Cladribine vs Placebo for Non-active Progressive Multiple Sclerosis (CLASP-MS).

Summary

The purpose of the study is to evaluate the efficacy and safety of subcutaneously administered cladribine versus placebo to stop inflammation and treat disease progression of non-active secondary progressive multiple sclerosis. Multiple sclerosis is an inflammatory disease of the central nervous system. In most patients, it starts with a relapsing course (RMS) which is caused by acute inflammatory lesions in the brain and spinal cord. RMS transforms at later stages into progressive disease (secondary progressive MS). Currently approved disease-modifying treatments are effective in reducing clinical relapses and brain and spinal lesions visible in MR, but they perform poorly in preventing disease progression and overall disability accumulation. The growing evidence shows that disease progression partially depends on chronic inflammation present in the CNS. Drugs, which may cross the blood-brain barrier and reach inflammatory cells residing in the CNS might be effective in this stage of the disease. Cladribine is one of the DMT approved for RMS. It is a synthetic purine analog with selective lymphocyte toxicity, which enter the CNS and is found in cerebrospinal fluid. In patients treated with cladribine, the oligoclonal bands tend to disappear proving that neuroinflammation is diminished. The participants of this clinical trial with the later non-active stage of MS are enrolled to be treated with cladribine subcutaneously or a non-active comparator (placebo) for 6 months and followed for the next 2 years, with an MRI scan and clinical evaluation every 6 months. The main questions it aims to answer are if in the non-active stage of MS cladribine is potent to lessen brain volume loss and if it is potent to attenuate inflammation in the CNS.

Eligibility

Inclusion Criteria:

* Written informed consent
* Diagnosis of relapse-onset, secondary progressive multiple sclerosis based on the 2017 McDonald criteria
* Progression of disability over 24 months defined as an increase in the EDSS score of 1 or more for patients with EDSS ≤ 5.5 or of 0.5 or more for patients with EDSS \> 5.5
* Lack of relapses over last 12 months
* EDSS of 3.5 - 7.5 inclusive
* Age of 30 - 65 years inclusive
* Duration of MS of 10 years or longer
* Pre-menopausal women must refrain from heterosexual intercourse or use a contraception method with a failure rate of \< 1% from enrolment up to 6 months after the last dose of the investigational medicinal product
* Men must refrain from heterosexual intercourse from enrolment up to 6 months after the last dose of the investigational medicinal product or use a barrier method of contraception, with their female partners using a contraception method with a failure rate of \<1%
* Able to fulfill all protocol requirements as judged by the investigator

Exclusion Criteria:

* Lack of written informed consent
* Previous cladribine treatment
* Hypersensitivity to the investigational medicinal product
* Eligible and willing to use interferon beta, siponimod, or mitoxantrone
* Unable to undergo magnetic resonance imaging
* Pregnancy or breastfeeding
* Does not agree to use contraception methods defined above
* Diseases of the nervous system, such as tumors, stroke, traumatic injury, encephalomyelitis, B12 deficiency, or demyelinating diseases other than multiple sclerosis
* Major comorbidities, such as cancer, liver failure, kidney failure, heart failure (NYHA II-III), or any other disease that may jeopardize patient safety or make it impossible for the patient to fulfill protocol requirements
* Relapse within last 12 months
* Chronic treatment with corticosteroids or immunosuppressants (eg, azathioprine, methotrexate, cyclosporine) within last 6 months
* Disease-modifying treatments for multiple sclerosis (no washout is required for interferons beta, glatiramer acetate, and dimethyl fumarate; washout of \> 6 months for teriflunomide, fingolimod, and natalizumab \[an accelerate elimination procedure may be used for teriflunomide instead\]; washout of \> 12 months for ocrelizumab, mitoxantrone, and alemtuzumab)
* Relapsing-remitting multiple sclerosis
* Primary progressive multiple sclerosis
* Hepatitis B or hepatitis C, including detectable HbsA, anti-HBc, or anti-HCV antibodies in serum
* HIV infection, including a positive screening test (anti-HIV 1/2, protein 24)
* Active or latent tuberculosis, including a positive result of the QuantiFERON TB Gold test during screening or within 3 months (an inconclusive test must be repeated; two inconclusive tests are taken as a positive result)
* Other infection that may be worsened by treatment with cladribine
* Lymphopenia (\< 1000/μl), neutrocytopenia (\< 1500/μl), or thrombocytopenia
* Alanine aminotransferase or aspartate aminotransferase \> 2 x ULN (can be repeated when 1.5-3x ULN); Total bilirubin \> 1.5 x ULN (can be repeated when 1.5-3 x ULN); Hemoglobin \> 9.5 g/dL (can be repeated when 9-9.4 g/dL)
* Lack of vaccination against COVID-19 - the time from the last dose of a full vaccination regimen is shorter than 6 weeks
* Any vaccination within last 6 weeks
* Lack of cancer screening or suspicion of cancer or necessity to carry out additional studies after the following examinations done at screening: chest X-ray in all participants; mammography or breast ultrasound in women; cervical smear in women; prostate-specific antigen in men
* Patient does not have detectable antibodies against Varicella zoster virus in serum or a proof of two-dose vaccination against this virus (last dose at least 6 months before enrolment)
* Use of oral or parenteral anticoagulants or antiplatelets other than acetylsalicylic acid

Conditions2

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