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Trial registered on ANZCTR


Registration number
ACTRN12622001186741p
Ethics application status
Submitted, not yet approved
Date submitted
18/08/2022
Date registered
5/09/2022
Date last updated
5/09/2022
Date data sharing statement initially provided
5/09/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Autologous Stem Cell Transplant in Neuro-Inflammatory diseases other than multiple sclerosis
Scientific title
A phase II interventional study: Safety and tolerability of Haematopoietic Stem Cell Transplantation for neuro-inflammatory disease
Secondary ID [1] 307813 0
Nil
Universal Trial Number (UTN)
Trial acronym
AiNI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuro-Inflammatory disease 327398 0
Condition category
Condition code
Neurological 324525 324525 0 0
Other neurological disorders

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 via subcutaneous injection. 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] 324280 0
Treatment: Other
Comparator / control treatment
No control- open label AHSCT
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332355 0
The primary objective of this submission is to assess safety and tolerability of HSCT in NID. This will be determined by length of stay in hospital from day 0 until discharge as well as time to engraftment (number of days from stem cell infusion until neutrophil engraftment). This will be assessed by inpatient medical records at the Alfred Hospital. The Investigators will be involved with patient discharge. Engraftment will be assessed by blood tests and physical exam during hospital admission by investigators.

This is a composite primary objective.
Timepoint [1] 332355 0
One-off intervention with post discharge follow ups for 10 years. Assessed at time of discharge, then at follow up visits will be performed 3 months, 6 months, and 12 months post transplant then yearly until 10 years post transplant.
Secondary outcome [1] 413160 0
A secondary objective of this study is to assess for specific transplant associated complications (first 100 days post-transplant). This includes bacteremia, febrile neutropenia mucositis requiring patient controlled analgesia (PCA) and/or total parenteral nutrition (TPN), serum sickness requiring treatment with steroids, admission to the Intensive Care Unit, or requirement for inpatient rehabilitation, This will be assessed by investigators and nursing staff by blood exams, physical exams, and doctor reviews during the patients stay in hospital post transplant,
Timepoint [1] 413160 0
These will be indicated during initial hospital stay and whether or not the patient requires re-admission to hospital or further treatment as a result of transplant associated complications for the first 100 days post transplant.
Secondary outcome [2] 413334 0
Measuring safety and tolerability of AHSCT by assessing death and morbidity 100 days post transplant (defined as death in the first 100 days not due to NID) by face to face nurse/doctor review. This will also be documented on patient's medical record.
Timepoint [2] 413334 0
Assessed at time of hospital stay, discharge, and Day 100 post transplant
Secondary outcome [3] 413335 0
Assessing efficacy of AHSCT in NID as determined by the proportion of patients who remain free from disease activity, as determined by clinical relapses based on the confirmed diagnosis of a relapse by their referring/treating neurologist and the transplant neurologist.
Timepoint [3] 413335 0
Assessed in follow up visits 3 months, 6 month, 12 months post transplant as well as during any standard of care neurologist visits.
Secondary outcome [4] 413336 0
Assessing incidence of pregnancy by face to face nurse/doctor review. This will also be documented on patient's medical record.
Timepoint [4] 413336 0
Assessed during 10 year follow up period
Secondary outcome [5] 413337 0
To assess the proportion of NID patients who commence a new disease modifying therapy (DMT) following AHSCT. Future therapies which may offer neuroprotection or remyelination will not be considered as DMTs for the purpose of this analysis
Timepoint [5] 413337 0
This will be assessed during the 10 year follow up period consisting of visits 3 moths, 6 months, 12 months post transplantation, then annually for 10 years, and during any standard of care neurology appointments.
Secondary outcome [6] 413424 0
To assess the proportion of NID patients who stabilise and/or improve in the following clinical outcome measures. These include: FIM (functional Independence Measure), mobility assessments (timed up and go, 10m walk test), upper limb functional assessments (9 hole peg test and grip strength), mood, cognition and fatigue (DASS-21(depression anxiety and stress scale), mFIS, SF-36)
Timepoint [6] 413424 0
These objectives will be assessed 3 months, 6 months, 12 months post transplant, then yearly post transplant for ten years.

Eligibility
Key inclusion criteria
• Age 18-65
o Age 65-70 (may be considered only if HCT-CI (Haemopoietic cell transplantation – comorbidity index) <3 and deemed fit both physically and cognitively by at least two investigators)
• Adequate organ function as measured by:
o Cardiac Left Ventricle Ejection Fraction greater than 45%
o Total Lung Capacity of at least 60%
o DLCO/VA (Diffusing Capacity Of The Lungs For Carbon Monoxide) of at least 50%.
o Negative serology for active Hepatitis B, active Hepatitis C and Human Immunodeficiency Virus.
o Negative CT skeletal survey in patients with Chronic inflammatory demyelinating polyradiculoneuropathy (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.
• Published data to support the role of AHSCT for the disease.
• Suitability for AHSCT will be determined by a multidisciplinary HSCT panel including a neurologist and haematologists/transplant physicians.
• If suitability is contended an expert opinion from and alternate national or international centre involved in AHSCT for AID may be sought.
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 disease.
• Patients where mimics have not been adequately excluded.
• Patients unable to undergo MRI scans.
• Patients with advanced NID 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
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/10/2022
Actual
Date of last participant enrolment
Anticipated
1/09/2026
Actual
Date of last data collection
Anticipated
1/09/2036
Actual
Sample size
Target
5
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23009 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 38324 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 312081 0
Hospital
Name [1] 312081 0
The Alfred-Melbourne
Country [1] 312081 0
Australia
Primary sponsor type
Hospital
Name
The Alfred- Melbourne
Address
99 Commercial Rd,
Melbourne 3004
VIC
Country
Australia
Secondary sponsor category [1] 313596 0
None
Name [1] 313596 0
Address [1] 313596 0
Country [1] 313596 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 311489 0
Alfred Hospital Ethics Committee and Governance Office
Ethics committee address [1] 311489 0
99 Commercial Rd
Melbourne 3004
VIC
Ethics committee country [1] 311489 0
Australia
Date submitted for ethics approval [1] 311489 0
03/08/2022
Approval date [1] 311489 0
Ethics approval number [1] 311489 0

Summary
Brief summary
Autologous haematopoietic stem cell transplantation (AHSCT) is a procedure that is typically 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. Stem cells are collected from the blood following stimulation with intravenous cyclophosphamide chemotherapy and granulocyte colony stimulating factor (GCSF) injections. Patients are then admitted into hospital to receive high doses of chemotherapy that intensely suppresses their immune system. Subsequently they have their stem cells transfused to re-grow a new immune system and provide protection from the toxic effects of the chemotherapy. It takes about 14 days for the new stem cells to grow and all patients are monitored carefully over the subsequent months and years to see if the immunosuppression controls their auto-immune disease.

Over the last 15 years AHSCT become much safer, and evidence has accumulated suggesting a proportion of patients with severe autoimmune conditions will respond to AHSCT. Often these patients had prolonged remissions of their AID. In well selected patients there is a possibility to establish a prolonged period of disease remission.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121282 0
A/Prof Anneke van der Walt
Address 121282 0
Lv 6, The Alfred Center (Clinical Neurosciences)
99 Commercial Rd
Melbourne 3004
VIC
Country 121282 0
Australia
Phone 121282 0
+61 3 9903 8662
Fax 121282 0
Email 121282 0
anneke.vanderwalt@monash.edu
Contact person for public queries
Name 121283 0
Ms Melinda Moss
Address 121283 0
Lv 6, The Alfred Center (Clinical Neurosciences)
99 Commercial Rd
Melbourne 3004
VIC
Country 121283 0
Australia
Phone 121283 0
+61 411 432 288
Fax 121283 0
Email 121283 0
msniresearch@alfred.org.au
Contact person for scientific queries
Name 121284 0
A/Prof Anneke van der Walt
Address 121284 0
Lv 6, The Alfred Center (Clinical Neurosciences)
99 Commercial Rd
Melbourne 3004
VIC

+61 3 9903 8662
Country 121284 0
Australia
Phone 121284 0
+61 3 9903 8662
Fax 121284 0
Email 121284 0
msniresearch@alfred.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


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.