Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for RRMS (RAM-MS)

• Register: ClinicalTrials.gov
• Last refreshed on: 15 January 2024
• Main ID: NCT03477500
• Date of registration: 13/02/2018
• Prospective Registration: Yes
• Primary sponsor: Haukeland University Hospital
• Public title: Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for RRMS (RAM-MS) RAM-MS
• Scientific title: Randomized Autologous heMatopoietic Stem Cell Transplantation Versus Alemtuzumab, Cladribine or Ocrelizumab for Patients With Relapsing Remitting Multiple Sclerosis (RAM-MS)
• Date of first enrolment: March 21, 2018
• Target sample size: 100
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03477500
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Single (Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

Denmark, Netherlands, Norway, Sweden

Contacts

• Name: Einar Kristoffersen, MD, PhD
• Affiliation: Haukeland University Hospital

• Name: Astrid Kittang, MD, PhD
• Affiliation: Haukeland University Hospital

• Name: Morten Blinkenberg, MD, PhD
• Affiliation: Rigshospitalet, Denmark

• Name: Margitta Kampman, MD, PhD
• Affiliation: Tromsø University Hospital

• Name: Joachim Burman, MD, PhD
• Affiliation: Akademiska sjukhuset, Uppsala

• Name: Øivind Torkildsen, MD, PhD
• Affiliation: Haukeland University Hospital

• Name: Kathrine K Liane, MD
• Affiliation: St. Olavs Hospital

• Name: Lars Bø, MD, Phd
• Affiliation: Haukeland University Hospital

• Name: Jan Lycke, MD, PhD
• Affiliation: Sahlgrenska University Hospital, Sweden

• Name: Trygve Holmøy, MD, PhD
• Affiliation: University Hospital, Akershus

• Name: Øivind Torkildsen, MD, PhD

• Name: Anne Kristine Lehmann, MD, PhD
• Affiliation: Haukeland University Hospital

Key inclusion & exclusion 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.



Age minimum: 18 Years
Age maximum: 50 Years
Gender: All

Health Condition(s) or Problem(s) studied

Multiple Sclerosis

Intervention(s)

Drug: Cladribine Pill

Drug: Alemtuzumab

Drug: Cyclophosphamide and ATG

Drug: Ocrelizumab

Primary Outcome(s)

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]

Secondary Outcome(s)

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]

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 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]

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]

Time to first protocol-defined disease activity event [Time Frame: 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) [Time Frame: 2 year (96 week) period, with planned extension for 5 year (240 week) period]

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]

Pre-planned study extension: [Time Frame: 5 year (240 week) period.]

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]

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]

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]

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]

NEDA-4 [Time Frame: 2 year (96 week) period]

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]

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]

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

Secondary ID(s)

2017-001362-25

Source(s) of Monetary Support

Please refer to primary and secondary sponsors