
Worsening	1 2.8%	1 2.6%	0 0%	8 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

19. Secondary Outcome

Title	Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (ITT)
Description	The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component was transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. Analysis was based on ordinal response, defined as follows for each component: a >= 10 point increase indicated disease improvement, a >= 10 point decrease indicated disease worsening, and a change <10 points indicated "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	19	10	20
Physical Component Score: Improvement	19 52.8%	6 15.4%	1 1.3%	0 NaN
Physical Component Score: No Change	6 16.7%	9 23.1%	6 8%	16 NaN
Physical Component Score: Worsening	1 2.8%	4 10.3%	3 4%	4 NaN
Mental Component Score: Improvement	10 27.8%	2 5.1%	1 1.3%	1 NaN
Mental Component Score: No Change	12 33.3%	12 30.8%	5 6.7%	12 NaN
Mental Component Score: Worsening	4 11.1%	5 12.8%	4 5.3%	7 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Physical Component Score. This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Physical Component Score. This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Mental Component Score. This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Mental Component Score. This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

20. Secondary Outcome

Title	Change From Baseline to Month 54 in Short Form 36 Health Survey (SF-36) (PP)
Description	The SF-36 measures health-related quality of life. It has 36 items and 2 component scores, the Physical Component Score and the Mental Component Score. Each component was transformed into a 0-100 scale (higher numbers indicate greater quality of life) and normalized to have a mean of 50 and standard deviation of 10 for the 1998 general US population. Analysis was based on ordinal response, defined as follows for each component: a >= 10 point increase indicated disease improvement, a >= 10 point decrease indicated disease worsening, and a change <10 points indicated "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	17	7	17
Physical Component Score: Improvement	19 52.8%	6 15.4%	1 1.3%	0 NaN
Physical Component Score: No Change	6 16.7%	9 23.1%	6 8%	14 NaN
Physical Component Score: Worsening	1 2.8%	2 5.1%	0 0%	3 NaN
Mental Component Score: Improvement	10 27.8%	2 5.1%	1 1.3%	1 NaN
Mental Component Score: No Change	12 33.3%	12 30.8%	5 6.7%	10 NaN
Mental Component Score: Worsening	4 11.1%	3 7.7%	1 1.3%	6 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Physical Component Score. This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Physical Component Score. This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Mental Component Score. This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	Mental Component Score. This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

21. Secondary Outcome

Title	Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (ITT)
Description	Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was <13 or >17 gm/dL, and altitude (Calgary site only). Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >15% in DLCO % Predicted indicated disease improvement, a decrease of >15% indicated disease worsening, and a change of <=15% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	19	10	20
Improvement	4 11.1%	5 12.8%	0 0%	0 NaN
No Change	19 52.8%	8 20.5%	0 0%	2 NaN
Worsening	3 8.3%	6 15.4%	10 13.3%	18 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

22. Secondary Outcome

Title	Change From Baseline to Month 54 in Diffusion in Liters of Carbon Monoxide (DLCO) (PP)
Description	Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function. Predicted values for DLCO were computed using the Crapo Morris equations and adjusted per the Cotes formula for anemia, if a participant's hemoglobin was <13 or >17 gm/dL, and altitude (Calgary site only). Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >15% in DLCO % Predicted indicated disease improvement, a decrease of >15% indicated disease worsening, and a change of <=15% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	17	7	17
Improvement	4 11.1%	5 12.8%	0 0%	0 NaN
No Change	19 52.8%	8 20.5%	0 0%	2 NaN
Worsening	3 8.3%	4 10.3%	7 9.3%	15 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

23. Secondary Outcome

Title	Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (ITT)
Description	Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards. Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >10% in FVC % Predicted indicated disease improvement, a decrease of >10% indicated disease worsening, and a change of <=10% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	19	10	20
Improvement	12 33.3%	7 17.9%	0 0%	1 NaN
No Change	13 36.1%	8 20.5%	2 2.7%	2 NaN
Worsening	1 2.8%	4 10.3%	8 10.7%	17 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

24. Secondary Outcome

Title	Change From Baseline to Month 54 in Forced Vital Capacity (FVC) (PP)
Description	Forced Vital Capacity (FVC) is the amount of air that can be forcibly exhaled after a full breath and is a measure of lung function. Predicted FVC was based on institutional standards. Analysis was based on an ordinal response variable, defined as follows: an increase from baseline of >10% in FVC % Predicted indicated disease improvement, a decrease of >10% indicated disease worsening, and a change of <=10% was considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	17	7	17
Improvement	12 33.3%	7 17.9%	0 0%	1 NaN
No Change	13 36.1%	8 20.5%	2 2.7%	2 NaN
Worsening	1 2.8%	2 5.1%	5 6.7%	14 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

25. Secondary Outcome

Title	Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (ITT)
Description	The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity. Analysis was based on an ordinal response variable, defined as follows: if the baseline mRSS was <=20, a decrease >=5 points from baseline indicated disease improvement and an increase >= 5 points indicated disease worsening; if the baseline mRSS was >20, then a decrease of >25% indicated disease improvement and an increase of >25% indicated disease worsening. Participants who do not meet the disease criteria outlined above were considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	19	10	20
Improvement	26 72.2%	14 35.9%	5 6.7%	5 NaN
No Change	0 0%	3 7.7%	1 1.3%	10 NaN
Worsening	0 0%	2 5.1%	4 5.3%	5 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

26. Secondary Outcome

Title	Change From Baseline to Month 54 in Modified Rodnan Skin Score (mRSS) (PP)
Description	The Modified Rodnan Skin Score (mRSS) is a measure of skin thickness. Skin thickness in 17 anatomic areas was rated on a 0-3 scale and scores are summed to obtain the mRSS (range from 0 - 51), with higher mRSS scores indicating worse disease activity. Analysis was based on an ordinal response variable, defined as follows: if the baseline mRSS was <=20, a decrease >=5 points from baseline indicated disease improvement and an increase >= 5 points indicated disease worsening; if the baseline mRSS was >20, then a decrease of >25% indicated disease improvement and an increase of >25% indicated disease worsening. Participants who do not meet the disease criteria outlined above were considered "no change". Data for participants without a Month 54 assessment was imputed using a last observation carried forward approach; improvement/worsening was assessed at each participant's last available study visit that occurred prior to or at Month 54, without confirmation at the next visit.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT- EFS Survivor	Cyclophosphamide-EFS Survivor	mHSCT- EFS Failure	Cyclophosphamide- EFS Failure
Arm/Group Description	Subjects in the mHSCT group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who met the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the mHSCT group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.	Subjects in the Cyclophosphamide group who failed the event-free survival (EFS) endpoint, defined as survival without significant organ damage or death.
Measure Participants	26	17	7	17
Improvement	26 72.2%	14 35.9%	5 6.7%	5 NaN
No Change	0 0%	3 7.7%	1 1.3%	10 NaN
Worsening	0 0%	0 0%	1 1.3%	2 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is not stratified. EFS survivors and failures are pooled within each treatment arm.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Kruskal-Wallis
	Comments	Computed as Mantel Haenszel Chi Square using modified ridit scores.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide, mHSCT- EFS Failure, Cyclophosphamide- EFS Failure
	Comments	This analysis is stratified by EFS status.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Van Elteren extension of the Wilcoxon Rank Sum

27. Secondary Outcome

Title	New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (ITT)
Description	Any events that met the criteria outlined below or were reported as adverse events between randomization and Month 54 post-randomization are summarized. 1) Development of new or worsening arrhythmias that require medical treatment for >= 3 months or require ablative therapy or pacemaker insertion. (Note that for a participant who has medically controlled arrhythmia at randomization, worsening was defined as breakthrough episodes severe enough to prompt change in medication, an increase in the dose of a medication, or addition of a new medication to maintain control of the arrhythmia.) 2) Congestive heart failure (CHF) requiring clinical treatment for >= 3 months develops. 3) Clinically significant pericardial effusion (excess fluid around the heart) that required pericardial window.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Development of new or worsening arrhythmias	6 16.7%	4 10.3%
CHF requiring clinical treatment	0 0%	4 10.3%
Clinically significant pericardial effusion	2 5.6%	1 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Development of new or worsening arrhythmias
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	CHF requiring clinical treatment
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Clinically significant pericardial effusion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments
	Method	Chi-squared
	Comments

28. Secondary Outcome

Title	New or Worsening Arrhythmias, Congestive Heart Failure, or Pericardial Effusion (PP)
Description	Any events that met the criteria outlined below or were reported as adverse events between randomization and Month 54 post-randomization are summarized. 1) Development of new or worsening arrhythmias that require medical treatment for >= 3 months or require ablative therapy or pacemaker insertion. (Note that for a participant who has medically controlled arrhythmia at randomization, worsening will be defined as breakthrough episodes severe enough to prompt change in medication, an increase in the dose of a medication or addition of a new medication to maintain control of the arrhythmia.) 2) Congestive heart failure (CHF) requiring clinical treatment for >= 3 months develops. 3) Clinically significant pericardial effusion (excess fluid around the heart) that required pericardial window.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Development of new or worsening arrhythmias	6 16.7%	4 10.3%
CHF requiring clinical treatment	0 0%	4 10.3%
Clinically significant pericardial effusion	2 5.6%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Development of new or worsening arrhythmias
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	CHF requiring clinical treatment
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments	Clinically significant pericardial effusion
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.15
	Comments
	Method	Chi-squared
	Comments

29. Secondary Outcome

Title	New or Worsening Pulmonary Hypertension (ITT)
Description	Any pulmonary arterial hypertension (PAH) events that occurred between randomization and Month 54 post-randomization were summarized. Development of PAH occurred if the participant met the following criteria, where the measurement value(s) could not be explained by other causes such as congestive heart failure or pulmonary emboli: 1) a post-baseline peak systolic pulmonary artery pressure > 55 mmHg by echocardiogram or 2) a mean pulmonary artery pressure > 30 mmHg at rest measured by right heart catheterization. If the post-baseline peak systolic pulmonary artery pressure was between 40 to 55 mmHg by echocardiogram, a right heart catheterization was done to confirm a diagnosis of pulmonary artery hypertension. The endpoint was met if the mean pulmonary artery pressure was > 30 mmHg at rest by right heart catheterization. Additionally, any adverse event reported as PAH was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	0 0%	5 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments
	Method	Chi-squared
	Comments

30. Secondary Outcome

Title	New or Worsening Pulmonary Hypertension (PP)
Description	Any pulmonary arterial hypertension (PAH) events that occurred between randomization and Month 54 post-randomization were summarized. Development of PAH occurred if the participant met the following criteria, where the measurement value(s) could not be explained by other causes such as congestive heart failure or pulmonary emboli: 1) a post-baseline peak systolic pulmonary artery pressure > 55 mmHg by echocardiogram or 2) a mean pulmonary artery pressure > 30 mmHg at rest measured by right heart catheterization. If the post-baseline peak systolic pulmonary artery pressure was between 40 to 55 mmHg by echocardiogram, a right heart catheterization would be done to confirm a diagnosis of pulmonary artery hypertension. The endpoint was met if the mean pulmonary artery pressure was > 30 mmHg at rest by right heart catheterization. Additionally, any adverse event reported as PAH was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	0 0%	5 12.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Chi-squared
	Comments

31. Secondary Outcome

Title	Occurrence of Scleroderma Renal Crisis (ITT)
Description	Documented scleroderma renal crisis (hypertensive or non-hypertensive) occurring from randomization to Month 54 post-randomization was summarized. A hypertensive scleroderma renal crisis occurred if a participant obtained both of the following: New-onset hypertension, defined as systolic blood pressure (SBP) >= 140 mmHg, diastolic blood pressure (DBP) >= 90 mmHg, a rise in SBP >= 30 mmHg compared to baseline, or a rise in DBP >= 20 mmHg compared to baseline, and one of the following features: 1) increase of >= 50 % above baseline in serum creatinine, 2) proteinuria (>= 2+ by dipstick confirmed by protein:creatinine ratio > 2.5), 3) hematuria (>= 2+ by dipstick or > 10 RBCs/HPF, without menstruation), 4) thrombocytopenia (< 100,000 plts/mm3), or 5) hemolysis (determined by blood smear or increased reticulocyte count). Additionally, any adverse event reported as a scleroderma renal crisis was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	2 5.6%	3 7.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Chi-squared
	Comments

32. Secondary Outcome

Title	Occurrence of Scleroderma Renal Crisis (PP)
Description	Documented scleroderma renal crisis (hypertensive or non-hypertensive) occurring from randomization to Month 54 post-randomization was summarized. A hypertensive scleroderma renal crisis occurred if a participant obtained both of the following: New-onset hypertension, defined as systolic blood pressure (SBP) >= 140 mmHg, diastolic blood pressure (DBP) >= 90 mmHg, a rise in SBP >= 30 mmHg compared to baseline, or a rise in DBP >= 20 mmHg compared to baseline, and one of the following features: 1) increase of >= 50 % above baseline in serum creatinine, 2) proteinuria (>= 2+ by dipstick confirmed by protein:creatinine ratio > 2.5), 3) hematuria (>= 2+ by dipstick or > 10 RBCs/HPF, without menstruation), 4) thrombocytopenia (< 100,000 plts/mm3), or 5) hemolysis (determined by blood smear or increased reticulocyte count). Additionally, any adverse event reported as a scleroderma renal crisis was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	0 0%	1 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments
	Method	Chi-squared
	Comments

33. Secondary Outcome

Title	Documented Myositis (ITT)
Description	Number of participants who experienced any event of myositis that occurred from randomization to Month 54 post-randomization. Documented myositis occurred if the participant had 1) elevated creatine phosphokinase (CPK), electromyography, and/or biopsy and 2) required > 30 mg per day prednisone for over 1 month or another therapy such as methotrexate (MTX) for treatment of myositis. Additionally, any adverse event reported as myositis was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Chi-squared
	Comments

34. Secondary Outcome

Title	Documented Myositis (PP)
Description	Number of participants who experienced any event of myositis that occurred from randomization to Month 54 post-randomization. Documented myositis occurred if the participant had 1) elevated creatine phosphokinase (CPK), electromyography, and/or biopsy and 2) required > 30 mg per day prednisone for over 1 month or another therapy such as methotrexate (MTX) for treatment of myositis. Additionally, any adverse event reported as myositis was included in the analysis.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	1 2.8%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments
	Method	Chi-squared
	Comments

35. Secondary Outcome

Title	Initiating Use of Disease-Modifying Antirheumatic Drugs (DMARDs) by Month 54 (ITT)
Description	Initiation of disease-modifying antirheumatic drugs (DMARDs). Participants were not expected to receive additional disease-modifying therapy for systemic sclerosis (SSc) in the absence of disease progression. In general, this includes the administration of any therapy clearly given for the purpose of treating the underlying SSc. It does not include concomitant treatments permitted in the protocol, such as use of methotrexate (15 g or less), anti-malarials, or minocycline for arthritis only. Systemic corticosteroids given at > 10 mg/day (prednisone or prednisone equivalent), without clearly defined non-SSc indications, and methotrexate given for non-arthritis indications are examples of qualifying DMARDs.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Intention to treat (ITT). The ITT population includes all randomized participants.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	36	39
Count of Participants [Participants]	3 8.3%	15 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Chi-squared
	Comments

36. Secondary Outcome

Title	Initiating Use of Disease-Modifying Antirheumatic Drugs by Month 54 (DMARDs) (PP)
Description	Initiation of disease-modifying antirheumatic drugs (DMARDs). Participants were not expected to receive additional disease-modifying therapy for systemic sclerosis (SSc) in the absence of disease progression. In general, this includes the administration of any therapy clearly given for the purpose of treating the underlying SSc. It does not include concomitant treatments permitted in the protocol, such as use of methotrexate (15 g or less), anti-malarials, or minocycline for arthritis only. Systemic corticosteroids given at > 10 mg/day (prednisone or prednisone equivalent), without clearly defined non-SSc indications, and methotrexate given for non-arthritis indications are examples of qualifying DMARDs.
Time Frame	54 Months Post-Randomization

Outcome Measure Data

Analysis Population Description

Per-protocol (PP). The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm, or receiving at least 9 of 12 planned doses in the cyclophosphamide arm.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	33	34
Count of Participants [Participants]	3 8.3%	15 38.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Chi-squared
	Comments

37. Secondary Outcome

Title	Regimen-Related Toxicities
Description	Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy.
Time Frame	Randomization through end of study follow-up (up to Month 72 post-randomization)

Outcome Measure Data

Analysis Population Description

Safety population. The safety population includes all participants for whom study treatment was initiated. For the mHSCT arm, treatment was initiated with the first dose of granulocyte colony stimulating factor for mobilization, and for the cyclophosphamide arm, treatment was initiated with the first dose of IV cyclophosphamide.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	34	37
Possibly Related	106	23
Probably Related	98	13
Definitely Related	90	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Regression, Linear
	Comments	P-value comes from a Poisson regression comparing the person-year adjusted event rates between the two treatment groups.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Person-Time (Years)
	Estimated Value	174.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Person-Time (P-T) rates (events/P-T) are as follows: Possibly related = 0.61, Probably related = 0.57, Definitely related = 0.52

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Person-Time (Years)
	Estimated Value	141.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Person-Time (P-T) rates (events/P-T) are as follows: Possibly related = 0.17, Probably related = 0.09, Definitely related = 0.04

38. Secondary Outcome

Title	Number of Subjects With Regimen-Related Toxicities
Description	Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy.
Time Frame	Randomization through end of study follow-up (up to Month 72 post-randomization).

Outcome Measure Data

Analysis Population Description

Safety population. The safety population includes all participants for whom study treatment was initiated. For the mHSCT arm, treatment was initiated with the first dose of granulocyte colony stimulating factor for mobilization, and for the cyclophosphamide arm, treatment was initiated with the first dose of IV cyclophosphamide.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	34	37
Possibly Related	33 91.7%	10 25.6%
Probably Related	27 75%	10 25.6%
Definitely Related	26 72.2%	3 7.7%

39. Secondary Outcome

Title	Infectious Complications
Description	Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.
Time Frame	Randomization through end of study follow-up (up to Month 72 post-randomization).

Outcome Measure Data

Analysis Population Description

Safety population. The safety population includes all participants for whom study treatment was initiated. For the mHSCT arm, treatment was initiated with the first dose of granulocyte colony stimulating factor for mobilization, and for the cyclophosphamide arm, treatment was initiated with the first dose of IV cyclophosphamide.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	34	37
Number [Events]	131	112

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	mHSCT, Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7
	Comments
	Method	Regression, Linear
	Comments	P-value comes from a Poisson regression comparing the person-year adjusted event rates between the two treatment groups.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	mHSCT
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Person-Time (Years)
	Estimated Value	174.4
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Person-Time (P-T) rate (events/P-T) is 0.76

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cyclophosphamide
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Person-Time (Years)
	Estimated Value	141.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	The Person-Time (P-T) rate (events/P-T) is 0.80

40. Secondary Outcome

Title	Number of Subjects With Infectious Complications
Description	Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.
Time Frame	Randomization through end of study follow-up (up to Month 72 post-randomization).

Outcome Measure Data

Analysis Population Description

Safety population. The safety population includes all participants for whom study treatment was initiated. For the mHSCT arm, treatment was initiated with the first dose of granulocyte colony stimulating factor for mobilization, and for the cyclophosphamide arm, treatment was initiated with the first dose of IV cyclophosphamide.

Arm/Group Title	mHSCT	Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)	Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
Measure Participants	34	37
Count of Participants [Participants]	33 91.7%	31 79.5%

41. Secondary Outcome

Title	Time to Absolute Neutrophil Count Engraftment
Description	Time to absolute neutrophil count (ANC) engraftment is defined as the number of days post-transplant until required levels of ANC are attained (for the mHSCT arm only). If engraftment did not occur within 28 days post-transplant, then the variable was set to 28 days. ANC engraftment required an ANC of > 500 cells/microliter, maintained for 3 consecutive days.
Time Frame	28 days post-transplant

Outcome Measure Data

Analysis Population Description

Per-protocol (PP) - mHSCT arm only. The PP population is defined as those participants who completed the assigned treatment protocol: undergoing autologous CD34-selected hematopoietic progenitor cell transplantation in the mHSCT arm.

Arm/Group Title	mHSCT
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)
Measure Participants	34
Median (Full Range) [Days]	10

Adverse Events

Time Frame	From randomization until study completion, an average of 72 months, or until 30 days after a participant withdrew early from the study. All-cause mortality was additionally identified through site contact or public records after participant withdrawal.
Adverse Event Reporting Description	AEs were collected in the safety population (all participants for whom study treatment was initiated, defined as: mHSCT arm, first dose of granulocyte colony stimulating factor for mobilization; cyclophosphamide arm, first dose of IV cyclophosphamide). In the mHSCT arm, Grade 4 cytopenias reported that occur between conditioning and Day 28 after infusion of the IP are not reported as SAEs. All-cause mortality is reported in the ITT population (all randomized participants).
Arm/Group Title	mHSCT		Cyclophosphamide
Arm/Group Description	Participants were administered granulocyte colony stimulating factor (G-CSF) and had hematopoietic stem cells removed from their blood. They then underwent high-dose immunosuppressive therapy using a conditioning regimen of total body irradiation (800 cGy given over 2 days with lung and kidney shielding limiting exposure to 200cGy), cyclophosphamide (60 mg/kg/day for 2 days), IV Methylprednisolone (1 mg/kg/day for 3 days), and equine antithymocyte globulin (ATGAM) (15 mg/kg/day for 3 days). Purified autologous stem cell were infused at a dose of >2.5x106 CD34+ cells/kg. After transplantation, participants received additional doses of IV Methylprednisolone (1 mg/kg/day for 3 days) and ATGAM (15 mg/kg/day for 3 days.)		Participants received 12 monthly pulses of high-dose intravenous cyclophosphamide (an initial dose of 500 mg/m^2, followed by 11 doses of 750 mg/m^2).
All Cause Mortality
	mHSCT		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/36 (19.4%)		14/39 (35.9%)
Serious Adverse Events
	mHSCT		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/34 (73.5%)		19/37 (51.4%)
Blood and lymphatic system disorders
Anaemia	0/34 (0%)	0	1/37 (2.7%)	1
Febrile neutropenia	2/34 (5.9%)	2	1/37 (2.7%)	1
Leukopenia	1/34 (2.9%)	1	0/37 (0%)	0
Lymphopenia	4/34 (11.8%)	6	3/37 (8.1%)	3
Neutropenia	2/34 (5.9%)	2	2/37 (5.4%)	2
Cardiac disorders
Arrhythmia	0/34 (0%)	0	1/37 (2.7%)	1
Atrial fibrillation	0/34 (0%)	0	2/37 (5.4%)	2
Atrial flutter	1/34 (2.9%)	2	0/37 (0%)	0
Cardiac failure congestive	0/34 (0%)	0	3/37 (8.1%)	4
Left ventricular failure	1/34 (2.9%)	1	0/37 (0%)	0
Myocardial infarction	0/34 (0%)	0	1/37 (2.7%)	1
Pericardial effusion	1/34 (2.9%)	1	0/37 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/34 (2.9%)	1	1/37 (2.7%)	1
Colonic obstruction	0/34 (0%)	0	1/37 (2.7%)	1
Diarrhoea	1/34 (2.9%)	1	0/37 (0%)	0
Faecaloma	0/34 (0%)	0	1/37 (2.7%)	1
Gastric antral vascular ectasia	0/34 (0%)	0	1/37 (2.7%)	1
Gastrointestinal haemorrhage	0/34 (0%)	0	1/37 (2.7%)	1
Ileus	0/34 (0%)	0	1/37 (2.7%)	1
Intestinal hypomotility	1/34 (2.9%)	1	2/37 (5.4%)	2
Nausea	1/34 (2.9%)	1	1/37 (2.7%)	1
Pancreatitis	0/34 (0%)	0	1/37 (2.7%)	1
Pneumatosis cystoides intestinalis	0/34 (0%)	0	1/37 (2.7%)	1
Pneumoperitoneum	0/34 (0%)	0	1/37 (2.7%)	1
Small intestinal obstruction	1/34 (2.9%)	4	1/37 (2.7%)	1
General disorders
Chest pain	0/34 (0%)	0	1/37 (2.7%)	1
Heparin-induced thrombocytopenia	1/34 (2.9%)	1	0/37 (0%)	0
Pyrexia	2/34 (5.9%)	2	0/37 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/34 (0%)	0	1/37 (2.7%)	1
Immune system disorders
Graft versus host disease	1/34 (2.9%)	1	0/37 (0%)	0
Hypersensitivity	1/34 (2.9%)	1	0/37 (0%)	0
Infections and infestations
Bacteraemia	1/34 (2.9%)	1	0/37 (0%)	0
Bronchitis viral	0/34 (0%)	0	1/37 (2.7%)	1
Cellulitis	1/34 (2.9%)	1	1/37 (2.7%)	2
Cellulitis staphylococcal	0/34 (0%)	0	1/37 (2.7%)	1
Fungaemia	0/34 (0%)	0	1/37 (2.7%)	1
Herpes zoster	1/34 (2.9%)	1	0/37 (0%)	0
Meningitis enterococcal	1/34 (2.9%)	1	0/37 (0%)	0
Pneumonia	5/34 (14.7%)	6	1/37 (2.7%)	1
Sepsis	1/34 (2.9%)	1	0/37 (0%)	0
Septic shock	1/34 (2.9%)	1	1/37 (2.7%)	1
Staphylococcal infection	0/34 (0%)	0	1/37 (2.7%)	1
Urinary tract infection	0/34 (0%)	0	2/37 (5.4%)	4
Viral infection	0/34 (0%)	0	1/37 (2.7%)	1
Injury, poisoning and procedural complications
Femoral neck fracture	0/34 (0%)	0	1/37 (2.7%)	1
Investigations
Pulmonary function test decreased	1/34 (2.9%)	1	4/37 (10.8%)	5
Metabolism and nutrition disorders
Failure to thrive	1/34 (2.9%)	1	0/37 (0%)	0
Fluid retention	1/34 (2.9%)	1	0/37 (0%)	0
Hypokalaemia	0/34 (0%)	0	1/37 (2.7%)	2
Musculoskeletal and connective tissue disorders
Bone pain	1/34 (2.9%)	1	0/37 (0%)	0
Myositis	1/34 (2.9%)	1	0/37 (0%)	0
Scleroderma	0/34 (0%)	0	2/37 (5.4%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/34 (2.9%)	1	0/37 (0%)	0
Breast cancer recurrent	0/34 (0%)	0	1/37 (2.7%)	1
Myelodysplastic syndrome	2/34 (5.9%)	2	0/37 (0%)	0
Papillary thyroid cancer	1/34 (2.9%)	1	0/37 (0%)	0
Nervous system disorders
Carotid artery stenosis	1/34 (2.9%)	1	0/37 (0%)	0
Dizziness	0/34 (0%)	0	1/37 (2.7%)	1
Dystonia	1/34 (2.9%)	1	0/37 (0%)	0
Psychiatric disorders
Depression	1/34 (2.9%)	1	1/37 (2.7%)	1
Major depression	0/34 (0%)	0	1/37 (2.7%)	1
Renal and urinary disorders
Renal failure	1/34 (2.9%)	1	0/37 (0%)	0
Scleroderma renal crisis	1/34 (2.9%)	1	3/37 (8.1%)	5
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/34 (0%)	0	1/37 (2.7%)	1
Aspiration	1/34 (2.9%)	1	0/37 (0%)	0
Capillary leak syndrome	1/34 (2.9%)	1	0/37 (0%)	0
Dyspnoea	1/34 (2.9%)	1	0/37 (0%)	0
Hypoxia	1/34 (2.9%)	1	0/37 (0%)	0
Interstitial lung disease	1/34 (2.9%)	1	1/37 (2.7%)	1
Pneumonia aspiration	1/34 (2.9%)	1	1/37 (2.7%)	2
Pneumonitis	3/34 (8.8%)	3	0/37 (0%)	0
Pulmonary alveolar haemorrhage	1/34 (2.9%)	1	0/37 (0%)	0
Pulmonary embolism	0/34 (0%)	0	1/37 (2.7%)	1
Pulmonary hypertension	0/34 (0%)	0	1/37 (2.7%)	1
Pulmonary oedema	0/34 (0%)	0	1/37 (2.7%)	1
Respiratory distress	1/34 (2.9%)	1	0/37 (0%)	0
Respiratory failure	0/34 (0%)	0	4/37 (10.8%)	4
Vascular disorders
Hypotension	2/34 (5.9%)	2	0/37 (0%)	0
Other (Not Including Serious) Adverse Events
	mHSCT		Cyclophosphamide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/34 (97.1%)		37/37 (100%)
Blood and lymphatic system disorders
Anaemia	19/34 (55.9%)	41	16/37 (43.2%)	23
Febrile neutropenia	2/34 (5.9%)	2	0/37 (0%)	0
Iron deficiency anaemia	2/34 (5.9%)	2	1/37 (2.7%)	1
Leukopenia	26/34 (76.5%)	42	6/37 (16.2%)	15
Lymphopenia	31/34 (91.2%)	73	25/37 (67.6%)	53
Neutropenia	26/34 (76.5%)	34	4/37 (10.8%)	6
Thrombocytopenia	29/34 (85.3%)	39	0/37 (0%)	0
Cardiac disorders
Palpitations	2/34 (5.9%)	2	1/37 (2.7%)	1
Tachycardia	2/34 (5.9%)	2	0/37 (0%)	0
Endocrine disorders
Hypothyroidism	5/34 (14.7%)	6	2/37 (5.4%)	2
Eye disorders
Conjunctivitis	3/34 (8.8%)	3	1/37 (2.7%)	1
Dry eye	0/34 (0%)	0	2/37 (5.4%)	2
Gastrointestinal disorders
Abdominal distension	3/34 (8.8%)	3	0/37 (0%)	0
Abdominal pain	0/34 (0%)	0	2/37 (5.4%)	5
Abdominal pain upper	2/34 (5.9%)	2	1/37 (2.7%)	1
Constipation	1/34 (2.9%)	1	8/37 (21.6%)	16
Diarrhoea	4/34 (11.8%)	7	5/37 (13.5%)	6
Dry mouth	0/34 (0%)	0	3/37 (8.1%)	3
Dysphagia	6/34 (17.6%)	6	5/37 (13.5%)	5
Gastritis	3/34 (8.8%)	3	0/37 (0%)	0
Gastrointestinal haemorrhage	2/34 (5.9%)	2	0/37 (0%)	0
Gastrointestinal motility disorder	1/34 (2.9%)	1	2/37 (5.4%)	2
Gastrooesophageal reflux disease	5/34 (14.7%)	6	5/37 (13.5%)	5
Haematochezia	0/34 (0%)	0	2/37 (5.4%)	3
Haemorrhoids	2/34 (5.9%)	2	0/37 (0%)	0
Nausea	3/34 (8.8%)	4	6/37 (16.2%)	23
Stomatitis	1/34 (2.9%)	1	2/37 (5.4%)	2
Vomiting	0/34 (0%)	0	2/37 (5.4%)	2
General disorders
Chest pain	1/34 (2.9%)	2	2/37 (5.4%)	3
Fatigue	6/34 (17.6%)	8	5/37 (13.5%)	8
Mucosal inflammation	2/34 (5.9%)	2	1/37 (2.7%)	1
Pain	2/34 (5.9%)	2	2/37 (5.4%)	2
Pyrexia	5/34 (14.7%)	5	1/37 (2.7%)	1
Infections and infestations
Bacteraemia	3/34 (8.8%)	3	0/37 (0%)	0
Body tinea	2/34 (5.9%)	2	1/37 (2.7%)	1
Bronchitis	3/34 (8.8%)	3	2/37 (5.4%)	2
Bronchitis acute	1/34 (2.9%)	1	2/37 (5.4%)	2
Cellulitis	4/34 (11.8%)	4	2/37 (5.4%)	2
Cystitis	2/34 (5.9%)	2	0/37 (0%)	0
Cytomegalovirus infection	4/34 (11.8%)	4	0/37 (0%)	0
Herpes zoster	11/34 (32.4%)	12	1/37 (2.7%)	1
Infected skin ulcer	2/34 (5.9%)	4	4/37 (10.8%)	10
Influenza	2/34 (5.9%)	2	0/37 (0%)	0
Localised infection	0/34 (0%)	0	2/37 (5.4%)	2
Nasopharyngitis	5/34 (14.7%)	12	2/37 (5.4%)	5
Paronychia	2/34 (5.9%)	2	1/37 (2.7%)	2
Pneumonia	4/34 (11.8%)	4	1/37 (2.7%)	1
Respiratory tract infection	1/34 (2.9%)	1	2/37 (5.4%)	2
Sinusitis	3/34 (8.8%)	4	0/37 (0%)	0
Tooth abscess	0/34 (0%)	0	2/37 (5.4%)	2
Upper respiratory tract infection	9/34 (26.5%)	14	8/37 (21.6%)	19
Urinary tract infection	1/34 (2.9%)	2	11/37 (29.7%)	20
Investigations
Alanine aminotransferase increased	9/34 (26.5%)	10	1/37 (2.7%)	1
Aspartate aminotransferase increased	3/34 (8.8%)	3	1/37 (2.7%)	1
Blood alkaline phosphatase increased	2/34 (5.9%)	2	1/37 (2.7%)	1
Blood creatinine increased	1/34 (2.9%)	1	3/37 (8.1%)	3
Ejection fraction decreased	3/34 (8.8%)	3	1/37 (2.7%)	1
Forced expiratory volume decreased	11/34 (32.4%)	13	5/37 (13.5%)	5
Pulmonary function test decreased	23/34 (67.6%)	30	12/37 (32.4%)	16
Vital capacity decreased	6/34 (17.6%)	6	6/37 (16.2%)	6
Weight decreased	2/34 (5.9%)	2	6/37 (16.2%)	6
Weight increased	6/34 (17.6%)	6	1/37 (2.7%)	1
Metabolism and nutrition disorders
Hypercholesterolaemia	2/34 (5.9%)	2	1/37 (2.7%)	1
Hyperglycaemia	3/34 (8.8%)	6	2/37 (5.4%)	4
Hyperkalaemia	0/34 (0%)	0	3/37 (8.1%)	3
Hypoalbuminaemia	3/34 (8.8%)	3	5/37 (13.5%)	9
Hypocalcaemia	2/34 (5.9%)	2	2/37 (5.4%)	5
Hyponatraemia	4/34 (11.8%)	4	0/37 (0%)	0
Hypophosphataemia	4/34 (11.8%)	4	0/37 (0%)	0
Vitamin B12 deficiency	0/34 (0%)	0	2/37 (5.4%)	2
Vitamin D deficiency	3/34 (8.8%)	3	2/37 (5.4%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	9/34 (26.5%)	9	4/37 (10.8%)	5
Arthritis	0/34 (0%)	0	4/37 (10.8%)	4
Back pain	2/34 (5.9%)	2	0/37 (0%)	0
Bursitis	3/34 (8.8%)	3	0/37 (0%)	0
Joint range of motion decreased	0/34 (0%)	0	2/37 (5.4%)	2
Joint stiffness	0/34 (0%)	0	4/37 (10.8%)	4
Muscle spasms	2/34 (5.9%)	2	3/37 (8.1%)	4
Muscular weakness	1/34 (2.9%)	1	2/37 (5.4%)	2
Musculoskeletal pain	3/34 (8.8%)	3	1/37 (2.7%)	1
Osteoarthritis	2/34 (5.9%)	2	0/37 (0%)	0
Osteoporosis	4/34 (11.8%)	4	0/37 (0%)	0
Pain in extremity	2/34 (5.9%)	2	3/37 (8.1%)	5
Shoulder pain	4/34 (11.8%)	5	0/37 (0%)	0
Tendon disorder	0/34 (0%)	0	3/37 (8.1%)	3
Tendonitis	2/34 (5.9%)	2	1/37 (2.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lung neoplasm	0/34 (0%)	0	2/37 (5.4%)	2
Nervous system disorders
Dizziness	1/34 (2.9%)	1	2/37 (5.4%)	3
Headache	4/34 (11.8%)	6	5/37 (13.5%)	7
Hypoaesthesia	2/34 (5.9%)	3	3/37 (8.1%)	3
Tremor	2/34 (5.9%)	2	0/37 (0%)	0
Psychiatric disorders
Anxiety	3/34 (8.8%)	4	2/37 (5.4%)	2
Depression	9/34 (26.5%)	11	8/37 (21.6%)	11
Insomnia	5/34 (14.7%)	6	5/37 (13.5%)	6
Renal and urinary disorders
Haematuria	0/34 (0%)	0	2/37 (5.4%)	4
Proteinuria	1/34 (2.9%)	1	2/37 (5.4%)	2
Reproductive system and breast disorders
Vulvovaginal dryness	2/34 (5.9%)	2	0/37 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	8/34 (23.5%)	13	4/37 (10.8%)	6
Dyspnoea	3/34 (8.8%)	3	3/37 (8.1%)	3
Dyspnoea exacerbated	0/34 (0%)	0	3/37 (8.1%)	3
Epistaxis	2/34 (5.9%)	2	0/37 (0%)	0
Hypoxia	2/34 (5.9%)	3	1/37 (2.7%)	1
Pharyngolaryngeal pain	1/34 (2.9%)	1	4/37 (10.8%)	4
Pulmonary fibrosis	0/34 (0%)	0	2/37 (5.4%)	2
Pulmonary hypertension	0/34 (0%)	0	2/37 (5.4%)	2
Rhinitis allergic	0/34 (0%)	0	2/37 (5.4%)	3
Skin and subcutaneous tissue disorders
Alopecia	3/34 (8.8%)	3	1/37 (2.7%)	1
Hyperkeratosis	2/34 (5.9%)	2	0/37 (0%)	0
Pruritus	6/34 (17.6%)	6	3/37 (8.1%)	3
Rash	9/34 (26.5%)	9	2/37 (5.4%)	4
Rash pruritic	2/34 (5.9%)	2	0/37 (0%)	0
Rosacea	2/34 (5.9%)	2	0/37 (0%)	0
Skin ulcer	7/34 (20.6%)	14	10/37 (27%)	24
Vascular disorders
Hot flush	1/34 (2.9%)	1	2/37 (5.4%)	2
Hypertension	2/34 (5.9%)	3	2/37 (5.4%)	2
Hypotension	3/34 (8.8%)	6	2/37 (5.4%)	2
Raynaud's phenomenon	4/34 (11.8%)	4	0/37 (0%)	0

Limitations/Caveats

Results are applicable for SSc with severe internal organ disease and may not be generalizable to all those with dcSSc. The hierarchical components of the GRCS are specific to this SSc population and may not be generalizable to other SSc populations.

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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.