RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab in MS

Study Overview
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Brief Summary
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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, cladribine or ocrelizumab. 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, cladribine or ocrelizumab.

Detailed Description
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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, cladribine or ocrelizumab) 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 the comparators). 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, cladribine or ocrelizumab have been chosen as the primary comparators, because they are 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, thse medications had 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.

Official Title
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Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for Patients With Relapsing Remitting Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Cyclophosphamide and ATG
* Drug: Alemtuzumab
* Drug: Cladribine Pill
* Drug: Ocrelizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) a. 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 µmol/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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HSCT (Cyclophosphamide and ATG)<br>Day 1: Cyclophosphamide 2.0 g/m2 body surface area Days 5-10: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight/day sc. Day 11 and until apheresis is discontinued: Granulocyte colony stimulating factor (filgrastim) 5 mcg/kg body weight x 2 sc/day. HSCT days -5 to -2: Cyclophosphamide 50 mg/kg/day. HSCT days -5 to -1: Anti-thymocyte globulin (ATG-rabbit, Thymoglobuline®) 0.5 mg/kg body weight iv on day -5, 1.0 mg ATG-rabbit/kg will be given iv on day -4, and 1.5 mg ATG-rabbit /kg will be given iv on days -3,-2 and -1 over 10 hours. HSCT day 0: Reinfusion of a minimum of 3,0 x 106 CD 34+ cells/kg body weight. | Drug: Cyclophosphamide and ATG<br>* Hematopoetic stem cell transplantation<br>* Other names: Sendoxan;|
| Active Comparator: Alemtuzumab, Cladribine or Ocrelizumab<br>Alemtuzumab, Cladribine or Ocrelizumab administered after the label of the study drug. | Drug: Alemtuzumab<br>* Alemtuzumab (Lemtrada)<br>* Other names: Lemtrada;Drug: Cladribine Pill<br>* Cladribine (Mavenclad)<br>* Other names: Mavenclad;Drug: Ocrelizumab<br>* Ocrelizumab (Ocrevus)<br>* Other names: Ocrevus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol). | A protocol-defined disease activity event is the occurrence of at least one of the following: A new T1 Gd-enhanced lesion on MRI of the brain and spinal cord A new T2 hyperintense lesion on MRI of brain and spinal cord A protocol-defined MS relapse (see below) 24 week confirmed disability progression based on increases in Expanded Disability Status Scale (EDSS) | 2 year (96 week) period with a 5 year (240 week) planned extension | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NEDA-4 | Proportion of patients with no evidence of disease activity, including atrophy (NEDA 4), as per protocol defined disease activity events (as defined in section 2.2) plus atrophy (measured yearly atrophy above threshold of 0, 4 %) | 2 year (96 week) period | 
| Pre-planned study extension: | Proportion of patients who have NEDA 4 | 5 year (240 week) period. | 
| Time to first protocol-defined disease activity event | Time to first sign of new disease activity, as measured as new relapses, EDSS-progression, MRI-activity or brain atrophy | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240 | EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points. | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| The proportion of patients who, at Week 96, have protocol-defined Confirmed Disability Improvement (CDI) , confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline | Disability progression, as measured with EDSS. EDSS is an ordinal scale in half-point increments that quantifies disability in participants with MS. It assesses the 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicate worse neurological function. Change was calculated by subtracting retreatment baseline (annual visit prior to the retreatment start date) value from EDSS scores at specified time points. | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Annualized rate of protocol-defined relapses during 96 weeks | ARR | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Time to onset of first protocol-defined relapse | Time to first relapse | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in MRI T2-weighted hyperintense lesion volume from baseline to weeks 96 (and 240) | Change in T2-weighted hyperintense lesion volume | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in MRI T1-weighted hypointense lesion volume from baseline to weeks 96 (and 240) | Change in MRI T1-weighted hypointense lesion volume | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in brain volume from baseline to week 96 (and week 240) | Change in brain volume | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Time to detection of a new MRI T2 lesion | Time to New MRI T2-lesion | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Total number of MRI T1-weighted Gd-enhanced lesions | Number of Gd-lesions | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Proportion of patients free from T1 Gd-enhancing lesions | Proportion of patients free from T1 Gd-enhancing lesions | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in Nine-hole-peg test (9-HPT) score from baseline to week 96 (and 240) | The 9HPT is a brief, standardized, quantitative test of upper extremity function. The participant picks up 9 pegs puts them in a block containing nine empty holes, and, once they are in the holes, removes them again as quickly as possible one at a time. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the non-dominant hand. The two trials for each hand are averaged | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in Timed 25 Foot Walk (T25FW) score from baseline to week 48, 96 (and 240) | The T25FW is a quantitative mobility and leg function performance test based on a timed walk over 25 feet. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. The score for the T25FW is the average of the 2 completed trials. The 95% CI of the percentage is based on normal approximation. | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 
| Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 (and 240) | BICAMS is a composite cognitive assessment tool comprising of the three components : Symbol Digit Modalities Test (SDMT) , California Verbal Learning Test-II (CVLT-II) and Brief visuospatial memory test- Revised (BVMT-R) | 2 year (96 week) period, with planned extension for 5 year (240 week) period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis,, HSCT, alemtuzumab, RCT