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Trial registered on ANZCTR


Registration number
ACTRN12619000348156
Ethics application status
Approved
Date submitted
19/02/2019
Date registered
6/03/2019
Date last updated
18/11/2019
Date data sharing statement initially provided
6/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Autologous Haematopoietic Stem Cell Transplantation for highly active treatment resistant multiple sclerosis.
Scientific title
A study to evaluate the safety of Autologous Haematopoietic Stem Cell Transplantation in patients with highly active treatment resistant multiple sclerosis.
Secondary ID [1] 297456 0
MSNI 2019.01
Universal Trial Number (UTN)
U1111-1228-8807
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Relapsing Remitting Multiple Sclerosis 311640 0
Condition category
Condition code
Neurological 310263 310263 0 0
Multiple sclerosis
Inflammatory and Immune System 310264 310264 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Autologous Haematopoietic Stem Cell Transplantation
Participants are assessed using inclusion and exclusion criteria specific for highly active, treatment resistant multiple sclerosis in order to determine whether they are eligible for an Autologous Stem cell transplant as part of the study.
Participants will undergo stem cell collection following intravenous infusion 2g/m2 cyclophosphamide. Intravenous fluids 0.9% Normal Saline(one litre every 6 hours) and mesna (dose 3g/m2) over 5 hours commencing one hour prior to cyclophosphamide, will be prescribed to run concurrently as per current standard practice in the Haematology Unit for malignant conditions. The intravenous fluids will run for 24 hours. This dose of Cyclophosphamide is given as a day patient in day oncology HOC unit (unless admission is determined to be necessary). Other supportive medications eg. anti-emetics as per local guidelines
From day 5 onwards daily GCSF 5mcg/kg twice daily for at least 7 days will be administered sub-cutaneously. The maximum duration for GCSF is 9 days. The duration of GCSF is determined by the level of stem cells in the blood.

Haematopoietic stem cells will then be collected and cryopreserved as per standard operating procedures in the Haematology Department.
Within 4-8 weeks from the collection of stem cells, the participant is hospitalized for the immune ablative and transplantation procedure. The timing of the transplantation procedure is determined by participant health and wellbeing, and availability of resources.The immune ablative regime consists of cyclophosphamide 50mg/kg (total of 200mg/kg) from day -5 to day -2 before transplantation, and rabbit antithymocyte globulin ATG (Thymoglobuline®) 0.5mg/kg intravenous infusion on day -5, 1.0mg/kg on day -4 and 1.5mg/kg pm days -3,-2 and -1. Methylprednisolone 1000mg intravenous infusion is to be infused 30minutes prior to rabbit ATG infusions. An additional 250mg of methylprednisolone should be used in the setting of ATG induced fever. Give mesna IV (40% of the cyclophosphamide dose) in 100 mL of normal saline over 30 minutes before the infusion of cyclophosphamide. Then commence mesna (120% of cyclophosphamide dose) in 1 litre of normal saline over 24 hours at the same time as cyclophosphamide, to finish 24 hours after the last dose of cyclophosphamide (on D-5, D-4, D-3 and D-2).
The collection and transplantation procedures will be performed as per The Alfred hospital's Standard of Care in the Haematology Department ward under the care of Haematologists, and haematology trained nursing staff. The minimum target dose of stem cells is 2 x 10^6 cells. The cells are administered by intravenous infusion.
Intervention code [1] 313711 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319151 0
The primary objective of the cohort study is to assess the safety, as measured by transplant related mortality at Day 100 (defined as death in the first 100 days not due to MS)
Timepoint [1] 319151 0
Day 100 post transplant
Primary outcome [2] 319321 0
To assess the efficacy of HSCT as measured by (a) mean time to first relapse (clinical and MRI), (b) mean time to 3 and 6 month sustained change in EDSS and (c) mean annualised relapse rate in participants with multiple sclerosis refractory to standard therapies.
Timepoint [2] 319321 0
Month 60
Secondary outcome [1] 367138 0
To assess tolerability of the autograft between d100 and d365, particularly with respect to infectious sequelae. This will be assessed by monitoring the occurrence of infectious sequelae as adverse events
Timepoint [1] 367138 0
Day 365 post transplant

Eligibility
Key inclusion criteria
1. Male and female participants aged 18-60 with MS (2017 revised McDonald criteria)
2. Expanded Disability Status Scale (EDSS) score between 0 and 6
3. Highly active RRMS despite continuing to use conventional treatment for RRMS within the past 2 years.
Definition of ‘highly active’ RRMS
i.
1. Greater than or equal to 1 severe relapses (Change in EDSS greater than or equal to 1 or 0.5 for those with pre relapse EDSS greater than or equal to 5.5) (or documented changes in neurological examination consistent with these magnitudes) and/or incomplete recovery from clinically significant relapses within the last 12 months
and
2. Greater than or equal to 1 gadolinium-positive (Gd+) lesion of diameter greater than or equal to 3 mm on MRI within the past 6 months.
or
3. Accumulation of any new T2 lesions on follow up MRI scans

ii.
1. Change in EDSS greater than or equal to 1 or 0.5 for those with pre relapse EDSS greater than or equal to 5.5)
and
2. evidence of new MRI activity either T1 or T2 performed on follow up MRI scans
4. Neurologically stable participants with no evidence of relapse for at least 30 days prior to study entry into the treatment period.
5. Females of childbearing potential must
a. have a negative pregnancy test at baseline prior to entry into the treatment period
b. use simultaneously two forms of effective contraception (either i.e partner) during and for 3 months after HSCT
c. females that are either post-menopausal for 12 months prior to entry into the treatment period or surgically sterile (through hysterectomy or bilateral oophorectomy) are not required to use birth control.
6. Able to provide informed consent and the absence of mental and cognitive deficits which can interfere with the capability of providing the informed consent for participation in the study prior to the Screening.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Participants with a non-relapsing form of MS (primary or secondary progressive MS)
2. Participants with any medically unstable condition, as assessed by the primary treating physician.
3. Participants with any of the following cardiovascular conditions:
a) history of cardiac arrest;
b) myocardial infarction within the past 6 months prior to enrolment or with current
unstable ischemic heart disease
c) cardiac failure at time of Screening (Class III, according to New York Heart
Association Classification) or any severe cardiac disease as determined by the
investigator.
d) Left Ventricular (LV) ejection fraction < 45%
e) hypertension, not controlled by prescribed medications
4. Participants with any of the following pulmonary conditions:
a) severe respiratory disease or pulmonary fibrosis;
b) tuberculosis, except for history of successfully treated tuberculosis or history of
prophylactic treatment after positive PPD skin reaction
c) abnormal chest x-ray suggestive of active pulmonary disease;
d) abnormal Pulmonary Function Tests: FEV1, FVC values lower than 70% of
predicted, DLCO values lower than 60% of predicted.
5. Participants with any of the following hepatic conditions
a) known history of alcohol abuse, chronic liver or biliary disease
b) total bilirubin greater than the upper limit of the normal range, unless in context of
Gilbert’s syndrome
c) conjugated bilirubin greater than the upper limit of the normal range
d) AST, ALT greater than 2 times the upper limit of the normal range
e) alkaline phosphatase (AP) greater than 1.5 times the upper limit of the normal
range;
f) gamma-glytamyl-transferase (GGT) greater than 3 times the upper limit of the normal
range
6. Participants with abnormal laboratory values
a) serum creatinine >150 µmol/L.
b) white blood cell (WBC) count <3.5x109/L or lymphocyte count <0.8x109/L
7. Participants with any of the following neurological or psychiatric conditions
a) history of substance abuse (drug or alcohol) or any other factor (i.e., serious
psychiatric condition) that may interfere with the subject’s ability to cooperate and
comply with the study procedures
b) progressive neurological disorder, other than MS, which may affect participation in
the study or require the use of medications not allowed by the protocol.
8. Participants unable to undergo MRI scans, including history of severe hypersensitivity
to gadolinium
9. Participation in any clinical research study evaluating another investigational drug or
therapy within 6 months prior to baseline.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and
11. Participants unwilling to use effective contraception

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
6/05/2019
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
50
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 13205 0
The Alfred - Prahran
Recruitment postcode(s) [1] 25761 0
3004 - Melbourne
Recruitment postcode(s) [2] 25762 0
3004 - Prahran

Funding & Sponsors
Funding source category [1] 302027 0
Hospital
Name [1] 302027 0
Alfred Health
Country [1] 302027 0
Australia
Primary sponsor type
Hospital
Name
Alfred Health
Address
55 Commercial Road
Melbourne 3004 VIC
Country
Australia
Secondary sponsor category [1] 301823 0
None
Name [1] 301823 0
Address [1] 301823 0
Country [1] 301823 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302706 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 302706 0
Ethics committee country [1] 302706 0
Australia
Date submitted for ethics approval [1] 302706 0
28/03/2019
Approval date [1] 302706 0
29/10/2019
Ethics approval number [1] 302706 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91118 0
Dr Cassie Nesbitt
Address 91118 0
The Alfred Hospital
55 Commercial Road
Melbourne 3004 VIC
Country 91118 0
Australia
Phone 91118 0
+61 3 9903 8662
Fax 91118 0
Email 91118 0
[email protected]
Contact person for public queries
Name 91119 0
Cassie Nesbitt
Address 91119 0
The Alfred Hospital
55 Commercial Road
Melbourne 3004 VIC
Country 91119 0
Australia
Phone 91119 0
+61 3 9903 8662
Fax 91119 0
Email 91119 0
[email protected]
Contact person for scientific queries
Name 91120 0
Cassie Nesbitt
Address 91120 0
The Alfred Hospital
55 Commercial Road
Melbourne 3004 VIC
Country 91120 0
Australia
Phone 91120 0
+61 3 9903 8662
Fax 91120 0
Email 91120 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.