Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial

NCT01445821 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: ASSIST IIb
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

ASSIST I was the first randomized trial in patients with scleroderma to not just slow disease progression but rather actually reverse it. It is the first treatment to have ever demonstrated reversal of lung disease in scleroderma with improvement in FVC, total lung capacity (TLC), high-resolution computed tomography (HRCT), and QOL. We now, therefore, purpose to compare the ASSIST I conditioning regimen of cyclophosphamide and rATG to a less intense regimen of rATG/cyclophosphamide/Fludarabine. In the new regimen the cyclophosphamide dose is decreased to 120mg/kg (60mg/kg/day x 2) compared to 200mg/kg (50mg/kg/day) in the standard regimen. The lower dose of cyclophosphamide will be less cardiotoxic. This study will determine if the less cardiotoxic regimen will be safer than the standard regimen and as effective as the standard regimen.

Conditions

Scleroderma, Systemic

Keywords

Autologous Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Treatment Failure

  Treatment failure will not occur until a minimum of 12 months after treatment at which time failure is defined as: 1. 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 2. Deterioration in percent predicted FVC by 10% below enrollment level, due to systemic sclerosis, and documented on 2 occasion at least 6 months apart

  up to and post 12 months of treatment

Secondary Outcomes (1)

• Survival of Treatment

  up to 12 months post treatment

Study Arms (2)

Cyclophosphamide rATG/HSCT

ACTIVE COMPARATOR

The 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.

Biological: Peripheral Blood Stem Cells; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: Filgrastim

Cyclophosphamide rATG/Fludarabine/HSCT

EXPERIMENTAL

The 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.

Biological: Peripheral Blood Stem Cells; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: Filgrastim; Drug: Fludarabine

Interventions

Peripheral Blood Stem Cells BIOLOGICAL

Mobilized leukapheresis product

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

Cyclophosphamide DRUG

An alkylating agent which causes prevention of cell division by forming adducts with DNA

Also known as: Cytoxan, Neosar, Endoxan

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

Mesna DRUG

Medication used to decrease the risk of hemorrhagic cystitis prophylaxis

Also known as: Mesnex

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

rATG DRUG

A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells

Also known as: Thymoglobulin

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

Methylprednisolone DRUG

Steroid

Also known as: Solu-Medrol

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

Filgrastim DRUG

Granulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Also known as: Neupogen, G-CSF, Granix, Zarxio

Cyclophosphamide rATG/Fludarabine/HSCT; Cyclophosphamide rATG/HSCT

Fludarabine DRUG

Purine analog which inhibits DNA synthesis or repair

Also known as: Fludara

Cyclophosphamide rATG/Fludarabine/HSCT

Eligibility Criteria

• Age: 17 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age 17- 60 years old at the time of pretransplant evaluation
• An established diagnosis of scleroderma
• Diffuse cutaneous scleroderma with involvement proximal to the elbow or knee and a Rodnan score (see Appendix V) of \> 14 AND
• Scleroderma with 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 (CXR) (ground glass appearance of alveolitis).
• Abnormal EKG \[non-specific ST-segment and T-wave (ST-T) (pattern in electrocardiogram) wave abnormalities, low QRS (a pattern seen in an electrocardiogram that indicates the pulses in a heart beat and their duration) voltage, or ventricular hypertrophy\], or pericardial effusion or pericardial enhancement 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 due to valvulae packing i.e. dilated and crowded circular folds may be present. GI involvement may also be confirmed by D-xylose malabsorption, patulous esophagus on HRCT, or esophageal manometry.
• As published in New England Journal of Medicine (NEJM), 2006, 345:25 2655-2709. Limited or diffuse Systemic Sclerosis with (SSCL) with lung involvement defined as active alveolitis on Bronchoalveolar Lavage (BAL) or ground-glass opacity on CT, a DLCO \< 80% predicted or decrease in lung function (DLCO/VA, DLCO, FVC) of 10% or more in last 12 months.

You may not qualify if:

• Significant end organ damage such as:
• Left Ventricular Function (LVEF) \< 40% on echocardiogram.
• Untreated life-threatening arrhythmia.
• Active ischemic heart disease or heart failure.
• End-stage lung disease characterized by TLC\<45% of predicted value, or DLCO hemoglobin corrected \< 30% predicted .
• Pulmonary arterial hypertension defined on right heart catheterization as:
• a resting Mean Pulmonary Artery Pressure (mPAP) \> 25 mmHg;
• a mPAP \> 30 mmHg following a 500-1000 ml normal saline bolus;
• pulmonary vascular resistance (PVR) \> 240 dynes\*s/cm5 (\> 3 Wood units) ; or
• a decrease in cardiac output with fluid challenge (500 - 1000 cc Normal Saline (NS) in 10 minutes) If fluid challenge cannot be done because right atrial (RA) pressure \> 12mm Hg or pulmonary capillary wedge pressure (PCWP) \> 15 m Hg at rest or must be stopped due to safety concerns, patient is excluded as candidate.
• Serum creatinine \> 1.4 mg/dl.
• Liver cirrhosis, transaminases \> 3x of normal limits or bilirubin \> 2.0 unless due to Gilbert's disease.
• Pericardial effusion \> 1 cm on cardiac MRI unless successful pericardiocentesis has been performed
• Occult or clinical constrictive pericarditis
• On echocardiogram tricuspid annular peak systolic excursion (TAPSE) ≤ 1.8 cm or, grade II or worse Right Ventricular (RV) or Left Ventricular (LV) diastolic dysfunction

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

MeSH Terms

Conditions

Scleroderma, Systemic

Interventions

Cyclophosphamide; Mesna; thymoglobulin; Methylprednisolone; Methylprednisolone Hemisuccinate; Filgrastim; Granulocyte Colony-Stimulating Factor; fludarabine; fludarabine phosphate

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

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; 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; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Kathleen Quigley
• Organization: Northwestern University

k-quigley@northwestern.edu

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 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Division of Medicine-Immunotherapy and Autoimmune Diseases; Professor in Medicine-Immunotherapy and Autoimmune Diseases

Study Record Dates

• First Submitted: September 29, 2011
• First Posted: October 4, 2011
• Study Start: September 15, 2011
• Primary Completion: January 5, 2017
• Study Completion: October 10, 2019
• Last Updated: July 23, 2020
• Results First Posted: July 23, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)