CLADRIBINE for Relapsing-remitting multiple sclerosis|Multiple sclerosis

Inclusion criteria

• {"criterion_text":"- Age between ≥18 to ≤50, both genders\n- 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.\n- Diagnosis of RRMS using revised McDonald criteria of clinically definite MS\n- An EDSS score of 0 to 5.5\n- 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.\tSignificant inflammatory disease activity is defined by: i.\tOne or more clinically reported multiple sclerosis (MS) relapse(s), ii.\tAND 1 or more T1 Gd-enhanced lesion(s), iii.\tOR 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.\n- 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.\n- 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

• {"criterion_text":"- Known hypersensitivity or other known serious side effects for any of the study medications, including co-medications such as high-dose glucocorticosteroids\n- Prior or current alcohol or drug dependencies\n- Cardiac insufficiency, cardiomyopathy, significant cardiac dysrhytmia, unstable or advanced ischemic heart disease (NYHA III or IV)\n- Significant hypertension: BP > 180/110\n- Active malignancy or prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix.\n- Known untreated or unregulated thyroid disease\n- Failure to willingly accept or comprehend risk of irreversible sterility as a side effect of therapy\n- 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.\n- Platelet (thrombocyte) count < 100 x 109/L\n- ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN)\n- Serum creatinine > 200 µmol/L\n- 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\n- Serum bilirubin > ULN\n- Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams\n- Diagnosis of primary progressive MS\n- Diagnosis of secondary progressive MS\n- 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.\n- 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.\n- Any hereditary neurological disease such as Charcot-Marie-Tooth disease or Spinocerebellar ataxia\n- Any disease that can influence the patient safety and compliance, or the evaluation of disability\n- History of hypersensitivity reaction to rabbit\n- Women who are pregnant, breast-feeding, or who plan to become pregnant within the timeframe of this study\n- 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\n- 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.\n- Immunocompromised patients, or patients currently reveiving immunosuppressive or myelosuppressive therapy\n- Moderate or severely impaired kidney function (creatinine-clearance below 60 ml/min)\n- 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.\n- 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.\n- Treatment with glucocorticoids or ACTH within one month prior to start of study treatment\n- Having experienced an MS relapse within one month prior to study inclusion\n- Prior or current major depression\n- 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."}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"NEDA is defined in-protocol as the absence of a protocol defined disease activity event; measured as the proportion of patients with no evidence of disease activity at 96 weeks and 240 weeks."}

Secondary endpoints

• {"endpoint_text":"- 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.\n- Time to first protocol-defined disease activity event as defined in section 2.2\n- Change in EQ-5D-5L from baseline to Week 96, and from baseline to Week 240\n- Change in Fatigue Severity Scale (FSS) from baseline to Week 96, and from baseline to Week 240\n- Change in Multiple Sclerosis Impact Scale (MSIS)-29 from baseline to Week 96, and from baseline to Week 240\n- Change in EDSS from baseline (Visit 4.1) to Week 96 , and from baseline to Week 240\n- 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\n- Annualized rate of protocol-defined relapses during 96 weeks and 240 weeks from start of study treatment\n- Time to onset of first protocol-defined relapse from start of study treatment\n- Change in MRI T2-weighted hyperintense lesion volume from baseline to Weeks 48 and 96, and from baseline to Week 144, 192 and 240\n- Change in MRI T1-weighted hypointense lesion volume from baseline to Weeks 48 and 96, and from baseline to Week 144, 192 and 240\n- 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\n- Time to detection of a new MRI T2 lesion\n- Total number of MRI T1-weighted Gd-enhanced lesions at weeks 24, 48, 96, 144, 192 and 240\n- Proportion of patients free from T1 Gd-enhancing lesions at weeks 24, 48, 96, 144, 192 and 240\n- Change in Nine-hole-peg test (9-HPT) score from baseline to week 48, 96 and 240\n- Change in Timed 25 foot walk (T25FW) score from baseline to week 48, 96 and 240\n- Change in The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) score from baseline to week 96 and 240\n- Overall survival rate at week 96 and 240\n- Work productivity and activity impairment at week 96, 144, 192 and 240","definition_or_measurement_approach":"Secondary endpoints include NEDA-4 (NEDA plus annualised brain atrophy above threshold 0.4% measured yearly with re-baseline at week 48), time-to-event measures (time to first protocol-defined disease activity event, time to first relapse), change-from-baseline patient-reported outcomes (EQ-5D-5L, FSS, MSIS-29), disability scores (EDSS changes, CDI/CDP), MRI lesion counts and volumes at specified weeks, functional tests (9-HPT, T25FW), cognitive assessment (BICAMS), overall survival, and work productivity measures as defined in protocol with measurement timepoints at weeks 24, 48, 96, 144, 192 and 240 where specified."}

Methods

• Patients are referred from neurological departments in participating countries (Norway, Denmark, Sweden, the Netherlands, and potentially other participating countries) to an assigned study site.

Denmark

Earliest CTIS Part Ii Submission Date

15-05-2024

Latest Decision Or Authorization Date

06-06-2024

Processing Time Days

22

Number Of Sites

1

Number Of Participants

5

Sweden

Earliest CTIS Part Ii Submission Date

15-05-2024

Latest Decision Or Authorization Date

07-06-2024

Processing Time Days

23

Number Of Sites

1

Number Of Participants

2

Netherlands

Earliest CTIS Part Ii Submission Date

15-05-2024

Latest Decision Or Authorization Date

06-06-2024

Processing Time Days

22

Number Of Sites

1

Number Of Participants

8

Norway

Earliest CTIS Part Ii Submission Date

04-06-2024

Latest Decision Or Authorization Date

12-06-2024

Processing Time Days

8

Number Of Sites

4

Number Of Participants

85

Primary sponsor

Full Name

Helse Bergen HF

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Norway

Third parties

• {"country":"Netherlands","full_name":"VUmc Stichting","duties_or_roles":"Code 1; Centralized blinded MRI reading","organisation_type":"Hospital/Clinic/Other health care facility"}