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Trial registered on ANZCTR


Trial ID
ACTRN12611000826943
Ethics application status
Approved
Date submitted
2/08/2011
Date registered
5/08/2011
Date last updated
5/08/2011
Type of registration
Retrospectively registered

Titles & IDs
Public title
Long term follow up of patients with severe Systemic Sclerosis (SSc) and Rheumatoid Arthritis (RA) who have undergone Haematopoietic Stem Cell Transplantation (HSCT).
Scientific title
A retrospective review of patients with severe Systemic Sclerosis and Rheumatoid Arthritis who have had a Haematopoietic Stem Cell Transplant as a means of immunosuppression to achieve disease remission - assessment of safety and efficacy of response.
Secondary ID [1] 262759 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Systemic Sclerosis and Rheumatoid Arthritis 270470 0
Condition category
Condition code
Inflammatory and Immune System 270624 270624 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Autologous stem cell transplantation (HSCT) is a procedure that is usually used to give high doses of chemotherapy to patients with blood cancers followed by stem cell infusion so that a new blood and immune system can regrow. Over the last 15 years, HSCT has become much safer. At the same time, numerous lines of evidence converged to suggest that a small number of patients with very severe immune conditions could also be treated by HSCT. The evidence came from patients who had chemotherapy for co-existant blood tumours and had an auto-immune disease (AID). Often these patients had prolonged remissions of their AID. In addition, there are animal models of HSCT in AID showing prolonged remissions with HSCT. AID patients suffer from an immune attack on their own body causing tightening of the skin (Systemic Sclerosis), spinal cord and brain problems (Multiple Sclerosis) and multiple other organs in the body (Systemic Lupus Erythromatosis, Crohn's disease and vasculitis). In some cases, people with auto-immune conditions can die from their condition, particularly when the disease has failed multiple treatments. It is possible to select the very sickest AID patients for more intensive therapy with HSCT and provide them with a lasting remission.

The procedure requires a two step process. The first step requires chemotherapy with one dose of a drug called cyclophosphamide (2grams) intravenously along with GCSF 10ug/kg subcutaneously x 7 days (a hormone to stimulate the bone marrow) to help stem cells to be collected via a vein in your arm. Within 2 months, patients come into hospital for the second step. Here patients will have high doses of intravenous chemotherapy (cyclophosphamide 200mg/kg over 4 days along with Anti-thymocyte globulin 10mg/kg x 4 days) that also intensely suppresses the immune system. After these 4 days the patient's own stem cells are transfused so they can re-grow a new immune system and protect the patients from the toxic effects of the chemotherapy. It takes about 14 days for the new stem cells to grow and then we will follow patients carefully over the next 10 years (initially every 3-6 months but after 1 year just annually) to see if the immunosuppression controls your auto-immune disease and that there are no long term sequelae.
Intervention code [1] 267102 0
Treatment: drugs
Comparator / control treatment
There is no comparator arm.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 269353 0
Safety and efficacy of HSCT.

Initial contact of telephone advising patients of centre which will invite them into study followed by letter with consent form, health assessment questionnaire and visual analogue scales.
The patients will be required to fill out a series of questionnaires to assess the impact of RA or SSc on their quality of life.
i. Health Assessment Questionnaire (HAQ)
ii. Visual Analogue Scales (VAS)
iii. Modified Rodnan Skin Score (For SSc patients only)
Subsequent to this, patients will be asked to come to Haematology outpatient to have their medical history taken and to answer questions related to the safety of past HSCT, particularly recurrence of their diseases, development of secondary tumour such as lymphoma, and risk of infection due to immunosuppressants.
Timepoint [1] 269353 0
Safety and efficacy of HSCT at 5 and 10 years post HSCT.
Secondary outcome [1] 279440 0
Immune reconstitution of T cell subsets post HSCT with a particular emphasis on thymic output.

The methods for this analysis include:
40mL of blood sample will be collected by venapuncture during the clinical session. The side effect of this procedure is minimal. However, there could be some bruising around the venapuncture site. Infection of the site is very rare.
Aliquots of whole blood will be used for phenotypic analysis of lymphocytes subsets (CD4, CD8, CD45RA, CD45RO). In particular VBeta oligoclonal population will be assessed using anti-VB2, 3, 12, 13 monoclonal antibodies.
PBMNC will be prepared using Ficoll density centrifugation. Normal stem cells will be compared for CLP phenotype with RA/SSc stem cell collections (Tissue Bank Consent H00/045). Antibodies used for CLP surface markers are CD7, CD34, Cd38, c-kit.
ELISA for inflammatory cytokines such as IL-7, TNF- alpha will be performed.
If time is permitting, TREC level in the blood samples will be measured using competitive PCR method to assess the thymic output.
If time is permitting, culture of RA stem cells using OP-9 cell line comparing RA and normal common lymphoid progenitor populations (previously submitted under study H06/148).
Timepoint [1] 279440 0
6 months, 1 year and 2 years post HSCT

Eligibility
Key inclusion criteria
Patients who have undergone HSCT for severe Systemic Sclerosis and Rheumatoid Arthritis at St Vincents Hospital between 1996 and 2010.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients unwilling to sign consent forms and those who have a psychiatric condition preventing them from participating.
Severe end organ damage such as:
Left Ventricular Ejection Fraction <50%
DLCO/VA < 50%
Right Atrial pressure > 45mm Hg

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)
Patients who have previously had a stem cell transplant at this hospital for Systemic sclerosis and Rheumatoid Arthritis are invited to participate by a letter. If they accept the invitiation they are then invited to attend the hospital to sign the informed consent form.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
No randomisation is required in this study.
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)
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
Current
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 269582 0
Hospital
Name [1] 269582 0
St. Vincents Hospital, Sydney.
Address [1] 269582 0
Victoria St,
Darlinghurst,
NSW 2010
Country [1] 269582 0
Australia
Funding source category [2] 269589 0
Hospital
Name [2] 269589 0
Haematology Department, St Vincents Hospital, Sydney
Address [2] 269589 0
Victoria St,
Darlinghurst,
NSW 2010
Country [2] 269589 0
Australia
Primary sponsor type
Hospital
Name
St Vincents Hospital, Sydney
Address
Victoria St,
Darlinghurst,
NSW 2010
Country
Australia
Secondary sponsor category [1] 266616 0
None
Name [1] 266616 0
Address [1] 266616 0
Country [1] 266616 0
Secondary sponsor category [2] 266620 0
Charities/Societies/Foundations
Name [2] 266620 0
St. Vincents Clinic Foundation
Address [2] 266620 0
Victoria St,
Darlinghurst,
NSW 2010
Country [2] 266620 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 269534 0
St Vincents Hospital Human Research Ethics Committee
Ethics committee address [1] 269534 0
St Vincents Hospital
Victoria St,
Darlinghurst,
NSW 2010
Ethics committee country [1] 269534 0
Australia
Date submitted for ethics approval [1] 269534 0
23/06/2008
Approval date [1] 269534 0
09/07/2008
Ethics approval number [1] 269534 0
1/08/0106

Summary
Brief summary
This trial aims to assess the safety and efficacy of Haematopoietic stem cell transplant (HSCT) for severe systemic sclerosis (SSc) and rheumatoid arthritis (RA). HSCT is reserved for patients with severe disease who have failed multiple previous therapies. Numerous lines of evidence have suggested that HSCT may have a role to play in these autoimmune conditions as a way of suppressing the inflammatory condition but also by possibly re-educating the immune system, especially, the thymus. This study aims to assess if the HSCT has been successful ( as measured by standard response criteria) and safe in these patients. Secondly it aims to assess if the thymus has a role to play in those who respond. This will be assessed by flow cytometry on stored specimens (collected with informed consent via a tissue bank consent form) with a particular emphasis on oligoclonal T cell subsets.
Trial website
Nil
Trial related presentations / publications
Nil at present for this component of the study. The RA patient clinical data was published in 2002 as below:
Moore J, Brooks P, Milliken S, Biggs J, Ma D, Handel M et al. A prospective randomised trial comparing CD34 selected versus unmanipulated haemopoietic stem cell transplantation for severe resistant rheumatoid arthritis. Arthritis and Rheumatism, 46: 2301-2309, 2002.
Public notes

Contacts
Principal investigator
Name 32964 0
Address 32964 0
Country 32964 0
Phone 32964 0
Fax 32964 0
Email 32964 0
Contact person for public queries
Name 16211 0
John Moore
Address 16211 0
Haematology Department,
St. Vincents Hospital,
NSW 2010
Country 16211 0
Australia
Phone 16211 0
61 2 83822677
Fax 16211 0
61 2 83822645
Email 16211 0
jmoore@stvincents.com.au
Contact person for scientific queries
Name 7139 0
John Moore
Address 7139 0
Haematology Department,
St. Vincents Hospital,
NSW 2010
Country 7139 0
Australia
Phone 7139 0
61 2 83822677
Fax 7139 0
61 2 83822645
Email 7139 0
jmoore@stvincents.com.au