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Trial record 4 of 7 for:    alemtuzumab | Interventional Studies | multiple sclerosis | Phase 3

RCT Comparing Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab in MS (RAM-MS)

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ClinicalTrials.gov Identifier: NCT03477500
Recruitment Status : Recruiting
First Posted : March 26, 2018
Last Update Posted : April 3, 2018
Sponsor:
Information provided by (Responsible Party):
Haukeland University Hospital

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, 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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Cyclophosphamide and ATG Drug: Alemtuzumab Phase 3

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) 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.


Study Type : Interventional
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Autologous Hematopoietic Stem Cell Transplantation Versus Alemtuzumab for Patients With Relapsing Remitting Multiple Sclerosis
Actual Study Start Date : March 21, 2018
Estimated Primary Completion Date : March 21, 2022
Estimated Study Completion Date : March 21, 2024

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: HSCT (Cyclophosphamide and ATG)

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
Hematopoetic stem cell transplantation
Other Name: Sendoxan
Active Comparator: Alemtuzumab
Alemtuzumab 12 mg iv daily on 5 consecutive days at first alemtuzumab treatment cycle, followed by 3 consecutive days at the second alemtuzumab treatment cycle 12 months later.
Drug: Alemtuzumab
Alemtuzumab (Lemtrada)
Other Name: Lemtrada



Primary Outcome Measures :
  1. Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol). [ Time Frame: 2 year (96 week) period with a 5 year (240 week) planned extension ]

    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)


Secondary Outcome Measures :
  1. NEDA-4 [ Time Frame: 2 year (96 week) period ]
    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. Pre-planned study extension: [ Time Frame: 5 year (240 week) period. ]
    Proportion of patients who have NEDA 4

  3. Time to first protocol-defined disease activity event [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Time to first sign of new disease activity, as measured as new relapses, EDSS-progression, MRI-activity or brain atrophy

  4. Change in Expanded Disability Status scale (EDSS) from baseline (Visit 4.1) to Weeks 96 and 240 [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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.

  5. 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 [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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.

  6. Annualized rate of protocol-defined relapses during 96 weeks [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    ARR

  7. Time to onset of first protocol-defined relapse [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Time to first relapse

  8. Change in MRI T2-weighted hyperintense lesion volume from baseline to weeks 96 (and 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Change in T2-weighted hyperintense lesion volume

  9. Change in MRI T1-weighted hypointense lesion volume from baseline to weeks 96 (and 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Change in MRI T1-weighted hypointense lesion volume

  10. Change in brain volume from baseline to week 96 (and week 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Change in brain volume

  11. Time to detection of a new MRI T2 lesion [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Time to New MRI T2-lesion

  12. Total number of MRI T1-weighted Gd-enhanced lesions [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Number of Gd-lesions

  13. Proportion of patients free from T1 Gd-enhancing lesions [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Proportion of patients free from T1 Gd-enhancing lesions

  14. Change in Nine-hole-peg test (9-HPT) score from baseline to week 96 (and 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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

  15. Change in Timed 25 Foot Walk (T25FW) score from baseline to week 48, 96 (and 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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.

  16. Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 (and 240) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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)


Other Outcome Measures:
  1. Difference in patient reported quality of life based on the EuroQoL Health Related Quality of Life - 5 Dimensions - 5 Levels (EQ-5D 5L) scores [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    EQ-5D 5L is a 5 item questionnaire (assessing - mobility, self-care, usual activities, pain/discomfort, anxiety/depression) and visual analogue scale (VAS) enables calculation of quality adjusted life years (QALY) to enable health economic analyses to be performed. Each dimension assessed has 5 response scales to select from: no problems, slight problems, moderate problems, severe problems, and extreme problems

  2. Overall survival rate [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Survival

  3. Rate and nature of adverse events [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Rate and nature of adverse events

  4. Fatigue Severity Scale (FSS) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    The FSS questionnaire contains nine statements that rate the severity of fatigue symptoms. A low value (e.g., 1); indicates strong disagreement with the statement, whereas a high value (e.g., 7); indicates strong agreement. A total score of 36 or more suggests presence of fatigue.

  5. Change in Multiple Sclerosis Impact Scale (MSIS) - 29 [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Multiple Sclerosis Impact Scale-29 (MSIS-29) is a validated MS specific questionnaire consisting of 29 questions of which 20 addressed the physical impact component and 9 assessed the psychological impact. A combined score can be generated, or both components can be reported separately. The psychological wellbeing assessment portion of the MSIS-29 was comprised of 9 questions in which subjects rate the impact of MS on their day-to-day life from 1=no impact to 5=extreme impact. The total Psychological Score was calculated using following formula: sum of score for 9 questions - 9/0.36. The total score range ranges from 0-100 where, lower total score indicates less psychologically-related impact while a higher total score indicates greater psychologically-related impact on a subject's functioning.

  6. Severity of relapses (residual disability (EDSS) after relapses) [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    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.

  7. Frequency of serious adverse events [ Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period ]
    Frequency of serious adverse events



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 CMV, EBV, HSV, VZV, hepatitis virus, toxoplasmosis, HTV, HIV or syphilis infections, as well as hepatitis 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, cladribine and alemtuzumab
  6. Treatment with glucocorticoids or ACTH within one month prior to study inclusion
  7. Having experienced an MS relapse within one month prior to study inclusion
  8. Prior or current major depression
  9. 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- follow-upup phases of this protocol.
  10. Prior or current alcohol or drug dependencies
  11. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmia, unstable or advanced ischemic heart disease (NYHA III or IV)
  12. Significant hypertension: BP > 180/110
  13. Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
  14. Known thyroid disease, and/or abnormal serum thyroid hormone status
  15. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
  16. WBC < 1,5 x 109/L
  17. Platelet (thrombocyte) count < 100 x 109/L
  18. ALAT and/or ASAT more than 2 times the upper normal reference limit (UNL)
  19. Serum creatinine > 200 µmol/L
  20. Serum bilirubin > 20 µmol/L
  21. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
  22. Diagnosis of primary progressive MS
  23. Diagnosis of secondary progressive MS
  24. Treatment with natalizumab, fingolimod and dimethylfumarate within the last 2 months (washout must be performed as specified in section 5.1 prior to inclusion in the study)
  25. Use of teriflunomide (Aubagio®) within the previous 2 years unless cleared from the body (plasma concentration < 0.02mcg/ml following elimination from the body with cholestyramine or activated powdered charcoal) as specified in section 5.1
  26. Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia
  27. Any disease that can influence the patient safety and compliance, or the evaluation of disability
  28. History of hypersensitivity reaction to rabbit
  29. Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study
  30. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03477500


Contacts
Contact: Øivind Torkildsen, MD, PhD +4755976032 ofto@helse-bergen.no
Contact: Lars Bø, MD, Phd 55977039 labo@helse-bergen.no

Locations
Denmark
Rigshospitalet Not yet recruiting
Copenhagen, Denmark
Contact: Morten Blinkenberg, MD, PhD       Morten.Blinkenberg@regionh.dk   
Contact: Finn T Sellebjerg, MD, PhD       finn.thorup.sellebjerg@regionh.dk   
Netherlands
VUmc Not yet recruiting
Amsterdam, Netherlands
Contact: Hugo Vrenken, PhD       H.Vrenken@vumc.nl   
Norway
Haukeland University Hospital Recruiting
Bergen, Norway
Contact: Øivind Torkildsen, MD, PhD    4755976032    ofto@helse-bergen.no   
Contact: Lars Bø, MD, PhD    55977039    labo@helse-bergen.no   
Akershus University Hospital Not yet recruiting
Oslo, Norway
Contact: Trygve Holmøy, MD, PhD       trygve.holmoy@medisin.uio.no   
University Hospital of North Norway Not yet recruiting
Tromsø, Norway
Contact: Margitta Kampman, MD, PhD       Margitta.T.Kampman@unn.no   
St. Olav's University Hospital Not yet recruiting
Trondheim, Norway
Contact: Kathrine Lian, MD       Kathrine.Krokenes.Lian@stolav.no   
Sweden
Sahlgrenska University Hospital Not yet recruiting
Gothenburg, Sweden
Contact: Jan Lycke, MD, PhD       jan.lycke@gu.se   
Akademiska sjukhuset Not yet recruiting
Uppsala, Sweden
Contact: Joachim Burman, MD, PhD       joachim.burman@neuro.uu.se   
Sponsors and Collaborators
Haukeland University Hospital
Investigators
Study Director: Lars Bø, MD, Phd Haukeland University Hospital
Study Chair: Anne Kristine Lehmann, MD, PhD Haukeland University Hospital
Study Chair: Aymen B Ahmed, MD, PhD Haukeland University Hospital
Study Chair: Einar Kristoffersen, MD, PhD Haukeland University Hospital
Study Chair: Øivind Torkildsen, MD, PhD Haukeland University Hospital
Principal Investigator: Trygve Holmøy, MD, PhD University Hospital, Akershus
Principal Investigator: Margitta Kampman, MD, PhD Tromsø University Hospital
Principal Investigator: Kathrine K Liane, MD St. Olavs Hospital
Principal Investigator: Joachim Burman, MD, PhD Akademiska sjukhuset, Uppsala
Principal Investigator: Morten Blinkenberg, MD, PhD Rigshospitalet, Denmark
Principal Investigator: Jan Lycke, MD, PhD Sahlgrenska University Hospital, Sweden
  Study Documents (Full-Text)

Documents provided by Haukeland University Hospital:

Additional Information:
Responsible Party: Haukeland University Hospital
ClinicalTrials.gov Identifier: NCT03477500     History of Changes
Other Study ID Numbers: 2017-001362-25
First Posted: March 26, 2018    Key Record Dates
Last Update Posted: April 3, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: Data will be available within publication of the results.
Access Criteria: Data access requests will be reviewed by the RAM-MS steering committee. Requestors will be required to sign a data access agreement.
URL: http://

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Haukeland University Hospital:
multiple sclerosis,
HSCT
alemtuzumab
RCT

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Alemtuzumab
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Adjuvants, Immunologic