| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing remitting multiple sclerosis. |
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| E.1.1.1 | Medical condition in easily understood language |
| Relapsing remitting multiple sclerosis |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of this study is to investigate the efficacy and the safety of HSCT compared to alemtuzumab, cladribine and ocrelizumab in patients with aggressive relapsing remitting multiple sclerosis. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
A wide array of immunological parameters and other biomakers will be investigated on samples from the RRMS study population (ref. section 7.3.3 - 7.3.8 in the protocol). For this purpose cerebrospinal fluid, whole blood, serum, plasma and blood cells samples will be stored in the Biobank Haukeland at Helse Bergen HF, Haukeland University Hospital. Some samples will only be collected from patients in Norway/at Haukeland University hospital (stool, sperm, transvaginal ultrasound, cells from graft samples and cells from apheresis procedure).
Samples from the Biobank Haukeland can also be used for future research in MS if in agreement with the RAMMS Project Group, and any researcher will then have to submit a separate protocol for approval by relevant medicine agencies and ethic committees.
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| E.3 | Principal inclusion criteria |
1. Age between ≥18 to ≤50, both genders
3. Diagnosis of RRMS using revised McDonald criteria of clinically definite MS
4. An EDSS score of 0 to 5.5
5. Significant inflammatory disease activity despite treatment with standard disease modifying therapy for at least 6 months, with one or more of the following medications; interferon beta, glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod, natalizumab
a. Significant inflammatory disease activity is defined as:
i. Having 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) over the last year while being treated with
immunomodulatory treatment by standard national guidelines .
The relapse(s) 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 more.
6. The patient is a RRMS-patient referred from neurological departments in Norway, Denmark, Sweden, the Netherlands to an assigned study site. |
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| E.4 | Principal 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 mitoxantrone, alemtuzumab, cladribin and ocrelizumab, and treatment with rituximab within the last 9 months prior to start of study treatment.
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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this prospective, randomized study is to determine differences between patients in the 2 treatment arms according to the following criteria:
Study Part I:
• Proportion of patients with no evidence of disease activity (NEDA, as defined per protocol) during a 2 year (96 week) period.
Study Part II:
• Proportion of patients with NEDA (as defined per protocol) during a 5 year (240 week) period.
NEDA is the absence of a protocol defined disease activity event.
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) (see below and Appendix C)
MS relapse is defined as an occurrence of new or worsening neurological symptoms attributable to MS, which must persist for greater than (>) 24 hours and should not be attributable to confounding clinical factors (e.g., fever, infection, injury, adverse reactions to medications) and immediately preceded by a stable or improving neurological state for least 30 days.
Disability progression is defined as an increase of one point in the EDSS score (or half a point if the baseline EDSS score was equal to 5.5), confirmed after 24 weeks, with an absence of relapse at the time of assessment. MRI imaging will be performed according to the Revised Consortium of Multiple Sclerosis Centers (CMSC) MRI Protocol and Guidelines.
Disability improvement is defined as a decrease of one point in the EDSS score, confirmed after 24 weeks, with an absence of relapse at the time of assessment. MRI imaging will be performed according to the Revised Consortium of Multiple Sclerosis Centers (CMSC) MRI Protocol and Guidelines
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Study Part I: primary enpoint evaluation after 2 years (week 96).
For Study Part II: primary endpoint evaluation after 5 years (week 240). |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints for this study are to evaluate the efficacy of the study treatments on the basis of the following endpoints:
Study Part I:
• 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 %) during a 2 year (96 week) period4, with re-baseline for brain athrophy at 48 weeks.
• Time to first protocol-defined disease activity event as defined in section 2.2
• Change in EQ-5D-5L from baseline to Week 96
• Change in Fatigue Severity Scale (FSS) from baseline to Week 96
• Change in Multiple Sclerosis Impact Scale (MSIS)-29 from baseline to Week 96
• Change in EDSS from baseline (Visit 4.1) to Week 96
• 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
• Annualized rate of protocol-defined relapses during 96 weeks
• Time to onset of first protocol-defined relapse
• Change in MRI T2-weighted hyperintense lesion volume from baseline to Weeks 48 and 96
• Change in MRI T1-weighted hypointense lesion volume from baseline to Weeks 48 and 96
• Change in brain volume from re-baseline at week 48, to week 96
• Time to detection of a new MRI T2 lesion
• Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96
• Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96
• Change in Nine-hole-peg test (9-HPT) score from baseline to week 48, 96
• Change in Timed 25 foot walk (T25FW) score from baseline to week 48, 96
• Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96
• Overall survival rate at week 96
• Work productivity and activity impairment at week 96
Study Part II:
• 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 %) during a 5 year (240 week) period4, with re-baseline for brain athrophy at 48 weeks.
• Time to first protocol-defined disease activity event as defined in section 2.2
• Change in EQ-5D-5L from baseline to Week 240
• Change in Fatigue Severity Scale (FSS) from baseline to Week 240
• Change in Multiple Sclerosis Impact Scale (MSIS)-29 from baseline to Week 240
• Change in EDSS from baseline (Visit 4.1) to Week 240
• The proportion of patients who, at Week 240, have protocol-defined Confirmed Disability Improvement (CDI), confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline
• Annualized rate of protocol-defined relapses during 240 weeks from start of study treatment
• Time to onset of first protocol-defined relapse from start of study treatment
• Change in MRI T2-weighted hyperintense lesion volume from baseline to Week 144, 192 and 240
• Change in MRI T1-weighted hypointense lesion volume from baseline to Week 144, 192 and 240
• Change in brain volume from re-baseline at week 48, to Week 144, 192 and 2404
• Time to detection of a new MRI T2 lesion
• Total number of MRI T1-weighted Gd-enhanced lesions at Week 240
• Proportion of patients free from T1 Gd-enhancing lesions at Week 240
• Change in Nine-hole-peg test (9-HPT) score from baseline to Week 240
• Change in Timed 25 foot walk (T25FW) score from baseline to Week 240
• Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to Week 240
• Overall survival rate at Week 240
• Work productivity and activity impairment at Week 144, 192 and 240
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For Study Part I seconday endpoints will be evaluated 6 months (week 24), 1 year (week 48) and 2 years (week 96) after start of treatment.
For Study Part II seconday endpoints will be evaluated 3 (week 144), 4 (week 192) and 5 years (week 240) after start of treatment . |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| During the course of the study additional samples of serum, plasma, blood, cerebrospinal fluid, sperm, and stool will be collected and stored in a Biobank for future research. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| alemtuzumab, cladribine and ocrelizumab |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Last visit completed by last patient 2 years after Visit 4.1 (treatment day 0). For the planned study extension this will be 5 years after Visit 4.1 (treatment day 0). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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