Autologous Stem Cell Transplantation in Patients with Systemic Sclerosis

Phase 2

Recruiting

• Conditions: Diffuse Sclerosis Systemic; Interstitial Lung Disease; Pulmonary Hypertension; Systemic Sclerosis
• Interventions: Drug: Cyclophosphamide; Drug: Mesna; Drug: Rituximab; Drug: Alemtuzumab; Drug: Thiotepa; Drug: GM-CSF; Drug: Intravenous immunoglobulin; Radiation: Total Body Irradiation; Drug: Anti Thymocyte Globulin

• Registration Number: NCT03630211
• Lead Sponsor: Paul Szabolcs

Brief Summary

The purpose of this study is to determine whether a regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect.

Detailed Description

This is a single center, phase II trial where after a process of stem cell mobilization and conditioning, subjects receive a CD34-selected autologous peripheral blood stem cell rescue. By virtue of positive selection for the stem/progenitor cell marker of CD34, the graft will be depleted for T, B and NK lymphocytes and other immune cells such as monocytes that may be pathogenic. This is an open label study and there will be no randomization or blinding as a part of this study.

The proposed regimen of high-dose immunoablative therapy will demonstrate safety that is consistent or improved with other published regimens in SSc patients, while maintaining a treatment effect.

The primary objectives of this study are to determine the safety and treatment effect of high-dose immunoablative therapy followed by transplantation of CD34+ positively selected peripheral blood stem cells (PBSC) for systemic scleroderma (SSc) patients using a regimen designed to maximize patient safety while also aiming to eradicate autoreactive clones responsible for the disease. Safety will be determined by monitoring for death of any cause, and severe or life-threatening infections. Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT). Enrolled subjects will be followed for survival, secondary malignancies, and SSC activity at least yearly up to 36 months post-HSCT.

The secondary objectives of this study are to:

* To assess cutaneous disease response to high dose immunosuppressive therapy (HDIT) by comparing pre- and post-transplant measurements of the modified Rodnan skin score (mRSS).

* To assess pulmonary disease response by longitudinally tracking FVC (pulmonary function test) and DLCO (diffusing capacity of the lung for carbon monoxide) yearly up to 36 months post-HSCT.

* To evaluate the treatment effect on disease activity/progression, as indicated by severity measures of cardiac, pulmonary, musculoskeletal, gastrointestinal, vascular and renal organ involvement, and need for concomitant disease-modifying antirheumatic drugs (DMARD) use.

* To evaluate quality of life by comparing pre- and post-transplant quality of life measurements. These measurements will include the Scleroderma Health Assessment Questionnaire (SHAQ), the Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF-36) and the Scleroderma Skin Patient Reported Outcome (SSPRO) pre- and post-mobilization.

Study Timeline

• Study Start: 2018-07-31
• Study First Submitted: 2018-08-07
• Study First Submitted QC: 2018-08-09
• Study First Posted: 2018-08-14
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-13
• Last Update Posted: 2025-03-17
• Primary Completion: 2025-08-01
• Study Completion: 2026-08-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Autologous Stem Cell Transplantation	Total Body Irradiation	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Anti Thymocyte Globulin	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Intravenous immunoglobulin	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Cyclophosphamide	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Mesna	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Rituximab	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Alemtuzumab	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	GM-CSF	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.
Autologous Stem Cell Transplantation	Thiotepa	CD34-selected autologous stem cell being performed on CliniMACS depletion device. Conditioning regimen will not start sooner than 3 weeks, and ideally no more than 90 days, after cyclophosphamide dose in the mobilization regimen.

Primary Outcome Measures

Name	Time	Method
Death	Post Transplant through study completion, an average of 36 months	How many, if any, patients die
Respiratory Failure	Post Transplant through study completion, an average of 36 months	defined by one of the following 3 criteria without explanation for causation other than disease progression: 1. decline in DLCO of ≥30% or FVC≥20% as measured by actual difference in percent predicted units; 2. Resting arterial p02 \< 60 mmHg or pCO2 \> 50 mmHg supplemental oxygen;3. Resting pulse oximetry of 88% or lower measured by forehead probe.
High Dose Immunoablative therapy-Safety	Up to 36 months post HSCT	Safety will be determined by monitoring for death of any cause, regimen-related toxicities, and severe or life-threatening infections.
Renal Failure	Post Transplant through study completion, an average of 36 months	Defined by chronic dialysis for \>6 months or renal transplantation
Treatment-related mortality (TRM)	Mobilization through study completion, an average of 36 months	defined as death occurring at any time after stem cell mobilization and definitely or probably resulting from treatment given in the study. TRM will be determined yearly with a focus on the first 2 years.
The occurrence of cardiomyopathy	Post Transplant through study completion, an average of 36 months	confirmed by clinical congestive heart failure (New York Heart Association) or LVEF (left ventricular ejection fraction) \<30% on echocardiogram
High Dose Immunoablative therapy-Treatment Effect	up to 36 months post HSCT (hematopoietic stem cell transplantation)	Treatment effect will be determined by assessing event-free survival in comparison to a SSc observational cohort control group treated with standard of care medication (mycophenolate mofetil) at 12 and 36 months post hematopoietic stem cell transplant (HSCT).

Secondary Outcome Measures

Name	Time	Method
An increase of mRSS (modified Rodnan skin score ) by ≥5 points for skin score	Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.	To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Increase by ≥25% if the baseline mRSS > 20.	Disease response will be defined as subject improvement. This will be assessed for both skin and interstitial lung disease at 12 and 24 months post-HSCT.	To assess cutaneous response the modified Rodnan skin score (mRSS) will be used.
Decrease in DLCO sustained for 3 months or longer on pulmonary function tests (PFT)	1 year post transplant through study completion, an average of 36 months	to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Development of scleroderma renal crisis (hypertensive or non-hypertensive)	Post Transplant through study completion, an average of 36 months	Hypertensive renal crisis can be defined as a rise in SBP ≥ 30 points or DBP ≥ 20 points from baseline and one of the following: 1) Increase in baseline serum creatinine of ≥ 50%, 2) thrombocytopenia \< 100,000 plts/mm3 or 3. hemolysis by blood smear or increased reticulocyte count.
Worsening of > 10% of FVC (pulmonary function testing)	1 year post transplant through study completion, an average of 36 months	to evaluate interstitial lung disease an increase of ≥15% in DLCO or ≥10% of FVC (actual change in % predicted units from baseline) sustained for ≥3 months on 2 determinations.
Worsening of cardiac involvement	Post Transplant through study completion, an average of 36 months	With use of Imaging, EKG, Echocardiogram, Cardiac MRI, right heart cauterization, implanted loop recorder and 2 week cardiac event monitor. Defined as new or worsening arrhythmias that require medical treatment of 3 months or longer, or require ablative therapy, pacemaker or defibrillator insertion or defined as a decline in ejection fraction of ≥10 EF units, determined by echocardiogram.

Trial Locations

Locations (2)

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States