Cardiac Safe Transplants for Systemic Sclerosis

Phase 2

Terminated

• Conditions: Systemic Sclerosis; Scleroderma
• Interventions: Drug: Rituximab; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: G-CSF; Biological: IVIg; Biological: Autologous Stem Cells

• Registration Number: NCT03593902
• Lead Sponsor: Northwestern University

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.

Study Timeline

• Study Start: 2018-05-17
• Study First Submitted: 2018-06-28
• Study First Submitted QC: 2018-07-10
• Study First Posted: 2018-07-20
• Primary Completion: 2019-10-03
• Study Completion: 2019-10-09
• Status Verified: 2020-06
• Results First Submitted: 2020-07-07
• Results First Submitted QC: 2020-08-10
• Last Update Submitted: 2020-08-10
• Results First Posted: 2020-08-12
• Last Update Posted: 2020-08-12

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 9

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Hematopoietic Stem Cell Transplantation	IVIg	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Autologous Stem Cells	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Rituximab	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Fludarabine	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Cyclophosphamide	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	rATG	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Mesna	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	G-CSF	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.
Hematopoietic Stem Cell Transplantation	Methylprednisolone	Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, fludarabine, cyclophosphamide, Mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant.

Primary Outcome Measures

Name	Time	Method
Change in Skin Score by mRSS	Pre Treatment and Post Treatment	Defined by at least a 25% improvement (decline) in skin score by modified Rodnan skin score (mRSS) if skin score is greater than 14 on enrollment. If skin score is less than 14 on enrollment, improvement is defined by at least a 5% improvement on mRSS. The modified Rodnan skin score (MRSS) is a measure for skin disease in scleroderma and is calculated by summation of skin thickness in 17 different body sites. The scale ranges from at total score of normal skin thickness (0) to severe thickness (51).

Secondary Outcome Measures

Name	Time	Method
Survival of Treatment	During Treatment and Post Treatment up to 1 year	Survival of Hematopoietic Stem Cell Transplant during treatment and post treatment up to 1 year.

Trial Locations

Locations (2)

Northwestern University, Feinberg School of Medicine; 🇺🇸 Chicago, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States