MedPath

Scleroderma: Cyclophosphamide or Transplantation

Phase 2
Completed
Conditions
Scleroderma, Systemic
Autoimmune Disease
Sclerosis
Interventions
Biological: mHSCT
Drug: cyclophosphamide
Registration Number
NCT00114530
Lead Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
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.

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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
75
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.
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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.

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Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
mHSCTmHSCTMyeloablative 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.
cyclophosphamidecyclophosphamideCyclophosphamide (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).
Primary Outcome Measures
NameTimeMethod
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
NameTimeMethod
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.

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).

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).

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.

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.

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.

All-Cause Mortality (Month 54, ITT)54 Months Post-Randomization

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

All-Cause Mortality (Month 48, ITT)48 Months Post-Randomization

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

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).

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.

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.

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.

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.

All-Cause Mortality (Month 54, PP)54 Months Post-Randomization

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

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.

All-Cause Mortality (Month 48, PP)48 Months Post-Randomization

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

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.

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.

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.

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.

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.

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.

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.

Regimen-Related ToxicitiesRandomization 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.

Infectious ComplicationsRandomization 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Time to Absolute Neutrophil Count Engraftment28 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.

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.

Number of Subjects With Infectious ComplicationsRandomization 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.

Number of Subjects With Regimen-Related ToxicitiesRandomization 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.

Trial Locations

Locations (17)

University of Toledo Health Science Campus

🇺🇸

Toledo, Ohio, United States

Medical University of South Carolina

🇺🇸

Charleston, South Carolina, United States

University of Calgary

🇨🇦

Calgary, Alberta, Canada

Dr. Markland Medical Professional Corporation

🇨🇦

Saskatoon, Saskatchewan, Canada

City of Hope National Medical Center

🇺🇸

Duarte, California, United States

University of Kentucky

🇺🇸

Lexington, Kentucky, United States

Washington University School of Medicine

🇺🇸

Saint Louis, Missouri, United States

Boston University School of Medicine

🇺🇸

Boston, Massachusetts, United States

UCLA Medical School

🇺🇸

Los Angeles, California, United States

Massachusetts General Hospital

🇺🇸

Boston, Massachusetts, United States

University of Michigan

🇺🇸

Ann Arbor, Michigan, United States

Duke University Medical Center

🇺🇸

Durham, North Carolina, United States

University of Pittsburgh

🇺🇸

Pittsburgh, Pennsylvania, United States

University of Texas-Houston Medical School

🇺🇸

Houston, Texas, United States

MD Anderson Cancer Center

🇺🇸

Houston, Texas, United States

Fred Hutchinson Cancer Research Center (FHCRC)

🇺🇸

Seattle, Washington, United States

Medical College of Wisconsin

🇺🇸

Milwaukee, Wisconsin, United States

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