Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000530729
Ethics application status
Approved
Date submitted
21/02/2022
Date registered
4/04/2022
Date last updated
4/04/2022
Date data sharing statement initially provided
4/04/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Autologous Stem Cell Transplant in other Neuro-Inflammatory diseases
Scientific title
Autologous Stem Cell Transplant in other Neuro-Inflammatory diseases
Secondary ID [1] 306611 0
NONE
Universal Trial Number (UTN)
Trial acronym
AiNI
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neuromyelitis Optica 325234 0
Stiff Person Syndrome 325235 0
Myasthenia Gravis 325236 0
Central Nervous System Vasculitis 325237 0
Condition category
Condition code
Inflammatory and Immune System 322633 322633 0 0
Other inflammatory or immune system disorders
Inflammatory and Immune System 322900 322900 0 0
Autoimmune diseases
Neurological 322901 322901 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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 patients 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 Cyclophosphamide, Anti-Thymocyte Globulin (ATG) and Rituximab 1 week before their stem cells will be re-infused (Day 0). Rituximab 500 mg will be given intravenously first 6 days prior (known as day -6) and again the day after (day +1) the stem cells infusion. Prior to each dose of Rituximab, patients will receive premedication of hydrocortisone 100mg intravenous as pre –medication. In addition, patients will also receive the following conditioning drugs: a daily dose of Cyclophosphamide 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] 322846 0
Treatment: Other
Intervention code [2] 322847 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 330448 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] 330448 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] 330692 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] 330692 0
assessed weekly until neutrophil engraftment has been confirmed
Primary outcome [3] 330693 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 of 4 weeks)
Timepoint [3] 330693 0
Assessed by daily physical assessment (daily for maximum of 4 weeks)
Secondary outcome [1] 406241 0
Efficacy of AHSCT will be assessed by the proportion of patients who remain free from disease activity, as determined by data-linkage to medical records documenting clinical relapses
Timepoint [1] 406241 0
Assessed every 3 months up to 12 months and yearly up to 5 years post-enrolment,

Eligibility
Key inclusion criteria
HSCT patients with NID
- 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.
- 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 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
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/04/2022
Actual
Date of last participant enrolment
Anticipated
22/02/2025
Actual
Date of last data collection
Anticipated
22/02/2035
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21708 0
St Vincent's Private Hospital (Darlinghurst) - Darlinghurst
Recruitment postcode(s) [1] 36759 0
2010 - Darlinghurst

Funding & Sponsors
Funding source category [1] 310755 0
Hospital
Name [1] 310755 0
St Vincent's Hospital,Sydney
Country [1] 310755 0
Australia
Primary sponsor type
Hospital
Name
St Vincent's Hospital, Sydney
Address
390 Victoria St
Darlinghurst NSW 2010
Country
Australia
Secondary sponsor category [1] 311999 0
None
Name [1] 311999 0
Address [1] 311999 0
Country [1] 311999 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310333 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 310333 0
390 Victoria St
Darlinghurst NSW 2010
Ethics committee country [1] 310333 0
Australia
Date submitted for ethics approval [1] 310333 0
06/08/2021
Approval date [1] 310333 0
28/10/2021
Ethics approval number [1] 310333 0
2021/ETH11174

Summary
Brief summary
The purpose of this study is to investigate whether treating a neurological immunological disorder with an Autologous Haematopoietic Stem Cell Transplant (AHSCT) will suppress or stop their immune system attacking their nervous system. This procedure could enable their body to develop a new immune system by treating their disease.

All patients referred for AHSCT by their treating neurologist will be assessed by a transplant neurologist and haematologist prior to having their cases discussed at a meeting involving all centres in Australia running a clinical trial of AHSCT for neurological diseases (all patient data will be de-identified). The meeting will be comprised of MS-specialised neurologists with a special interest in AHSCT for NID and transplant haematologists again with expertise in AID.

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 dected through blood tests, the patient undergoes undergo daily leukapheresis until minimium number of stem cells are collected. Once this is done, the patient returns after a period of time, the patient is hospitalised for the transplantation procedure. Chemotherapy is given to knock out the current immune system using Cyclophosphamide, Rituximab and Anti-Thymocyte Globulin (ATG) and then reinfusing their own stem cells to ‘grow’ a new immune system.

Patients are chosen to participate in this study because they have an aggressive neuroimmunological condition which is not responding to routine therapy. The study will investigate whether their disease can be controlled by AHSCT. This study will also investigate how their body develops a new immune system after using these different types of chemotherapy.

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
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117270 0
A/Prof John Moore
Address 117270 0
St Vincent's Hospital,Sydney
Kinghorn Cancer Centre
370 Victoria St
Darlinghurst NSW 2010
Country 117270 0
Australia
Phone 117270 0
+61 02 93555656
Fax 117270 0
Email 117270 0
SVHS.Haemresearch@svha.org.au
Contact person for public queries
Name 117271 0
Ms Patricia Plenge
Address 117271 0
St Vincent's Hospital,Sydney
Kinghorn Cancer Centre
370 Victoria St
Darlinghurst NSW 2010
Country 117271 0
Australia
Phone 117271 0
+61 02 93555656
Fax 117271 0
Email 117271 0
SVHS.Haemresearch@svha.org.au
Contact person for scientific queries
Name 117272 0
Ms Patricia Plenge
Address 117272 0
St Vincent's Hospital,Sydney
Kinghorn Cancer Centre
370 Victoria St
Darlinghurst NSW 2010
Country 117272 0
Australia
Phone 117272 0
+61 02 93555656
Fax 117272 0
Email 117272 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.