Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial (DIScl2011)

• ClinicalTrials.gov Identifier: NCT01445821
• Recruitment Status: Terminated
• First Posted: October 4, 2011
• Results First Posted: July 23, 2020
• Last Update Posted: July 23, 2020
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Scleroderma, Systemic
• Interventions: Biological: Peripheral Blood Stem Cells; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: Filgrastim; Drug: Fludarabine
• Enrollment: 44

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Cyclophosphamide rATG/HSCT	Cyclophosphamide rATG/Fludarabine/HSCT
Arm/Group Description	Conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells	Conditioning regimen will be 120 mg/kg of IV cyclophosphamide given in 2 equal fractions on days -3 and -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused IV before each dose of rATG. PBSC will be infused IV on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and cont. until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF);glycoprotein that stimulates the bone marrow to produce granulocytes/stem cells Fludarabine: Purine analog which inhibits DNA synthesis/repair
Period Title: Overall Study
Started	22	22
Completed	22	22
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Cyclophosphamide rATG/HSCT	Cyclophosphamide rATG/Fludarabine/HSCT	Total
Arm/Group Description		Conditioning regimen: 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: An alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells	Conditioning regimen: 120 mg/kg of IV cyclophosphamide given in 2 equal fractions on days -3 and -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused IV before each dose of rATG. PBSC will be infused IV on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and cont. until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF);glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells Fludarabine: Purine analog which inhibits DNA synthesis/repair	Total of all reporting groups
Overall Number of Baseline Participants		22	22	44
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	22 participants	44 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	22 100.0%	22 100.0%	44 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	22 participants	22 participants	44 participants
		42.8; (23 to 59)	45.6; (19 to 60)	44.2; (19 to 60)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	22 participants	44 participants
	Female	16 72.7%	18 81.8%	34 77.3%
	Male	6 27.3%	4 18.2%	10 22.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	22 participants	22 participants	44 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	2 9.1%	2 4.5%
	White	20 90.9%	17 77.3%	37 84.1%
	More than one race	2 9.1%	3 13.6%	5 11.4%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	22 participants	22 participants	44 participants
		22	22	44
Skin Score Prior to Treatment [1]; Mean (Full Range); Unit of measure: Units on a scale
	Number Analyzed	22 participants	22 participants	44 participants
		26.1; (13 to 48)	22.8; (11 to 40)	24.14; (11 to 48)
		[1] Measure Description: Modified Rodnan Skin Score range from 0 (normal thickness of skin) to 51 (severe thickness of skin)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Failure
Description	Treatment failure will not occur until a minimum of 12 months after treatment at which time failure is defined as: Increase of skin score (if > 14 on enrollment) by > 25% above enrollment value and must be documented on 2 occasions at least 6 months apart; Deterioration in percent predicted FVC by 10% below enrollment level, due to systemic sclerosis, and documented on 2 occasion at least 6 months apart
Time Frame	up to and post 12 months of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide rATG/HSCT	Cyclophosphamide rATG/Fludarabine/HSCT
Arm/Group Description:	Conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells	Conditioning regimen will be 120 mg/kg of intravenous cyclophosphamide given in 2 equal fractions on days -3 and -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: An alkylating agent which causes prevention of cell division by forming adducts with DNA Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylpredni
Overall Number of Participants Analyzed	17	15
Measure Type: Count of Participants; Unit of Measure: Participants
	2 11.8%	2 13.3%

2. Secondary Outcome

Title	Survival of Treatment
Description	Survival of Hematopoietic Stem Cell Transplant.
Time Frame	up to 12 months post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cyclophosphamide rATG/HSCT	Cyclophosphamide rATG/Fludarabine/HSCT
Arm/Group Description:	Conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells	Conditioning regimen will be 120 mg/kg of intravenous cyclophosphamide given in 2 equal fractions on days -3 and -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. PBSC will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: An alkylating agent which causes prevention of cell division by forming adducts with DNA Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylpredni
Overall Number of Participants Analyzed	22	22
Measure Type: Count of Participants; Unit of Measure: Participants
	22 100.0%	21 95.5%

Adverse Events

Time Frame	during treatment at 6 months then yearly for up to 5 years post transplant
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Cyclophosphamide rATG/HSCT		Cyclophosphamide rATG/Fludarabine/HSCT
Arm/Group Description	Control arm will have the same conditioning regimen used in ASSIST study. The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 and then 1.5 mg/kg from day-4 thru day -1. Methylprednisolone 1000 mg will be used infused intravenously before each dose of rATG. Peripheral blood stem cells (PBSC) will be infused intravenously on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: An alkylating agent which causes prevention of cell division by forming adducts with DNA Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonl		Conditioning regimen will be 120 mg/kg of IV cyclophosphamide given in 2 equal fractions on days -3 and -2 with IV mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5 then 1.5 mg/kg from day-4 thru day -1. Fludarabine 30 mg/m2 will be given IV on days -5, -4, and -3. Methylprednisolone 1000 mg will be used infused IV before each dose of rATG. PBSC will be infused IV on day 0. Filgrastim 5-10 mcg/kg will be started on day + 5 and cont. until neutrophil engraftment. Peripheral Blood Stem Cells: Mobilized leukapheresis product Cyclophosphamide: Alkylating agent Mesna: Used to decrease the risk of hemorrhagic cystitis rATG: Immunosuppressive agent which contains antibodies specific to the antigens Methylprednisolone: Steroid Filgrastim: Granulocyte-colony stimulating factor (G-CSF);glycoprotein that stimulates the bone marrow to produce granulocytes/stem cells Fludarabine: Purine analog which inhibits DNA synthesis/repair
All-Cause Mortality
	Cyclophosphamide rATG/HSCT		Cyclophosphamide rATG/Fludarabine/HSCT
	Affected / at Risk (%)		Affected / at Risk (%)
Total	2/22 (9.09%)		3/22 (13.64%)
Serious Adverse Events
	Cyclophosphamide rATG/HSCT		Cyclophosphamide rATG/Fludarabine/HSCT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/22 (9.09%)		3/22 (13.64%)
General disorders
Scleroderma Disease Related † [1]	2/22 (9.09%)	2	3/22 (13.64%)	3
† Indicates events were collected by systematic assessment; [1] Mortality due to disease progression
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Cyclophosphamide rATG/HSCT		Cyclophosphamide rATG/Fludarabine/HSCT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/22 (13.64%)		2/22 (9.09%)
Cardiac disorders
Disease Related Pericardial Effusion † [1]	2/22 (9.09%)	2	2/22 (9.09%)	2
Cardiac Tamponade † [2]	0/22 (0.00%)	0	1/22 (4.55%)	1
Respiratory, thoracic and mediastinal disorders
Plueral Effusion † [3]	1/22 (4.55%)	1	0/22 (0.00%)	0
† Indicates events were collected by systematic assessment; [1] Scleroderma related pericardial effusion; [2] Cardiac Tamponade Requiring Pericardiocentesis; [3] Pleural Effusion

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Kathleen Quigley
• Organization: Northwestern University
• Phone: 312-695-8192
• EMail: k-quigley@northwestern.edu

• Responsible Party: Richard Burt, MD, Northwestern University
• ClinicalTrials.gov Identifier: NCT01445821
• Other Study ID Numbers: ASSIST IIb
• First Submitted: September 29, 2011
• First Posted: October 4, 2011
• Results First Submitted: June 15, 2020
• Results First Posted: July 23, 2020
• Last Update Posted: July 23, 2020