Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000536763
Ethics application status
Approved
Date submitted
21/02/2022
Date registered
5/04/2022
Date last updated
26/11/2023
Date data sharing statement initially provided
5/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Autologous Stem Cell Transplant in Multiple Sclerosis
Scientific title
Autologous Haematopoietic Stem Cell Transplant in Multiple Sclerosis
Secondary ID [1] 306399 0
NONE
Universal Trial Number (UTN)
Trial acronym
AiMS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple Sclerosis 325233 0
Condition category
Condition code
Neurological 322632 322632 0 0
Multiple sclerosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patient with Multiple Sclerosis who meets the eligibility criteria will be enrolled in the intervention study. It is proposed that the patients would be enrolled in sequential cohorts. Patients would be assigned to one of the available cohorts (in a block of 15:15 fashion), unless there is a clear medical reason determined by the transplant physician that they should be treated with a particular regimen (eg: history of allergic reaction to one of the drugs).

The intervention involves patients being admitted into hospital to mobilise their Peripheral Blood Stem Cells using a single dose 2g/m2 cyclophosphamide being given as an inpatient. Intravenous fluids will be prescribed to run concurrently with cyclophosphamide as per current standard practice in the Haematology Unit for malignant conditions and patients will be reviewed by the medical team daily. The following day once the cyclophosphamide has being given, patients will be discharged from the ward. Prior to discharge, daily granulocyte stimulating factor (GCSF) 10mcg/kg/day is commenced (24hrs after completion of cyclophosphamide) and subsequent doses will be administered (at home) and continue until stem cell collections are complete. Patients are contacted by the transplant coordinator at the beginning of the week after being discharged to check whether they are having any difficulties injecting themselves and overall physical and mental wellbeing. Patients will then start leukapheresis (stem cell collection) once their peripheral blood CD34+ count is >10/uL until a minimum CD34+ collection. Patients may require a vascath insertion on the day prior to leukapheresis if venous access is not adequate – this would require a second consent form as per standard practice in the Haematology Department.
Patients return for medical review as determined by the treating transplant physician subject to the patients level of wellbeing. After a clinically appropriate time period following the collection of stem cells, the patient is re-hospitalised to undergo the transplantation procedure. The procedure for this study involves been admitted into hospital for the administration of one of two regimens; Cyclophosphamide/Anti-Thymocyte Globulin (ATG) or Carmustine, Etoposide, Cytarabine and Melphalan with ATG 1 week prior to reinfusing their own stem cells to ‘grow’ a new immune system.

Cohort 1: Carmustine given intravenously at 300mg/m2 on Day -6 followed by a daily intravenous ATG will also be given at the following doses: 0.5mg/kg on Day -5, 1mg/kg on Day -4, 1.5mg/kg on Day-3, Day-2 and Day -1 (total dose 6mg/kg) with methylprednisolone given intravenously at1mg/kg as premedication prior to every dose of ATG. In addition, cytosine arabinoside intravenously 200mg/m2/day daily from Day -5 to Day -2 and etoposide intravenously at 200mg/m2/day daily from Day -5 to Day -2 plus one dose of melphalan intravenously at 140mg/m2 on Day -1
Cohort 2: a daily dose of Cyclophosphamide at 50mg/kg is administered intravenously on Day -5, Day -4, Day -3, Day -2 with intravenous fluids prescribed to run concurrently. A daily intravenous ATG will also be given at the following doses: 0.5mg/kg on Day -5, 1mg/kg on Day -4, 1.5mg/kg on Day-3, Day-2 and Day -1 (total dose 6mg/kg) with methylprednisolone given intravenously at1mg/kg as premedication prior to every dose of ATG.

Following Autologous Haematopoietic Stem Cell Transplantation (AHSCT), supportive therapies such as blood/platelet transfusions will be given intravenously depending on the results of blood tests. Prophylactic anti-microbials such as Bactrim, fluconazole and valaciclovir will also be used. It is anticipated that the duration of dosing of anti-microbials up to 3 months post-stem cell reinfusion depending on the wellbeing of the patient.
Beginning on day +7, daily per oral prednisone at 0.5mg/kg (or IV methylprednisolone 0.5mg/kg daily) will be given for 5 days then 0.25mg/kg for 5 days then 10mg for 5 days then 5mg for 5 days as prophylaxis for serum sickness. If serum sickness develops, the same medication will be given however at treatment doses and will commence with 1mg/kg of prednisone orally and weaned as per physician discretion.

All patients will have standardised follow up assessment visits as per post-transplant standard of care ranging from weekly, fortnightly to monthly depending on their wellbeing in the first 100 days post AHSCT, and for specific clinical trial outcome assessment at 3, 6, 12, 24 months and subsequently yearly, up to 10 years.
Intervention code [1] 322843 0
Treatment: Other
Intervention code [2] 322844 0
Treatment: Drugs
Comparator / control treatment
MS patients consented for enrolment in the comparator arm will agree to have their deidentified clinical data information collected via data-linkage to medical records for treatment history and demographics and outcome of transplant recorded. This group will have standard care treatment as per their treating neurologist

Haematological group will provide consent to have their deidentified clinical data information collected via data-linkage to medical records for treatment history and demographics and outcome of transplant recorded. This group will have standard care transplant treatment as per their treating haematologist.

To summarise, the two comparator groups are MS patients receiving routine MS therapy under the care of their neurologist the Haematology patients who are receiving standard of care therapy which in this case is a stem cell transplant. The comparator groups will have
blood, stool and saliva collected. The samples biobanked will comprise of blood, stool and saliva collected at routine visits. If Cerebral spinal fluid (CSF) is being collected (ONLY Haematology group ) as part of routine pre and post-transplant timepoints, an additional sample will also be collected and analyzed.

The rationale for the comparator groups is to collect biobanked samples which can be used as a comparison for the changes to the immune system that occur with MS itself, and with any haematology patient having AHSCT. The comparator groups do not receive any interventional therapy as part of the trial.

The blood, saliva, CSF and stool samples collected in the study will be analysed by scientists independent of the clinical intervention. There is no direct influence from the biobanked samples on the clinical intervention, but this translational research will be used to further understand how AHSCT provides prolonged remission from autoimmune disease.
Control group
Active

Outcomes
Primary outcome [1] 330445 0
The primary objective of this submission is to assess safety HSCT as determined by data-linkage to medical records documenting length of stay in hospital from day 0 until discharge. Length of stay following AHSCT which is determined by a daily physical examination of the patient (whereby the patient will not be discharged until they are physically well enough for this to occur) and daily blood tests (whereby the patient will not be discharged until all blood results are within the acceptable limits) as per standard of care for any patient admitted to hospital.
Timepoint [1] 330445 0
Assessed by daily physical assessment and via collection of blood samples analyzing full blood count and biochemistry for toxicity and organ function
Primary outcome [2] 330695 0
The primary objective of this submission is to assess safety of HSCT as determined as determined by data-linkage to medical records documenting time to engraftment (number of days from HSC infusion until neutrophil engraftment).
Timepoint [2] 330695 0
assessed weekly until neutrophil engraftment has been confirmed
Primary outcome [3] 330696 0
The primary objective of this submission is to assess tolerability of HSCT as determined by data-linkage to medical records documenting length of stay in hospital from day 0 until discharge (maximum 4 weeks)
Timepoint [3] 330696 0
Assessed by daily physical assessment (daily for maximum of 4 weeks)
Secondary outcome [1] 406236 0
To assess the proportion of MS patients who have improvement in their Expanded Disability Status Scale (EDSS) as determined by data-linkage to medical records
Timepoint [1] 406236 0
Assess EDSS at 3, 6, 12, 24 months and subsequently yearly to 120 months after enrolment in the study.

Eligibility
Key inclusion criteria
HSCT patients with MS
-Age 18-65
-Age 65-70 (may be considered only if HCT-CI<3 and deemed fit both physically and cognitively by at least two investigators)
-Adequate organ function as measured by:
o Cardiac LV Ejection Fraction > 45%
o Total Lung Capacity > 60%
o DLCO/VA > 50%.
o Negative serology for active HBV, active HCV and HIV.
o Negative CT skeletal survey in patients with CIDP and a para-protein
o Serological assessments of haematology, liver, kidney and thyroid function reviewed by transplant physician and specialty input sought were required.

-No evidence of chronic infection or significant systemic illness where a treating specialist has concerns about HSCT.
-Clearance from treating physician in the case of prior or co-existent malignancy
-No current history of substance abuse (drug or alcohol) or other factor (eg: serious psychiatric impairment) that may interfere with patient’s ability to comply with the study procedure and follow up.
-Negative pregnancy test.
-Sperm collection or ova cryopreservation is to be offered prior to HSCT in those of child-bearing age.
-Patients must agree to use a form of effective contraception (either i.e. partner) during and for 3 months after HSCT (females that are either post-menopausal for 12 months prior to randomization or surgically sterile [through hysterectomy or bilateral oophorectomy] are not required to use birth control).
-Able to provide informed consent and the absence of mental and cognitive deficits which can interfere with the capability of providing the informed consent.
-AHSCT deemed an appropriate high-intensity immunotherapeutic treatment in the opinion of the referring physician.
-Diagnosis of relapsing MS made by a neurologist according to the 2017 revised McDonald’s criteria
-EDSS score 0-6.5
-Patients with an EDSS 6.5 – 8 may be considered eligible if an increase in EDSS of >2 points occurred in the preceding 3 months in the context of an acute, radiologically proven MS relapse. If EDSS is 6.5-8 a second independent neurologist will be required to assess the patient’s suitability for AHSCT.
-Active MS despite the use of high efficacy disease modifying therapy* for >3 months prior to the relapse. ‘Active MS’ defined as:
o >1 clinical relapse in the opinion of the referring neurologist
AND/OR
o Evidence of radiological disease activity (T1 lesion, T2/FLAIR lesion, Gd+ lesion) and evidence that this new activity did not preclude commencement of high-efficacy DMT.
-Patients with a history of highly active disease (as determined by clinical history/previous MRI) prior to commencement of high efficacy treatment, where the risk of continuing the treatment is determined to be significant (eg: patients who are stable on Natalizumab with a JC virus antibody positive status) may be eligible for AHSCT without evidence of current disease activity.
o Confirmation regarding suitability for AHSCT will be required by an external MS neurologist in this case (in addition to the referring neurologist and trial neurologist)

*High efficacy DMT currently includes: natalizumab, ocrelizumab, ofatumumab, alemtuzumab, fingolimod and cladribine. Future DMT’s of a similar class/mechanisms of action will also be considered high efficacy eg: future CD-20 monoclonal antibodies (mAbs) for MS


Inclusion criteria for Multiple Sclerosis patients NOT receiving AHSCT who will be enrolled in the comparator arms (observational and tissue banking study)
-Age 18-65
-Clinically definite MS as determined by a neurologist
-All decisions regarding patients management are made between the patients treating Neurologist and the patient independent to this trial. Tissue collection/biobanking is performed at time of routine clinical investigation/monitoring

Haematological group will be deemed eligible if the standard eligibility criteria are met used by all stem cell transplant centres as per outlines published in Bone Marrow Transplantation Journal (2019), "Indications for haematopoeitic stem cell transplantation for haematological disorders, solid tumours and immune disorders: current practice in Europe, 2019".
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Any patient during the screening phase whilst being considered for HSCT arm who does not meet inclusion criteria.
-Any patient on the study treatment arm deemed not suitable for transplant by a consensus of HSCT specialists as determined at the HSCT MDT.
-Any patient unable to understand the purpose and risks of the study or adhere to the post-transplant management including medication adherence and appointment attendance.
-Patients with a predominately progressive form of MS (‘primary’ or ‘inactive secondary’ progressive MS).
-Patients where MS mimics have not been adequately excluded.
-Patients unable to undergo MRI scans.
-Patients with advanced disease where the risks of transplant are deemed to outweigh potential benefits.

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)
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
11/04/2022
Actual
8/06/2022
Date of last participant enrolment
Anticipated
22/02/2025
Actual
Date of last data collection
Anticipated
6/03/2032
Actual
Sample size
Target
30
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21703 0
St Vincent's Private Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 36755 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 310754 0
Hospital
Name [1] 310754 0
St Vincent's Hospital,Sydney
Country [1] 310754 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
Kinghorn Cancer Centre
370 Victoria St
Darlinghurst NSw 2010
Country
Australia
Secondary sponsor category [1] 311984 0
None
Name [1] 311984 0
Address [1] 311984 0
Country [1] 311984 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310332 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 310332 0
St Vincent's Hospital
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [1] 310332 0
Australia
Date submitted for ethics approval [1] 310332 0
06/08/2021
Approval date [1] 310332 0
28/10/2021
Ethics approval number [1] 310332 0
2021/ETH11173

Summary
Brief summary
This study will to investigate whether using Cyclophosphamide/Anti-Thymocyte Globulin (ATG) will be as safe as Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) with ATG. We also want to know if it is as effective in suppressing your MS. This study will also investigate how a new immune system develops (by studying your blood), including the microbiome (by studying stool and saliva samples), after using these different types of chemotherapy.

The AHSCT procedure involves two stages: collecting and then giving back the patients stem cells. In the first stage, the patients blood stem cells are collected by initially giving high dose of intravenous chemotherapy called cyclophosphamide followed by subcutaneous injections of granulocyte stimulating factor to stimulate the stem cells to 'grow in number'. Once the required number of stem cells are detected through blood tests, the patient undergoes undergo daily leukapheresis until minimum number of stem cells are collected. Once this is done, the patient returns after a period of time, the patient is re-hospitalised for the transplantation procedure. Chemotherapy will be given to knock out the current immune system consisting of one of two regimens; Cyclophosphamide/Anti-Thymocyte Globulin (ATG) or Carmustine, Etoposide, Cytarabine and Melphalan with ATG and then reinfusing their own stem cells to ‘grow’ a new immune system. Patients would be enrolled in sequential cohorts to fully assess safety, tolerability and efficacy of both BEAM and cyclophosphamide conditioning with rabbit ATG as outlined below. Patients would be assigned to a cohort (in a block of 15:15 fashion) unless there is a clear medical reason determined by the transplant physician that they should be treated with a particular regimen (eg: history of allergic reaction to one of the drugs).

We hypothesize that HSCT will continue to be safe and beneficial (as measured by resolution of disease characteristics) to patients with severe treatment-resistant neuroinflammatory disease whilst using a variation in conditioning regimen.

There are three groups being enrolled. Patients enrolled to have a AHSCT will be compared to patients having standard MS treatment and those undergoing a AHSCT for a hematological cancer
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117266 0
A/Prof John Moore
Address 117266 0
St Vincent'sHospital,Sydney
Kinghorn Cancer centre
370 Victoria St
DArlinghurst NSW 2010
Country 117266 0
Australia
Phone 117266 0
+61 02 93555656
Fax 117266 0
Email 117266 0
SVHS.Haemresearch@svha.org.au
Contact person for public queries
Name 117267 0
Ms Patricia Plenge
Address 117267 0
St Vincent's Hospital,Sydney
Kinghorn Cancer centre
370 Victoria St
Darlinghurst NSW 2010
Country 117267 0
Australia
Phone 117267 0
+61 02 93555656
Fax 117267 0
Email 117267 0
SVHS.Haemresearch@svha.org.au
Contact person for scientific queries
Name 117268 0
Ms Patricia Plenge
Address 117268 0
St Vincent'sHospital,Sydney
Kinghorn Cancer centre
370 Victoria St
Darlinghurst NSW 2010
Country 117268 0
Australia
Phone 117268 0
+61 02 93555656
Fax 117268 0
Email 117268 0
SVHS.Haemresearch@svha.org.au

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


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.