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Trial registered on ANZCTR


Registration number
ACTRN12613000339752
Ethics application status
Approved
Date submitted
22/02/2013
Date registered
27/03/2013
Date last updated
5/07/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Single Centre Phase II Study Of Haematopoietic Stem Cell Transplantation (HSCT) for Severe Auto-Immune Diseases.
Scientific title
A Single Centre Phase II Study Of the safety and efficacy of Haematopoietic Stem Cell Transplantation For Severe Auto-Immune Diseases.
Secondary ID [1] 282002 0
nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Auto Immune disorders 288438 0
Condition category
Condition code
Inflammatory and Immune System 288786 288786 0 0
Other inflammatory or immune system disorders
Musculoskeletal 288802 288802 0 0
Other muscular and skeletal disorders
Neurological 288803 288803 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients are assessed using inclusion and exclusion criteria, some of which are specific for the underlying auto-immune disease, in order to determine whether they are eligible for an Autologous Stem cell transplant. If eligible, all patients are given Cyclophosphamide 2g/m2 as per standard practice on a Saturday or Sunday, followed by G-CSF 10mcg/kg for the next 10-12 days until the following Monday when stem cells are collected. Minimum target CD34+ stem cell collection will be 2 x 10^6/kg.

Patients will be admitted into hospital for their autologous stem cell transplant within 4-8 weeks of stem cell collection. Patients with all autoimmune diseases (except multiple sclerosis) will then undergo chemo-immunotherapy. This consists of Cyclophosphamide 50mg/kg administered via a central venous line on days -5, -4, -3, and -2. Anti-thymocyte Globulin (ATG - Horse, ATGAM) 10mg/kg will be administered on Days -6, -5, -4 and -3 after a test dose is administered on Day -6. A minimum of 2 x 10^6/kg CD34+ cells without manipulation will be infused on Day 0.

Patients with multiple sclerosis will undergo BEAM therapy combined with Horse ATG (Atgam). Such a procedure is reported in the guidelines of the cooperative group European Bone Marrow Transplantation (EBMT) and European League Against Rheumatism (EULAR). This includes administration of carmustine 300mg/m^2 on Day -6; then cytosine arabinoside 200mg/m^2 /day and etoposide 200mg/m^2 /day on Days -5, -4, -3, -2; then Melfalan 140mg/m^2 on Day -1. Reinfusion of stem cells occurs on Day 0. This is followed by methylprednisolone 5mg/Kg /day and horse antithymocyte globulin 20mg/Kg /day on Days +1 and +2.

Standard supportive measures including hydration, antiemetics, and antimicrobial prophylaxis are followed as per institutional protocols.
Intervention code [1] 286572 0
Treatment: Other
Intervention code [2] 286573 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288926 0
Safety, as measured by transplant related mortality (TRM) by day 100. This is defined as death upto 100 days post transplant, not due to the original disease.
Timepoint [1] 288926 0
day 100
Primary outcome [2] 288927 0
Efficacy of HSCT in various auto-immune conditions that are refractory to standard therapies. This will be assessed using standardised clinical and laboratory criteria, specific for each auto-immune disease.
Timepoint [2] 288927 0
3 months, 6months, 12months then yearly up to 5 years
Secondary outcome [1] 301371 0
the proportion of Systemic Sclerosis patients who have attained a 25% reduction in skin scores, using Modified Rodman Skin score at pre-mobilisation
Timepoint [1] 301371 0
at 3, 6, 12, 24 months and subsequently yearly up to 5 years
Secondary outcome [2] 301372 0
proportion of Multiple Sclerosis who become wheel chair bound (EDSS 7) at pre-mobilisation. This will be determined clinically and with reference to medical records.
Timepoint [2] 301372 0
at 3, 6, 12, 24 months and subsequently yearly up to 5 years
Secondary outcome [3] 301373 0
proportion of Multiple Sclerosis paitents who have improvement in their T2 lesion on MRI at pre-mobilisation
Timepoint [3] 301373 0
12, 24 months and subsequently yearly up to 5 years
Secondary outcome [4] 301374 0
Evaluate whether remission and disease activity correlates with immunological parameters, including immune reconstitution and auto-antibodies. This will be assessed using blood tests.
Timepoint [4] 301374 0
pre-mobilisation and at 12, 24 months and subsequently yearly up to 5 years.
Secondary outcome [5] 301375 0
assess Quality of Life and Health Assessment of patients post HSCT using QOL questionnaires and HAQ forms
Timepoint [5] 301375 0
pre-mobilisation and at 3, 6, 12, 24 months and subsequently yearly up to 5 years

Eligibility
Key inclusion criteria
Adequate organ function as measured by:
Cardiac LV Ejection Fraction greater than 45%, total Lung Capacity greater than 60%, Pulmonary artery pressure greater than 50mmHg, DLCO greater than or equal to 50%.
Negative serology for HBV, HCV and HIV.
Negative pregnancy test.
Able to provide informed consent and the absence of mental and cognitive deficits which can interfere with the capability of providing the informed consent.
Absence of severe chronic infection.
Severe auto-immune disease less than 7 years duration (excluding Multiple Sclerosis) OR Multiple sclerosis of any duration unresponsive to multiple standard therapies including corticosteroids.
HSCT deemed best high-intensity immunotherapeutic treatment in the opinion of the referring physician.

Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age

Specific Inclusion Criteria for each disease:
1.Systemic Sclerosis:
Early, rapidly progressive inflammatory diffuse scleroderma with truncal skin involvement and/or involving lungs and/or heart (myocarditis) which has failed to stabilize with anti-rheumatic agents. All patients with severe Systemic Sclerosis will undergo right catheterisation prior to cyclophosphamide mobilisation to assess for pulmonary artery pressure. Ideally patients will also have signs of ongoing disease-related inflammation immediately prior to ASCT. Early disease is defined as disease in which the timing from second symptom onset to ASCT was 7 years or less

2. Systemic lupus erythematosus (SLE):
Diagnosis according to ACR-criteria with antinuclear antibodies positive on at least two successive tests at three months interval plus disease duration less than 7 years since the diagnosis or first time of intensive immunosuppressive drugs. Unresponsive to multiple therapies including at least 6 months of the best standard local therapy using prednisone, intravenous cyclophosphamide or mycophenolate mofetil either alone or successively with or without anti CD 20 (Rituximab). Major organ damage (eg: cerebritis, nephritis, pulmonary, cardiac or skin vasculitis) is present despite optimal immunosuppression.

3. Multiple Sclerosis (MS):
I. Diagnosis of relapsing remitting MS (RRMS) made by a Neurologist according to
the 2010 revised McDonald’s criteria
II EDSS score 0-6.5 NB: EDSS of 6.5 (this corresponds to able to walk, needing at most bilateral assistance to walk 20m without resting). Patients with an EDSS of 0-2 will require a second independent physician to assess the patient’s suitability for HSCT
III Disease duration of at least 15 years from diagnosis of MS
IV New MRI activity within last 12 months: Inflammatory active MS as defined by at least 1 Gd+ (>3mm) lesion (off steroids for one month) or at least 2 new T2 lesions on MRI within the last 12 months, compared to a reference scan not older than 36 months and preferably within the last 24 months from the date of eligibility review OR
a history of highly active disease, as determined by previous MRI prior to commencement of high efficacy treatment (alemtuzumab and/or natalizumab), in patients where the long term immunosuppresive risk on treatment is determined to be of significance to patients morbidity/mortality (long term risk of infection, malignancy or organ failure secondary to treatment). Confirmation regarding suitability for HSCT from an external neurologist will be required in this case.
V Relapsing-remitting MS (RRMS), who have failed at least one licensed disease modifying drug of high efficacy (currently including alemtuzumab and natalizumab) because of demonstrated lack of efficacy (as evident from relapse, MRI activity as above, or EDSS increase) after being on Disease Modifying Therapy (DMT) for at least 6 months OR
in RRMS patients where the long term immunosuppressive risk on above treatment is determined to be of significance to patients morbidity/mortality (long term risk of infection, malignancy or organ failure secondary to treatment).

4. Other Auto-Immune Conditions:
Diseases such as vasculitis, Chrohn’s disease, Behcet’s disease refractory to all available therapies and in the opinion of the referring physician, HSCT is a valid therapeutic option for that patient. These patients will require an independent physician to assess the patient’s suitability for HSCT.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- If specific auto immune disorders does not meet the individual eligibility criteria.
- Any patient on the study treatment arm deemed not suitable for transplant by HSCT specialist
- Any patient unable to understand the purpose and risks of the study
- Patients deemed by their treating neurologist to have entered phase of secondary progressive

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
open label
Specific conditioning regimens are used dependent on AutoImmune disorder
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 639 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 6372 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 286780 0
Hospital
Name [1] 286780 0
St Vincent's Hospital, Sydney
Address [1] 286780 0
390 Victoria St
Darlinghurst NSW 2010
Country [1] 286780 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
390 Victoria St
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 285563 0
None
Name [1] 285563 0
Address [1] 285563 0
Country [1] 285563 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288845 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 288845 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [1] 288845 0
Australia
Date submitted for ethics approval [1] 288845 0
08/12/2010
Approval date [1] 288845 0
26/01/2011
Ethics approval number [1] 288845 0

Summary
Brief summary
Diseases such as Scleroderma, Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), vasculitis, Chrohn’s disease, Behcet’s disease refractory to all available therapies and in the opinion of the referring physician, HSCT is a valid therapeutic option for that patient. These patients will require an independent physician to assess the patient’s suitability for HSCT. Patients will undergo GSCF stimulated stem cell collection following chemotherapy. Patients are readmitted for autlogous transplant and will have specific high dose immunosuppresssive therapy depending on their disorder followed by stem cell re infusion
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 38042 0
Dr John Moore
Address 38042 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 38042 0
Australia
Phone 38042 0
61 2 9355 5656
Fax 38042 0
61 2 9355 5735
Email 38042 0
svhcancer_research@stvincents.com.au
Contact person for public queries
Name 38043 0
Dr John Moore
Address 38043 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 38043 0
Australia
Phone 38043 0
61 2 9355 5656
Fax 38043 0
61 2 9355 5735
Email 38043 0
svhcancer_research@stvincents.com.au
Contact person for scientific queries
Name 38044 0
Dr John Moore
Address 38044 0
St Vincent's Hospital, Sydney
390 Victoria St
Darlinghurst NSW 2010
Country 38044 0
Australia
Phone 38044 0
61 2 9355 5656
Fax 38044 0
61 2 9355 5735
Email 38044 0
svhcancer_research@stvincents.com.au

No data has been provided for results reporting
Summary results
Not applicable