Scleroderma, SystemicPhase 3DIScl2011NCT01445821
Autologous Stem Cell Systemic Sclerosis Immune Suppression Trial
A Phase 3 study testing Peripheral Blood Stem Cells, Cyclophosphamide and Mesna in people with Scleroderma, Systemic, run by Northwestern University at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 17 to 60 years
- Conditions the study is for
- Scleroderma, Systemic
- What is being tested?
- Peripheral Blood Stem Cells, Cyclophosphamide and Mesna
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 44 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Sep 2011to 10 Oct 2019
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 17 to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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).
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- 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.
- OR
- 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.
Who cannot join
- 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:
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- 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
- On cardiac MRI, a diastolic septal bounce or diastolic septal flattering (D-sign), or diffuse myocardial gadolinium enhancement, or diffuse hypokinesis (patchy late gadolinium myocardial enhancement are not exclusion criteria)
- Ventricular tachycardia (sustained or non-sustained, multifocal or unifocal) on EKG or 24 hour Holter
- HIV positive.
- 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, 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.
- Inability to give informed consent.
- Major hematological abnormalities such as platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul.
- Hepatitis B or C positive
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Randomized Study of Different Non-myeloablative Conditioning Regimens With Hematopoietic Stem Cell Support in Patients With Scleroderma (Autologous Systemic Sclerosis Immune Suppression Trial - II ASSIST-IIb)
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.
Read the detailed description
Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation (HSCT), peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide (2 g/m2) followed by 5-10 mcg/kg subcutaneous filgrastrim daily from day 5 until completion of apheresis. Mobilized hematopoietic stem cells (HSC) will be collected by apheresis on day 10 and cryopreserved without selection or manipulation. There will be an interval of at least 17 days between mobilization of PBSC and start of conditioning regimen.
- Conditions
- Scleroderma, Systemic
- Being tested
- Peripheral Blood Stem Cells, Cyclophosphamide, Mesna, rATG, Methylprednisolone
- Keywords
- Autologous Stem Cell Transplantation
- Medical subject headings
- Scleroderma, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Peripheral Blood Stem CellsBiological
Mobilized leukapheresis product
CyclophosphamideDrug
Also called Cytoxan, Neosar, Endoxan
An alkylating agent which causes prevention of cell division by forming adducts with DNA
MesnaDrug
Also called Mesnex
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
rATGDrug
Also called Thymoglobulin
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
Also called Solu-Medrol
Steroid
FilgrastimDrug
Also called Neupogen, G-CSF, Granix, Zarxio
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
FludarabineDrug
Also called Fludara
Purine analog which inhibits DNA synthesis or repair
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Biological: Peripheral Blood Stem Cells; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: Filgrastim; Drug: Fludarabine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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:
- 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
Measured: up to and post 12 months of treatment
Secondary outcomes (1)
Survival of Treatment
Survival of Hematopoietic Stem Cell Transplant.
Measured: up to 12 months post treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Oct 2011 (estimated)
- Study start15 Sep 2011
- Primary completion5 Jan 2017
- Study completion10 Oct 2019
Why it stopped: Developed a better regimen: DIAD. Cast. 2018 NCT03593902
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Scleroderma, SystemicStudies of the same condition, open and under way.
- More trials run by Northwestern UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 44 participants (actual)
Sponsor and investigators
- Lead sponsor
- Northwestern University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Richard Burt, MD, Northwestern University
- Investigators
- Richard Burt, MD, Principal investigator, Northwestern University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01445821
- Sponsor's protocol ID
- ASSIST IIb
- Acronym
- DIScl2011
- Status last verified
- Jun 2020
- First submitted
- 29 Sep 2011
- Last updated
- 23 Jul 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomized Study of Different Non-myeloablative Conditioning Regimens With Hematopoietic Stem Cell Support in Patients With Scleroderma (Autologous Systemic Sclerosis Immune Suppression Trial - II ASSIST-IIb)
- ClinicalTrials.gov ID
- NCT01445821
- Acronym / sponsor ID
- DIScl2011 / ASSIST IIb
- Conditions
- Scleroderma, Systemic
- Keywords
- Autologous Stem Cell Transplantation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Developed a better regimen: DIAD. Cast. 2018 NCT03593902
- Enrolment
- 44 participants (actual)
- Lead sponsor
- Northwestern UniversityUniversity, hospital or other
- Study start
- 15 Sep 2011 (actual)
- Primary completion
- 5 Jan 2017 (actual)
- Study completion
- 10 Oct 2019 (actual)
- First posted
- 4 Oct 2011 (estimated)
- Results
- Posted 23 Jul 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Mobilization. For patients in both arms undergoing hematopoietic stem cell transplantation (HSCT), peripheral blood stem cells (PBSC) will be mobilized with cyclophosphamide (2 g/m2) followed by 5-10 mcg/kg subcutaneous filgrastrim daily from day 5 until completion of apheresis. Mobilized hematopoietic stem cells (HSC) will be collected by apheresis on day 10 and cryopreserved without selection or manipulation. There will be an interval of at least 17 days between mobilization of PBSC and start of conditioning regimen.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Cyclophosphamide rATG/HSCT | Active comparator | Biological: Peripheral Blood Stem Cells, Drug: Cyclophosphamide, Drug: Mesna, Drug: rATG, Drug: Methylprednisolone, Drug: FilgrastimThe 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. |
| Cyclophosphamide rATG/Fludarabine/HSCT | Experimental | Biological: Peripheral Blood Stem Cells, Drug: Cyclophosphamide, Drug: Mesna, Drug: rATG, Drug: Methylprednisolone, Drug: Filgrastim, Drug: FludarabineThe 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. |
Who may qualify
- Ages
- 17 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (10 listed)
- 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
- OR
- 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.
Key exclusion criteria (25 listed)
- Significant end organ damage such as:
- HIV positive.
- 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, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Peripheral Blood Stem CellsMobilized leukapheresis product | Biological | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| CyclophosphamideAlso: Cytoxan, Neosar, EndoxanAn alkylating agent which causes prevention of cell division by forming adducts with DNA | Drug | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| MesnaAlso: MesnexMedication used to decrease the risk of hemorrhagic cystitis prophylaxis | Drug | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| rATGAlso: ThymoglobulinA predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells | Drug | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| MethylprednisoloneAlso: Solu-MedrolSteroid | Drug | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| FilgrastimAlso: Neupogen, G-CSF, Granix, ZarxioGranulocyte-colony stimulating factor (G-CSF); a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream | Drug | Cyclophosphamide rATG/Fludarabine/HSCT, Cyclophosphamide rATG/HSCT |
| FludarabineAlso: FludaraPurine analog which inhibits DNA synthesis or repair | Drug | Cyclophosphamide rATG/Fludarabine/HSCT |
Primary outcome
Number of Participants With Treatment Failure
Time frame: up to and post 12 months of treatment
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
1 secondary outcome
Survival of Treatment
Time frame: up to 12 months post treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Jul 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard Burt, MD principal investigator
Northwestern University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Peripheral Blood Stem Cells, Cyclophosphamide and Mesna in people with Scleroderma, Systemic, run by Northwestern University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 23 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Treatment Failure (time frame: up to and post 12 months of treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2020.