This study has been transitioned to CTIS with ID 2024-510630-40-00 check the CTIS register for the current data. The objective of this prospective, randomized study is to investigate the efficacy and safety of HSCT compared to the comparator group (…
ID
Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
Study Part I and II:
The secondary efficacy endpoints for this study are to evaluate the efficacy of
HSCT compared to the comparator group (alemtuzumab, cladribine or ocrelizumab
on the basis of the following endpoints:
• 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 weeks) and 5 year (240 weeks) period, 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 and Week 240
• Change in Fatigue Severity Scale (FSS) from baseline to Week 96 and Week 240
• Change in Multiple Sclerosis Impact Scale (MSIS)-29 from baseline to Week 96
and Week 240
• Change in EDSS from baseline (Visit 4.1) to Weeks 96 and 240
• The proportion of patients who, at Week 96 and 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 96 weeks and 240 weeks
• Time to onset of first protocol-defined relapse
• Change in MRI T2-weighted hyperintense lesion volume from baseline to Week 48
and 96, and Week 144, 192 and 240
• Change in MRI T1-weighted hypointense lesion volume from baseline to Week 48
and 96, and Week 144, 192 and 240
• Change in brain volume from re-baseline at Week 48, to Week 96, and Week 144,
192 and 240
• Time to detection of a new MRI T2 lesion
• Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96, 144,
192 and 240
• Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96,
144, 192 and 240
• Change in Nine-hole-peg test (9-HPT) score from baseline to week 48, 96 and
240
• Change in Timed 25 foot walk (T25FW) score from baseline to week 48, 96 and
240
• Change in The Brief International Cognitive Assessment for Multiple Sclerosis
(BICAMS) score from baseline to week 96 and 240
• Overall survival rate at week 96 and week 240
• Work productivity and activity impairment at week 96, 144, 192 and 240
Background summary
Relapsing-remitting MS is treated with immunomodulatory medications to prevent
relapses and to delay disability development. Immunomodulatory treatment
reduces the annually MS relapse rate in RRMS 20-70 %, and recent studies
indicate a slower progression of disability compared to studies prior to the
era of immunomodulatory MS-treatment. A major proportion of RRMS patients
experience disease activity despite the use of registered immunomodulatory
MS-treatment, and these patients have significant risk of developing severe
disability at a young age. Accordingly, there is a need for improved
immunomodulatory treatment options that rapidly and consistently prevent CNS
inflammation, MS-relapses and progression of clinical disability. International
studies indicate that autologous stem cell transplantation can halt the disease
activity in patients with relapsing remitting MS. However, the patient
populatoin and study design differ in various studies. Therefore, the relative
effect of stem cell transplantation versus the currently best available MS
therapy (alemtuzumab, cladribine or ocrelizumab) need to be established in a
randomized study directly comparing these treatment schemes.
Study objective
This study has been transitioned to CTIS with ID 2024-510630-40-00 check the CTIS register for the current data.
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.
In Norway, the clinical study is supplemented with a health economic
evaluation.
Study design
This study is a prospective, multicentre, interventional, unblinded,
randomized, parallel group study in patients with relapsing remitting MS
experiencing treatment failure in the preceeding year in spite of ongoing
immunomodulatory treatment. If a new immunomodulatory MS treatment is
registered during the study recruitment phase it will be evaluated if the new
treatment should be added as comparator.
Intervention
In this study cyclophosphamide, anti-thymocyte globulin, alemtuzumab,
cladribine and ocrelizumab are defined as Investigational Medicinal Product(s)
(IMPs).
Arm A: Stem cell therapy. Including mobilization and harvesting; 10 days,
conditioning and reinfusion; 30 days.
Arm B:
Alemtuzumab - at start of treatment; infusion for 5 consecutive days, and 1
year later; infusion for 3 consecutive days
Cladribine - administered as 1 treatment course per year over 2 years. Each
treatment course consists of 2 treatment weeks, one at the beginning of the
first month and one at the beginning of the second month of the respective
treatment year. Each treatment week consists of 4 or 5 treatment days.
Ocrelizumab - at the start of treatment the initial dose is split in two
separate intravenous infusions; the first infusion (1/2 dose), and the second
infusion (1/2 dose) 2 weeks later. Thereafter intravenous infusion of a single
full dose once very 6 months.
Study burden and risks
For both treatment groups, extra burden of study particiaption includes
returning to the hospital for the study visits, examinations during the
screening visit (chest X-ray, blood tests, spirometry), venapunction during
every visit, feces swab (optional), spinal puncture (optional, voluntary
procesdure), MRI's, neurological examination, completion of questionnaires and
performing neurological tests such as 9-hole peg test and time-25-foot walk,
and selected tests from the Brief International Cognitive Assessment for
Multiple Sclerosis. For stem cell therapy, hospitalization of 23-24 days will
be required.
Side effects of the study medication/ stem cell transplantation may occur. One
of the side effects/risk of stem cell transplantation that is explicitly
mentioned is irreversible sterility. Women of childbearing potential will be
offered fertility preservation measures (freezing of eggs) and will start
hormone therapy for maturation and harvesting of eggs simultaneously with the
pre transplantation evaluation. Men will be offered to deposit sperm in the
sperm bank before procedures for stem cell harvesting.
Data suggest that the treatment related mortality with HSCT can be decreased to
1-2 % in experienced centres using HSCT with mainly conditioning of high and
medium intensities, and it has been even lower (<= 0.3 %) in MS patients treated
with low intensity conditoning regimens.
The risk to subjects in this trial will be minimized by compliance with
eligibility criteria, close clinical monitoring, avoidance of prohibited
treatments and adherence to protocol contraception requirements and
Investigator guidance regarding specific safety areas. The inclusion of an
active comparator arm ensures that all patients in the study will receive
active therapy.
MS is associated with an extensive loss of quality-adjusted life years. Despite
the risk of treatment related mortality and serious side effects, the overall
long term benefits associated with HSCT (better efficacy compared to registered
immunomodulatory therapy) thus support continued research on HSCT and treatment
of RRMS.
Jonas Lies vei 65
Bergen 5021
NO
Jonas Lies vei 65
Bergen 5021
NO
Listed location countries
Age
Inclusion criteria
1. Diagnosis of RRMS using revised McDonald criteria of clinically definite MS
2. Age between > 18 to <50, both genders
3. An EDSS score of 0 to 5.5
4. 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:
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
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. 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 (UNL)
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)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-510630-40-00 |
| EudraCT | EUCTR2017-001362-25-NL |
| ClinicalTrials.gov | NCT03477500 |
| CCMO | NL70640.000.19 |