Please select the eligibility criteria that correspond to the clinical trial below.
Title: Trial of High Dose Cyclophosphamide and Rabbit Antithymocyte Globulin (rATG) With Hematopoietic Stem Cell Support in Patients With Systemic Scleroderma: A Randomized Trial
Brief Summary: Scleroderma is a systemic disorder categorized as an immunologically mediated disease that causes collagen deposition of skin and visceral organs. The molecular pathogenesis of scleroderma has been elusive, although vasculopathy and immune mediated mechanisms are thought to be important. Once extensive cutaneous or visceral disease occurs, prognosis is significantly shorter than the general population. Although various treatments have been tried, none of them seems to have changed the natural history of scleroderma. Standard dose immunosuppressive treatment has been disappointing. Recently, cyclophosphamide at 1-2 mg/kg/day orally or 800-1400 mg intravenous (IV) monthly for 6-9 months has proven effective in treatment of scleroderma alveolitis (1). Recent phase I studies of immunoablation with autologous peripheral blood stem cell transplantation (PBSCT) showed some promising data, but the exact efficacy is undetermined (2,3). We now propose, as a phase II randomized study, autologous unmanipulated PBSCT versus pulse cyclophosphamide in patients with systemic scleroderma.


Options:
A: Inclusion Criteria:

* The presence of either limited (cutaneous thickening distal but not proximal to elbows and knees, with or without facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees, often involving the chest or abdomen) scleroderma, as determined by American College of Rheumatology criteria
* Dyspnea on exertion (grade 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index)
* FVC less than or equal to 80 percent of predicted value at screening and less than or equal to 85 percent predicted at baseline
* Onset of the first non-Raynaud manifestation of SSc within the prior 84 months
* Presence of any ground glass opacification on thoracic high resolution computerized tomography (HRCT)
* Repeat FVC at the baseline visit (Visit 2) within 10 percent of the FVC measured at screening and less than or equal to 85 percent predicted.

Exclusion Criteria:

* FVC less than 45 percent of predicted value at either screening or baseline
* Carbon monoxide diffusing capacity (DLCO) (HBg-corrected) less than 30 percent of predicted value and less than 40 percent of predicted when documentation of pulmonary artery pressures by echocardiogram, right heart catheterization or magnetic resonance imaging identifies clinically significant pulmonary hypertension. All participants with a DLCO less than 40 percent predicted must have documentation of pulmonary artery pressures in order to be considered for inclusion.
* FEV1/FVC ratio less than 65 percent at either screening or baseline
* Clinically significant abnormalities on HRCT not attributable to scleroderma
* Diagnosis of clinically significant resting pulmonary hypertension requiring treatment, as ascertained before study evaluation or as part of a standard of care clinical assessment performed outside of the study protocol
* Persistent unexplained hematuria (more than 10 red blood cells per high-power field \[RBCs/hpf\])
* History of persistent leukopenia (white blood cell count less than 4000) or thrombocytopenia (platelet count less than 150,000)
* Clinically significant anemia (less than 10g/dl)
* Baseline liver function test (LFTs) or bilirubin more than 1.5 times the upper limit of normal, other than that due to Gilbert's disease
* Concomitant and present use of captopril
* Serum creatinine more than 2.0mg/dL
* Uncontrolled congestive heart failure
* Pregnancy (documented by urine pregnancy test) and/or breast feeding
* Prior use of oral CYC or MMF for more than 8 weeks or the receipt of more than two intravenous doses of CYC in the past
* Use of CYC and/or MMF in the 30 days before random assignment
* Active infection (lung or elsewhere) whose management would be compromised by CYC or MMF
* Other serious concomitant medical illness (e.g., cancer), chronic debilitating illness (other than scleroderma), or unreliability or drug abuse that might compromise the patient's participation in the study
* Current use, or use within the 30 days prior to random assignment, of prednisone (or equivalent) in doses of more than 10 mg/day
* If of child bearing potential (a female participant \<55 years of age who has not been postmenopausal for \> 5 years and who has not had a hysterectomy and/or oophorectomy), failure to employ two reliable means of contraception (which may include surgical sterilization, barrier methods, spermicidals, intrauterine devices, and/or hormonal contraception).
* Use of contraindicated medications; more information on this criterion can be found in the study protocol
* Smoking of cigars, pipes, or cigarettes in the 6 months before study entry
* Use of medications with putative disease-modifying properties within the past month (e.g., D-penicillamine, azathioprine, methotrexate, Potaba)
B: Inclusion Criteria:

1. Patients with limited or diffuse systemic scleroderma if they had evidence of active alveolitis on examination of bronchoalveolar-lavage (BAL) fluid (defined as neutrophilia of ≥3 percent, eosinophilia of ≥2 percent, or both)on thoracic high-resolution computed tomography (CT), any ground-glass opacity,
2. Onset of the first symptom of scleroderma other than Raynaud's phenomenon within the previous seven years,
3. An FVC between 45 and 85 percent of the predicted value
4. Grade 2 exertional dyspnea according to the baseline instrument of the Mahler Dyspnea Index (as measured with the use of the magnitude-of-task component).

Exclusion Criteria:

1. A single-breath carbon monoxide diffusing capacity (DlCO) that was less than 30 percent of the predicted value,
2. A history of smoking within the preceding six months, other clinically significant pulmonary abnormalities,
3. Clinically significant pulmonary hypertension requiring drug therapy.
4. Patients taking prednisone at a dose of more than 10 mg per day, those who had previously been treated for more than four weeks with oral cyclophosphamide or had received two or more intravenous doses,
5. Patients who recently received other potentially disease-modifying medications.
C: 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.
D: Inclusion Criteria:

* Age 60 year or \< 60 year old at the time of pretransplant evaluation.
* An established diagnosis of scleroderma.
* Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score of \> 14

AND

Scleroderma with any one of the following:

* Diffusing capacity of the lung for carbon monoxide (DLCO) \< 80% of predicted or decrease in lung function \[DLCO, diffusing capacity divided by the alveolar volume (DLCO/VA) or forced vital capacity (FVC) \] of 10% or more over 12 months.
* Active alveolitis on bronchoalveolar lavage.
* Pulmonary fibrosis or alveolitis on computed tomography (CT) scan or chest x-ray (CXR) (ground glass appearance of alveolitis).
* Renal disease that is not explained by a bacterial infection or other renal disorders. (Subjects must have two or more of the following: proteinuria - greater than trace on dipstick, hematuria - urine blood on dipstick or sediment, hypertension that requires treatment with anti-hypertensive medications or untreated but with a diastolic blood pressure (BP) \> 95 mm/hg.)
* Abnormal electrocardiogram (EKG) (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement on magnetic resonance imaging (MRI)
* Gastrointestinal tract involvement confirmed on radiological study. Radiologic findings of scleroderma are small bowel radiographs showing thickened folds with dilated loops, segmentation, and flocculation +/- diverticulae, or pseudodiverticulae. A hide-bound appearance due to valvulae packing i.e. dilated and crowded circular folds, may be present. Gastrointestinal (GI) involvement may also be confirmed by D-xylose malabsorption, patulous esophagus, or esophageal manometry.

OR

As published in NEJM, 2006, 345:25 2655-2709. Limited or diffuse SSL with lung involvement defined as active alveolitis on bronchoalveolar lavage (BAL) or ground-glass opacity on CT, a DLCO \< 80% predicted or decrease in lung function (DLCO/VA,DLCO, FVC) of 10% or more in last 12 months.

Exclusion Criteria:

* Poor performance status Eastern Cooperative Oncology Group (ECOG 2) at the time of entry.
* Significant end organ damage such as:

  1. Left Ventricular Ejection Fraction (LVEF) \< 40% or deterioration of LVEF during exercise test on Multiple Gated Acquisition (MUGA) or echocardiogram.
  2. Untreated life-threatening arrhythmia.
  3. Active ischemic heart disease or heart failure.
  4. End-stage lung disease characterized by total lung capacity (TLC) \<45% of predicted value.
  5. Pulmonary hypertension (systolic pulmonary arterial pressure \> 40 mmHg or mean pulmonary arterial pressure (PAP) \> 25 mmHG measurement by pulmonary arterial catheter).
  6. Serum creatinine \> 2.0 mg/dl.
  7. Liver cirrhosis, transaminases \> 3x of normal limits or bilirubin \> 2.0 unless due to Gilberts disease.
  8. Pericardial effusion\> 200ml unless successful pericardiocentesis
  9. Tricuspid annular peak systolic excursion (TAPSE) ≤ 1.9 cm
  10. MRI of heart showing D sign (intraventricular flattering)
* Human immunodeficiency virus (HIV) positive.
* Uncontrolled diabetes mellitus, or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment.
* Prior history of malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured by local surgical therapy, such as (but not limited to) head and neck cancer, or stage I or II breast cancer will be considered on an individual basis.
* Positive pregnancy test, inability or unable to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
* Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
* Inability to give informed consent.
* Major hematological abnormalities such as platelet count \< 100,000/ul or absolute neutrophil count (ANC) \< 1000/ul.
* Patients with duration of disease \> 5 years.
* Exclude if \> than 6 prior monthly IV cyclophosphamide treatments.

Answer: D