RecruitingPhase 2ACTRN12619000348156

Autologous Haematopoietic Stem Cell Transplantation for highly active treatment resistant multiple sclerosis.

A study to evaluate the safety of Autologous Haematopoietic Stem Cell Transplantation in patients with highly active treatment resistant multiple sclerosis.

Sponsor

Alfred Health

Enrollment

50 participants

Start Date

May 6, 2019

Study Type

Interventional

Conditions

Relapsing Remitting Multiple Sclerosis

Summary

We propose to study the benefits and risks of Autologous Haematopoetic Stem Cell Transplant (AHSCT) in people who have an aggressive form of MS not controlled by conventional treatment. Participants will have AHSCT at The Alfred hospital, and they will be closely monitored for 5 years post the transplant to ensure their safety, and also level of Multiple Sclerosis disease activity.

Eligibility

Sex: Both males and femalesMin Age: 18 YearssMax Age: 60 Yearss

Inclusion Criteria20

Male and female participants aged 18-60 with MS (2017 revised McDonald criteria)
Expanded Disability Status Scale (EDSS) score between 0 and 6
Highly active RRMS despite continuing to use conventional treatment for RRMS within the past 2 years.
Definition of ‘highly active’ RRMS
i.
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
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
Accumulation of any new T2 lesions on follow up MRI scans
ii.
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
evidence of new MRI activity either T1 or T2 performed on follow up MRI scans
Neurologically stable participants with no evidence of relapse for at least 30 days prior to study entry into the treatment period.
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.
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.

Exclusion Criteria44

Participants with a non-relapsing form of MS (primary or secondary progressive MS)
Participants with any medically unstable condition, as assessed by the primary treating physician.
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
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.
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
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
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.
Participants unable to undergo MRI scans, including history of severe hypersensitivity
to gadolinium
Participation in any clinical research study evaluating another investigational drug or
therapy within 6 months prior to baseline.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and
Participants unwilling to use effective contraception

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Interventions

Autologous Haematopoietic Stem Cell Transplantation Participants are assessed using inclusion and exclusion criteria specific for highly active, treatment resistant multiple sclerosis in order to det

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.