Cardiac Safe Transplants for Systemic Sclerosis

NCT03593902 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: DIAD.CAST.2018
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 2

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.

Conditions

Systemic Sclerosis; Scleroderma

Keywords

Autologous Stem Cell Transplantation; Hematopoietic Stem Cell Transplant

Outcome Measures

Primary Outcomes (1)

• Change in Skin Score by mRSS

  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).

  Pre Treatment and Post Treatment

Secondary Outcomes (1)

• Survival of Treatment

  During Treatment and Post Treatment up to 1 year

Study Arms (1)

Hematopoietic Stem Cell Transplantation

EXPERIMENTAL

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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: G-CSF; Biological: IVIg; Biological: Autologous Stem Cells

Interventions

Rituximab DRUG

Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer

Also known as: Rituxan

Hematopoietic Stem Cell Transplantation

Fludarabine DRUG

A chemotherapy medication commonly used in the treatment of leukemia and lymphoma

Also known as: Fludara

Hematopoietic Stem Cell Transplantation

Cyclophosphamide DRUG

A medication used as chemotherapy and to suppress the immune system

Also known as: Cytoxan

Hematopoietic Stem Cell Transplantation

Mesna DRUG

A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder

Also known as: Mesnex

Hematopoietic Stem Cell Transplantation

rATG DRUG

A rabbit polyclonal antibody to lymphocytes

Also known as: Thymoglobulin, Anti-Thymocyte Globulin (Rabbit)

Hematopoietic Stem Cell Transplantation

Methylprednisolone DRUG

A corticosteroid medication used to suppress the immune system and decrease inflammation

Also known as: Solu-Medrol, Depo-Medrol

Hematopoietic Stem Cell Transplantation

G-CSF DRUG

A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Also known as: Neupogen, Filgrastim, Granix, Zarxio

Hematopoietic Stem Cell Transplantation

IVIg BIOLOGICAL

Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects

Also known as: Bivagam, Carimune NF, Gammagard, Privigen, Octagam

Hematopoietic Stem Cell Transplantation

Autologous Stem Cells BIOLOGICAL

Infusion of patient's own stem cells

Hematopoietic Stem Cell Transplantation

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 - 65 years old at the time of pre-transplant evaluation
• An established diagnosis of systemic sclerosis
• 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:
• DLCO \< 80% of predicted or decrease in lung function (DLCO, DLCO/VA or FVC) of 10% or more over 12 months.
• Pulmonary fibrosis or alveolitis on CT scan or chest x-ray (ground glass appearance of alveolitis).
• Abnormal EKG (non-specific ST-T wave abnormalities, low QRS voltage, or ventricular hypertrophy), or pericardial effusion or pericardial enhancement without constriction on MRI
• 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.
• 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.
• Septal flattening or D-sign on MRI (without deep breathing)
• PASP \>40 mm Hg or \>45 mm Hg with fluid challenge\*
• mPAP \>25 mm Hg or \>30 mm Hg with fluid challenge\*
• 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.

You may not qualify if:

• Active ischemic heart disease or untreated coronary artery disease
• Untreated life-threatening cardiac arrhythmia on EKG or 24-hour holter
• Pericardial effusion \> 1 cm on cardiac MRI unless successful pericardiocentesis has been performed
• LVEF \<35%
• End-stage lung disease characterized by TLC\<45% of predicted value, or DLCO hemoglobin corrected \< 30 % predicted.
• Creatinine clearance \<40 by 24-hour urine
• History of breast implants that have not been removed (unless they cannot be surgically removed due to risks of surgery)
• Liver cirrhosis, transaminases \>2x of normal limits, or bilirubin \> 2.0 unless due to Gilbert's disease
• 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
• Prior history of malignancy
• 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
• Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible
• Major hematological abnormalities such as platelet count \< 100,000/ul or absolute neutrophil count (ANC) \< 1000/ul
• HIV positive
• Hepatitis B or C positive

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (2)

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Related Publications (1)

• 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.

  PMID: 32612255 DERIVED

MeSH Terms

Conditions

Scleroderma, Systemic; Scleroderma, Diffuse

Interventions

Rituximab; fludarabine; fludarabine phosphate; Cyclophosphamide; Mesna; thymoglobulin; Antilymphocyte Serum; Methylprednisolone; Methylprednisolone Hemisuccinate; Methylprednisolone Acetate; Granulocyte Colony-Stimulating Factor; Filgrastim; Immunoglobulins, Intravenous; Octagam

Condition Hierarchy (Ancestors)

Connective Tissue Diseases; Skin and Connective Tissue Diseases; Skin Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Immune Sera; Biological Products; Complex Mixtures; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Biological Factors; Immunoglobulin G; Immunoglobulin Isotypes

Limitations and Caveats

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

Results Point of Contact

• Title: Kathleen Quigley
• Organization: Northwestern University

kathleen.quigley@nm.org

312-695-8192

Study Officials

• Richard Burt, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 28, 2018
• First Posted: July 20, 2018
• Study Start: May 17, 2018
• Primary Completion: October 3, 2019
• Study Completion: October 9, 2019
• Last Updated: August 12, 2020
• Results First Posted: August 12, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)