Clinical trial NCT03477500: Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for RRMS (RAM-MS)
Official title: Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for Patients With Relapsing Remitting Multiple Sclerosis (RAM-MS)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: multiple sclerosis,
HSCT
alemtuzumab
RCT
Lead sponsor: Haukeland University Hospital
Sponsor class: OTHER
First posted: 2018-03-26
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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, 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Age between ≥18 to ≤50, both genders
2. 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.
3. Diagnosis of RRMS using revised McDonald criteria of clinically definite MS1
4. An EDSS score of 0 to 5.5
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.
6. The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden or possibly other European countries to an assigned study site.
7. 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:

1. Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids
2. 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
3. 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
4. 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.
5. 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
6. Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
7. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
8. Having experienced an MS relapse within one month prior to study inclusion
9. Prior or current major depression
10. 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.
11. Prior or current alcohol or drug dependencies
12. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
13. Significant hypertension: BP \> 180/110
14. Active malignancy, or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
15. Known untreated or unregulated thyroid disease
16. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
17. 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.
18. Platelet (thrombocyte) count \< 100 x 109/L
19. ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL)
20. Serum creatinine \> 200 µmol/L
21. Serum bilirubin \> ULN
22. Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)
23. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
24. Diagnosis of primary progressive MS
25. Diagnosis of secondary progressive MS
26. 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.
27. 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.
28. Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia
29. Any disease that can influence the patient safety and compliance, or the evaluation of disability
30. History of hypersensitivity reaction to rabbit
31. Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study
32. 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.

Primary outcomes:
measure: Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol).
timeFrame: 2 year (96 week) period with a 5 year (240 week) planned extension
Secondary outcomes:
measure: NEDA-4
timeFrame: 2 year (96 week) period
measure: Pre-planned study extension:
timeFrame: 5 year (240 week) period.
measure: Time to first protocol-defined disease activity event
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: 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
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Annualized rate of protocol-defined relapses during 96 weeks
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Time to onset of first protocol-defined relapse
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in MRI T2-weighted hyperintense lesion volume from baseline to weeks 96 (and 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in MRI T1-weighted hypointense lesion volume from baseline to weeks 96 (and 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in brain volume from baseline to week 96 (and week 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Time to detection of a new MRI T2 lesion
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Total number of MRI T1-weighted Gd-enhanced lesions
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Proportion of patients free from T1 Gd-enhancing lesions
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in Nine-hole-peg test (9-HPT) score from baseline to week 96 (and 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in Timed 25 Foot Walk (T25FW) score from baseline to week 48, 96 (and 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 (and 240)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Other outcomes:
measure: Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Overall survival rate
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Rate and nature of adverse events
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Fatigue Severity Scale (FSS)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Change in Multiple Sclerosis Impact Scale (MSIS) - 29
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Severity of relapses (residual disability (EDSS) after relapses)
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
measure: Frequency of serious adverse events
timeFrame: 2 year (96 week) period, with planned extension for 5 year (240 week) period
Locations:
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Amsterdam
country: Netherlands
facility: VUmc
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Oslo
country: Norway
facility: Akershus University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St. Olav's University Hospital
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Uppsala
country: Sweden
facility: Akademiska sjukhuset
Study officials:
affiliation: Haukeland University Hospital
name: Lars Bø, MD, Phd
role: STUDY_DIRECTOR
affiliation: Haukeland University Hospital
name: Anne Kristine Lehmann, MD, PhD
role: STUDY_CHAIR
affiliation: Haukeland University Hospital
name: Astrid Kittang, MD, PhD
role: STUDY_CHAIR
affiliation: Haukeland University Hospital
name: Einar Kristoffersen, MD, PhD
role: STUDY_CHAIR
affiliation: Haukeland University Hospital
name: Øivind Torkildsen, MD, PhD
role: STUDY_CHAIR
affiliation: University Hospital, Akershus
name: Trygve Holmøy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Tromsø University Hospital
name: Margitta Kampman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Olavs Hospital
name: Kathrine K Liane, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Akademiska sjukhuset, Uppsala
name: Joachim Burman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rigshospitalet, Denmark
name: Morten Blinkenberg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sahlgrenska University Hospital
name: Jan Lycke, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: