Ram-Ms

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Bergen HF

Participant type

Patients

Age range

18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20], Diseases [C] - Nervous System Diseases [C10]

Trial duration

12 Feb 2018 → ongoing

Decision date (initial)

2024-06-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

KlinBeForsk · Helse Vest

External identifiers

EU CT number

2024-510630-40-00

EudraCT number

2017-001362-25

ClinicalTrials.gov

NCT03477500

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The objective of this prospective, randomized study is to investigate the efficacy and safety of HSCT compared to the comparator group (alemtuzumab, cladribine or ocrelizumab) in patients with aggressive relapsing remitting MS.

Secondary objectives 1

1. In Norway, the clinical study is supplemented with a health economic evaluation.

Conditions and MedDRA coding

Multiple sclerosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

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 for the duration of the study OR until 4, 6 and 12 months after last dose administered for alemtuzumab, cladribine or ocrelizumab respectively (the longest alternative applies). If treated with cladribine, women must use double barrier method during each treatment course and until 4 weeks after last dose in each treatment course is administered.
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 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 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 (or potentially from other countries participating in the study), 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 32

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 with the last 9 months prior to start of study treatment.
6. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment
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-up phases of this protocol.
10. Prior or current alcohol or drug dependencies
11. Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)
12. Significant hypertension: BP > 180/110
13. Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.
14. Known untreated or unregulated thyroid disease
15. Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy
16. 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.
17. Platelet (thrombocyte) count < 100 x 109/L
18. ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)
19. Serum creatinine > 200 µmol/L
20. Serum bilirubin > ULN
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 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.
25. 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.
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.
31. Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy
32. Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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: Proportion of patients with no evidence of disease activity after a 2 year (96 week) and 5 year (240 week) period. NEDA is the absence of a protocol defined disease activity event.

Secondary endpoints 20

1. 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) and a 5 year (240 week) period4, with re-baseline for brain athrophy at 48 weeks.
2. Time to first protocol-defined disease activity event as defined in section 2.2
3. Change in EQ-5D-5L from baseline to Week 96, and from baseline to Week 240
4. Change in Fatigue Severity Scale (FSS) from baseline to Week 96, and from baseline to Week 240
5. Change in Multiple Sclerosis Impact Scale (MSIS)-29 from baseline to Week 96, and from baseline to Week 240
6. Change in EDSS from baseline (Visit 4.1) to Week 96 , and from baseline to Week 240
7. The proportion of patients who, at Week 96 and at Week 240, have protocol-defined Confirmed Disability Improvement (CDI) , confirmed stable EDSS or Confirmed Disability Progression (CDP) compared to baseline
8. Annualized rate of protocol-defined relapses during 96 weeks and 240 weeks from start of study treatment
9. Time to onset of first protocol-defined relapse from start of study treatment
10. Change in MRI T2-weighted hyperintense lesion volume from baseline to Weeks 48 and 96, and from baseline to Week 144, 192 and 240
11. Change in MRI T1-weighted hypointense lesion volume from baseline to Weeks 48 and 96, and from baseline to Week 144, 192 and 240
12. Change in brain volume from re-baseline at week 48, to week 96, from re-baseline at week 48, to Week 144, 192 and 240
13. Time to detection of a new MRI T2 lesion
14. Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96, 144, 192 and 240
15. Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96, 144, 192 and 240
16. Change in Nine-hole-peg test (9-HPT) score from baseline to week 48, 96 and 240
17. Change in Timed 25 foot walk (T25FW) score from baseline to week 48, 96 and 240
18. Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 and 240
19. Overall survival rate at week 96 and 240
20. Work productivity and activity impairment at week 96, 144, 192 and 240

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Bergen HF

Sponsor organisation

Helse Bergen HF

Address

Haukelandsveien 22

City

Bergen

Postcode

5021

Country

Norway

Scientific contact point

Organisation

Helse Bergen HF

Contact name

Lars Bø

Public contact point

Organisation

Helse Bergen HF

Contact name

Lars Bø

Third parties 1

Locations

4 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications