RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS

  • STATUS
    Recruiting
  • End date
    Mar 21, 2024
  • participants needed
    100
  • sponsor
    Haukeland University Hospital
Updated on 19 February 2021
corticosteroids
cyclophosphamide
interferon
natalizumab
MRI
alemtuzumab
fingolimod
disease or disorder
glatiramer acetate
dimethyl fumarate
teriflunomide

Summary

This study is a randomized multicentre, multinational, treatment interventional study of RRMS patients with breakthrough inflammatory disease activity in spite of ongoing standard immunomodulatory medication. The study has two treatment arms; arm A: HSCT (hematopoietic stem cell transplantation) and arm B: alemtuzumab, a registered immunomodulatory treatment of RRMS. A pre-planned 3-year follow-up extension period will be performed depending on future funding.

The aim of the study is to assess the effectiveness and side effects of a new treatment intervention in RRMS; HSCT, and, thereby, the value of HSCT in clinical practice. Data from recently published patient series indicate that HSCT may have a significantly higher treatment effect than currently registered RRMS immunomodulatory treatments. This study will determine the relative role of HSCT versus alemtuzumab.

Description

This is a randomized study of autologous HSCT using a low intensity, non-ablative conditioning regimen with cyclophosphamide and ATG versus treatment with the currently presumed best available immunomodulatory medication (alemtuzumab) in RRMS patients with significant inflammatory disease activity in spite of ongoing immunomodulatory MS treatment.

Significant disease activity is defined as having one or more clinically reported multiple sclerosis (MS) relapse(s), AND 1 or more T1 Gd-enhanced lesion(s), OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) over the last year while being treated on immunomodulatory medication by standard national guidelines. The relapse(s) must have occurred 3 or more months after the onset of an immunomodulatory treatment, as immunomodulatory treatment in MS may reach full effect after 3 months or more.

Both the knowledge of the treatment effect of registered immunomodulatory therapies for RRMS, and the number of treatments approved for RRMS by the European Medicines Agency (EMA) are rapidly increasing. During the study period, there may thus appear new supplementing information on other MS immunomodulatory treatments that favour the use of a new comparator (replacing or supplementing alemtuzumab as a comparator). This will be evaluated by the PMC if applicable during the study period and the planned extension period.

If the treatment efficacy obtained by HSCT is better than the currently most efficacious standard, immunomodulatory treatment in randomized treatment trials, HSCT will likely be approved as a part of the standard treatment recommendations for a significant proportion of RRMS patients. A randomized study regarding with statistical power to evaluate the clinical outcome of autologous HSCT compared to a standard immunomodulatory treatment in MS has not yet been published. Except for Sweden, HSCT is currently not registered as a part of standard MS treatment in the public health services of Europe. The HSCT regimen for the study will be identical to the regimen used in similar patient populations in Sweden, Norway and Denmark.

Alemtuzumab has been chosen as the primary comparator, because it is the immunomodulatory medication currently authorised by the EMA for treatment of RRMS with the most favourable therapeutic effects. In a meta-analysis of immunomodulatory treatment effects in RRMS, alemtuzumab was the immunomodulatory drug with the most eminent reduction of annualized relapse rate and 3 month confirmed disability progression.

In this study, a health economic evaluation will be included. Accordingly, the proposed study should provide a robust basis for future official decisions regarding the role of HSCT in RRMS treatment.

Details
Condition Multiple Sclerosis, Radiologically Isolated Syndrome, Dermatite Atopique modérée ou grave, multiple sclerosis (ms)
Treatment alemtuzumab, Cyclophosphamide and ATG
Clinical Study IdentifierNCT03477500
SponsorHaukeland University Hospital
Last Modified on19 February 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 50 yrs?
Gender: Male or Female
Do you have Multiple Sclerosis?
Do you have any of these conditions: Multiple Sclerosis or multiple sclerosis (ms) or Dermatite Atopique modérée ou grave or Radiologically Isolated Syndrome?
Do you have any of these conditions: Radiologically Isolated Syndrome or multiple sclerosis (ms) or Dermatite Atopique modérée ou grave or Multiple Sclerosis?
Do you have any of these conditions: Radiologically Isolated Syndrome or multiple sclerosis (ms) or Multiple Sclerosis or Dermatite Atopique modérée ou grave?
Age between 18 to 50, both genders
Women of childbearing potential (WOCBP) and men in a sexual relation with WOCBP must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly
Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1
An EDSS score of 0 to 5.5
Significant inflammatory disease activity in the last year despite treatment with standard disease modifying therapy (interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, natalizumab)
Significant inflammatory disease activity is defined by: i. One or more clinically reported multiple sclerosis (MS) relapse(s), ii. AND 1 or more T1 Gd-enhanced lesion(s), iii. OR three or more new or enlarging T2 lesions on magnetic resonance imaging (MRI) The relapse(s) must have been treated with iv or oral high dose corticosteroids prescribed by a neurologist, and must have occurred 3 or more months after the onset of an immunomodulatory treatment, as MS immunomodulatory treatment may reach full effect after 3 months or more2
The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden or possibly other European countries to an assigned study site
Signed informed consent and expected patient cooperation regarding the treatment schemes and procedures planned in the treatment and follow-up periods must be obtained and documented according to ICH GCP and national/local regulations

Exclusion Criteria

Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids
Any illness or prior treatment that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy or high-dose glucocorticosteroids
Any ongoing infection, including Tbc, CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HIV or syphilis infections, as well as heaptitis B surface antigen positivity and/or hepatitis C PCR positivity verified at Visit 1
Patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV), unless tested for antibodies to VZV. VZV negative patients can only be included if they receive vaccination against VZV at least 6 weeks prior to inclusion
Current or previous treatments with long-term effects that may influence the treatment effects or potential toxicities/side effects of the treatment arms. This includes, but is not restricted to previous treatment with rituximab, mitoxantrone, alemtuzumab, cladribin and ocrelizumab
Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
Having experienced an MS relapse within one month prior to study inclusion
Prior or current major depression
Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol
Prior or current alcohol or drug dependencies
Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
Significant hypertension: BP > 180/110
Active malignancy, or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix
Known untreated or unregulated thyroid disease
Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
WBC < 1,5 x 109/L if not caused by a reversible effect of documented ongoing medication. If WBC < 1,5 x 109/L is caused by a reversible effect of documented ongoing medication the WBC count must be > 1,5 x 109/L before start of study treatment
Platelet (thrombocyte) count < 100 x 109/L
ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL)
Serum creatinine > 200 mol/L
Serum bilirubin > ULN
Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)
Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
Diagnosis of primary progressive MS
Diagnosis of secondary progressive MS
Treatment with natalizumab and fingolimod within the last 2 months, and treatment with dimetylfumurat within the last month (washout must be performed as specified in section 5.1) prior to start of study medication
Use of teriflunomide (Aubagio) within the previous 2 years unless cleared from the body (plasma concentration < 0.02 mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal) as specified in section 5.1 prior to start of study medication
Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia
Any disease that can influence the patient safety and compliance, or the evaluation of disability
History of hypersensitivity reaction to rabbit
Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study
Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded
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