CAST: Cardiac Safe Transplants for Systemic Sclerosis

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03593902
• Collaborator: (none)
• Enrollment: 9
• Locations: 2
• Arm: 1
• Actual Duration (Months): 16.8
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Systemic Sclerosis; Scleroderma	Drug: Rituximab; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: G-CSF; Biological: IVIg; Biological: Autologous Stem Cells	Phase 2/Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Autologous Hematopoietic Stem Cell Transplant for Patients With Systemic Sclerosis and Cardiac Dysfunction
• Actual Study Start Date: May 17, 2018
• Actual Primary Completion Date: Oct 3, 2019
• Actual Study Completion Date: Oct 9, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hematopoietic Stem Cell Transplantation 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.

Drug: Rituximab; Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer; Other Names: Rituxan ; Drug: Fludarabine; A chemotherapy medication commonly used in the treatment of leukemia and lymphoma; Other Names: Fludara ; Drug: Cyclophosphamide; A medication used as chemotherapy and to suppress the immune system; Other Names: Cytoxan ; Drug: Mesna; A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder; Other Names: Mesnex ; Drug: rATG; A rabbit polyclonal antibody to lymphocytes; Other Names: Thymoglobulin Anti-Thymocyte Globulin (Rabbit) ; Drug: Methylprednisolone; A corticosteroid medication used to suppress the immune system and decrease inflammation; Other Names: Solu-Medrol Depo-Medrol ; Drug: G-CSF; A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream; Other Names: Neupogen Filgrastim Granix Zarxio ; Biological: IVIg; Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects; Other Names: Bivagam Carimune NF Gammagard Privigen Octagam ; Biological: Autologous Stem Cells; Infusion of patient's own stem cells

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University, Feinberg School of Medicine	Chicago	Illinois	United States	60611
2	Northwestern University	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University

Investigators

• Principal Investigator: Richard Burt, MD, Northwestern University

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 9, 2019
• Study Protocol - Oct 9, 2019

More Information

Publications

None provided.

• Responsible Party: Richard Burt, MD, Professor, Northwestern University
• ClinicalTrials.gov Identifier: NCT03593902
• Other Study ID Numbers: DIAD.CAST.2018
• First Posted: Jul 20, 2018
• Last Update Posted: Aug 12, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Richard Burt, MD, Professor, Northwestern University: Autologous Stem Cell Transplantation; Hematopoietic Stem Cell Transplant
• Additional relevant MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Rituximab; Fludarabine; Thymoglobulin; Antilymphocyte Serum; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Hematopoietic Stem Cell Transplantation
Arm/Group Description	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. Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia and lymphoma Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder rATG: A rabbit polyclonal antibody to lymphocytes Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Hematopoietic Stem Cell Transplantation
Arm/Group Description	Hematopoietic Stem Cell Therapy will be performed: 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. Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia and lymphoma Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder rATG: A rabbit polyclonal antibody to lymphocytes Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and
Overall Participants	9
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 88.9%
>=65 years	1 11.1%
Sex: Female, Male (Count of Participants)
Female	6 66.7%
Male	3 33.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 22.2%
White	7 77.8%
More than one race	0 0%
Unknown or Not Reported	0 0%
Modified Rodnan skin score (units on a scale) [Mean (Full Range) ]
Mean (Full Range) [units on a scale]	25

Outcome Measures

1. Primary Outcome

Title	Change in Skin Score by mRSS
Description	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).
Time Frame	Pre Treatment and Post Treatment

Outcome Measure Data

Analysis Population Description

The number analyzed in one or more rows differs from the overall number analyzed because some patients did not follow up after the treatment.

Arm/Group Title	Hematopoietic Stem Cell Transplantation
Arm/Group Description	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. Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia and lymphoma Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder rATG: A rabbit polyclonal antibody to lymphocytes Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and
Measure Participants	9
Pre Treatment	25
Post Treatment	16

2. Secondary Outcome

Title	Survival of Treatment
Description	Survival of Hematopoietic Stem Cell Transplant during treatment and post treatment up to 1 year.
Time Frame	During Treatment and Post Treatment up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hematopoietic Stem Cell Transplantation
Arm/Group Description	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. Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia and lymphoma Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder rATG: A rabbit polyclonal antibody to lymphocytes Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and
Measure Participants	9
Count of Participants [Participants]	9 100%

Adverse Events

Time Frame	During Treatment and the First 100 days Post Treatment
Adverse Event Reporting Description	Grade 4 Toxicities
Arm/Group Title	Hematopoietic Stem Cell Transplantation
Arm/Group Description	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. Rituximab: Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer Fludarabine: A chemotherapy medication commonly used in the treatment of leukemia & lymphoma Cyclophosphamide: A medication used as chemotherapy and to suppress the immune system Mesna: A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder rATG: A rabbit polyclonal antibody to lymphocytes Methylprednisolone: A corticosteroid medication used to suppress the immune system and decrease inflammation G-CSF: A glycoprotein that stimulates the bone marrow to produce granulocytes and
All Cause Mortality
	Hematopoietic Stem Cell Transplantation
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Hematopoietic Stem Cell Transplantation
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Hematopoietic Stem Cell Transplantation
	Affected / at Risk (%)	# Events
Total	0/9 (0%)

Limitations/Caveats

Early termination of study due to PI Sabbatical led to small number of participants analyzed.

More Information

Certain Agreements

All Principal Investigators ARE 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.