Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000151437
Ethics application status
Approved
Date submitted
28/01/2016
Date registered
9/02/2016
Date last updated
11/01/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase II study:
Haematopoietic Stem Cell Transplantation for highly active
treatment resistant multiple sclerosis .
Scientific title
A Phase II study:
Haematopoietic Stem Cell Transplantation for highly active
treatment resistant multiple sclerosis .
Secondary ID [1] 288507 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsing Remitting Multiple Sclerosis 297449 0
Condition category
Condition code
Neurological 297637 297637 0 0
Multiple sclerosis
Inflammatory and Immune System 297638 297638 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients are assessed using inclusion and exclusion criteria, specific for the highly active, treatment resistant multiple sclerosis in order to determine whether they are eligible for an Autologous Stem cell transplant. If eligible, all patients are given intravenous Cyclophosphamide 2g/m2 as per standard practice followed by G-CSF 10mcg/kg for the next 10-12 days until the following Monday when stem cells are collected by taking 150-200mls of blood which is processed in the laboratory. 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 based on speed of laboratory processing to produce transplant cells. Patients will then undergo chemo-immunotherapy.
with BEAM therapy combined with Horse ATG (Atgam). This includes intravenous administration of all the following agents carmustine 300mg/m2 on Day -6; then cytosine arabinoside 200mg/m2 /day and etoposide 200mg/m2 /day on Days -5, -4, -3, -2; then Melfalan 140mg/m2 on Day -1. Reinfusion of stem cells occurs on Day 0. This is followed by intravenous methylprednisolone 5mg/Kg /day and intravenous 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] 293746 0
Treatment: Other
Intervention code [2] 293747 0
Treatment: Drugs
Comparator / control treatment
Uncontrolled
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297178 0
Safety, as measured by transplant related mortality (TRM) by day 100. This is defined as death up to 100 days post transplant, not due to the original disease following review of the medical record.
Timepoint [1] 297178 0
Day 100 post transplant
Secondary outcome [1] 320249 0
Efficacy of HSCT in highly active multiple sclerosis that is refractory to standard therapies. This will be assessed using standardised clinical and laboratory criteria, including MRI and EDSS.
Timepoint [1] 320249 0
6months, 12months then yearly up to 5 years post transplant

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 less 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.

Specific Inclusion Criteria for multiple sclerosis
Age between 18-55
EDSS between 2.5-5.5
10 years or less since first treated for MS
And meets criteria (below) on both clinical and MRI grounds, for highly active MS within the past 2 years despite ongoing use of a PBS approved therapy
Clinical
i) a minimum of at least 1 severe relapse with an increase in EDSS of 1 (or 0.5 for those with pre relapse EDSS of 5.5 or above)
in motor, cerebellar or brain stem deficit (or documented changes in neurological examination consistent with these magnitudes)
and/or
ii) incomplete recovery from clinically significant relapses

MRI
i. at least one gadolinium-positive (Gd+) lesion of diameter 3 mm or greater on MRI within the past 6 months.
or
ii. accumulation of at least 0.3 T2 lesions/month on two consecutive MRIs 6–12 months apart.

Previous Treatment with Nataluzimab is allowed but a minimum of 6 months MUST have elapsed since completion of treatment.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Progressive forms of multiple sclerosis with no evidence of recent disease activity on MRI.

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
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
15/01/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 5202 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 12664 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 292774 0
Hospital
Name [1] 292774 0
Austin Health
Country [1] 292774 0
Australia
Primary sponsor type
Hospital
Name
Austin Health
Address
145 Studley Road
Heidelberg Vic 3084
Country
Australia
Secondary sponsor category [1] 291561 0
None
Name [1] 291561 0
N/A
Address [1] 291561 0
N/a
Country [1] 291561 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294269 0
Austin Health
Ethics committee address [1] 294269 0
145 Studley Road
Heidelberg Vic 3084
Ethics committee country [1] 294269 0
Australia
Date submitted for ethics approval [1] 294269 0
02/03/2015
Approval date [1] 294269 0
19/06/2015
Ethics approval number [1] 294269 0

Summary
Brief summary
Over the past 15 years a number of new treatments have proved successful in the treatment of multiple sclerosis. There a remains though a small group of patients who do not respond and who continue to have attacks despite treatment causing further permanent neurological disability in a cumulative fashion. This disability can take the form of muscle weakness, impairing walking ability, visual loss, impaired balance, bladder and bowel dysfunction and loss of higher intellectual faculties. Patients with aggressive forms of MS also have a shortened life span as a result of their disease.
Haematopoietic stem cell transplantation (HSCT) is a procedure originally used to treat patients with blood cancers. A high dose of chemotherapy is given which not only kills the malignant cells but also normal healthy bone marrow and blood cells. In order for the patient to survive these cells must be replaced by giving the patient a stem cell infusion following the chemotherapy . The stem cells replenish the bone marrow and a new blood and immune system then grows from it.
Over the last 15 years, HSCT has become much safer. At the same time, numerous lines of evidence have emerged suggesting that a small number of patients with severe autoimmune diseases such as MS not controlled by other treatments could also respond to treatment with HSCT. This evidence came initially from patients with a co-existent auto-immune disease (AID) including multiple sclerosis (MS) who had chemotherapy for blood tumours. It was observed that not only did their cancers remain in prolonged remission after HSCT but so did the manifestations of their autoimmune disease.
The procedure requires an initial dose of chemotherapy with a drug called cyclophosphamide to help stem cells to be collected via a vein in the arm. Subsequently the patient is admitted into hospital tohave high doses of chemotherapy that intensely suppresses the immune system. At this point the stem cells collected at the earlier time point are reinfused through the vein so they can re-grow a new immune system and protect the patient from the toxic effects of the chemotherapy. It takes about 14 days for the new stem cells to grow and then follow up is conducted carefully over several years to see if this method of immunosuppression and immune reconstitution prevents the reemergence of multiple sclerosis. The procedure is not without risk with the major complications of infection and death. Overall the risk of death where the procedure is done for an autoimmune disease is quoted at between 1-5 %.
The Neurology Unit at Austin Health has conducted trials in MS since 1996 and the Haematology Unit performs HSCT on a regular basis for patients with blood malignancies. The unit’s morbidity and mortality results for HSCT are on par with the world’s leading hospitals. We intend to explore therapy in patients with an aggressive form of MS and then follow them in a rigorous fashion over 5 years to gauge its effectiveness.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 63126 0
Prof Richard Macdonell
Address 63126 0
Austin Health
145 Studley Road
Heidelberg Vic 3084
Country 63126 0
Australia
Phone 63126 0
+61 3 9496 3705
Fax 63126 0
+61 3 9496 2153
Email 63126 0
richard.macdonell@austin.org.au
Contact person for public queries
Name 63127 0
Prof Richard Macdonell
Address 63127 0
Austin Health
145 Studley Road,
Heidelberg Vic 3084
Country 63127 0
Australia
Phone 63127 0
+61 3 9496 3705
Fax 63127 0
+61 3 9496 2153
Email 63127 0
richard.macdonell@austin.org.au
Contact person for scientific queries
Name 63128 0
Prof Richard Macdonell
Address 63128 0
Austin Health
145 Studley Road
Heidelberg Vic 3084
Country 63128 0
Australia
Phone 63128 0
+61 3 9496 3705
Fax 63128 0
+61 3 9496 2153
Email 63128 0
richard.macdonell@austin.org.au

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No Supporting Document Provided


Results publications and other study-related documents

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