Clinical trial NCT03593902: Cardiac Safe Transplants for Systemic Sclerosis
Official title: Autologous Hematopoietic Stem Cell Transplant for Patients With Systemic Sclerosis and Cardiac Dysfunction
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Systemic Sclerosis
Scleroderma
Keywords: Autologous Stem Cell Transplantation
Hematopoietic Stem Cell Transplant
Lead sponsor: Northwestern University
Sponsor class: OTHER
First posted: 2018-07-20
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is designed to treat systemic sclerosis (scleroderma) patients with an autologous stem cell transplant using a regimen of immune suppressant drugs and chemotherapy that is less toxic to your heart.

Detailed description: The autologous hematopoietic stem cell transplant used in this research study is an investigational procedure that uses cyclophosphamide and fludarabine (chemotherapy), rabbit anti-thymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be causing your disease), and rituximab (a biologic drug that targets B cells of your immune system). After use of these treatments, the patient will receive their own previously collected blood stem cells (autologous stem cell transplant). The ability of these experimental treatments to stop relapses and progression (worsening) of your systemic sclerosis will be assessed.

Eligibility criteria: Inclusion Criteria:

1. Age 18 - 65 years old at the time of pre-transplant evaluation
2. An established diagnosis of systemic sclerosis
3. Diffuse cutaneous systemic sclerosis with involvement proximal to the elbow or knee and a modified Rodnan Skin Score of ≥ 14 (see Appendix A)

AND

Any one of the following:

1. DLCO \< 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or more over 12 months.
2. Pulmonary fibrosis or alveolitis on CT scan or chest x-ray (ground glass appearance of alveolitis).
3. Abnormal EKG (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement without constriction on MRI
4. Gastrointestinal tract involvement confirmed on radiological study. Radiologic findings of scleroderma are small bowel radiographs showing thickened folds with dilated loops, segmentation, and flocculation +/- diverticula, or pseudodiverticula. A hide-bound appearance may be present (e.g. dilated and crowded circular folds). GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on high-resolution computed tomography (HRCT), or esophageal manometry.

OR

Limited cutaneous systemic sclerosis (SSc) (modified Rodnan Skin Score \<14) with lung involvement defined as active alveolitis on bronchoalveolar lavage (BAL), ground-glass opacity on CT scan, a DLCO \< 80% predicted, or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months.

Other Inclusion Criteria for "CAST" Conditioning Regimen (presence of any of the following):

1. Septal flattening or D-sign on MRI (without deep breathing)
2. PASP \>40 mm Hg or \>45 mm Hg with fluid challenge\*
3. mPAP \>25 mm Hg or \>30 mm Hg with fluid challenge\*
4. Non-ischemia diffuse ventricular hypokinesis or non-ischemia wall hypokinesis

   * Fluid challenge is 1000 ml normal saline over 10 minutes. Fluid challenge will not be done if right atrial pressure is \>13 mm Hg at rest or pulmonary capillary wedge pressure is \>20 mm Hg at rest.

Exclusion Criteria:

1. Active ischemic heart disease or untreated coronary artery disease
2. Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter
3. Pericardial effusion \> 1 cm on cardiac MRI unless successful pericardiocentesis has been performed
4. LVEF \<35%
5. End-stage lung disease characterized by TLC\<45% of predicted value, or DLCO hemoglobin corrected \< 30 % predicted.
6. Creatinine clearance \<40 by 24-hour urine
7. History of breast implants that have not been removed (unless they cannot be surgically removed due to risks of surgery)
8. Liver cirrhosis, transaminases \>2x of normal limits, or bilirubin \> 2.0 unless due to Gilbert's disease
9. 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
10. Prior history of malignancy
11. Positive pregnancy test, inability or unable to pursue effective means of birth control, or failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
12. Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible
13. Major hematological abnormalities such as platelet count \< 100,000/ul or absolute neutrophil count (ANC) \< 1000/ul
14. HIV positive
15. Hepatitis B or C positive
16. PASP \>50 mmHg without fluid challenge
17. mPAP \>34 mmHg without fluid challenge
18. Coronary artery disease not reversed by cardiology and interventional radiology

Primary outcomes:
measure: Change in Skin Score by mRSS
timeFrame: Pre Treatment and Post Treatment
Secondary outcomes:
measure: Survival of Treatment
timeFrame: During Treatment and Post Treatment up to 1 year
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University, Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
Study officials:
affiliation: Northwestern University
name: Richard Burt, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burt RK, Han X, Quigley K, Arnautovic I, Shah SJ, Lee DC, Freed BH, Jovanovic B, Helenowski IB. Cardiac safe hematopoietic stem cell transplantation for systemic sclerosis with poor cardiac function: a pilot safety study that decreases neutropenic interval to 5 days. Bone Marrow Transplant. 2021 Jan;56(1):50-59. doi: 10.1038/s41409-020-0978-2. Epub 2020 Jul 1.