Evaluation of Subcutaneous Cladribine Efficacy and Safety in Secondary Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2024-516992-33-02
- Protocol
- 504-15-021-21003
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** and safety of subcutaneously administered cladribine compared with placebo in patients with secondary progressive multiple sclerosis (SPMS). The study targets patients who have experienced disease progression in the last 24 months without any relapses in the past 12 months. The primary efficacy endpoint is the slowing of brain volume loss in SPMS patients receiving cladribine relative to those receiving placebo. This is clinically relevant as it addresses the need for effective treatments in managing disease progression in SPMS, a condition characterized by a gradual worsening of neurological function.
Secondary objectives include:
- Evaluation of the usefulness of QSM imaging for assessing disease activity in the progressive phase.
- Searching for protein and imaging biomarkers for monitoring treatment in the progressive phase.
Participants
The clinical trial involves participants diagnosed with **secondary progressive multiple sclerosis** (SPMS), specifically those who have experienced disease progression within the last 24 months without any relapses in the past 12 months. The study population includes both male and female subjects, aged between 30 and 65 years, who meet the 2017 McDonald criteria for SPMS. Participants are required to have a baseline Expanded Disability Status Scale (EDSS) score between 3.5 and 7.5 and must have had their first symptoms at least 10 years prior to enrollment. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if of childbearing potential. The sponsor has not provided information regarding the total number of participants in the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **cladribine** administered subcutaneously in patients with secondary progressive multiple sclerosis (SPMS). This study is a phase 2, randomized, double-blind, placebo-controlled trial. The trial aims to assess the slowing of brain volume loss as the primary efficacy endpoint, with secondary endpoints including disability progression, cognitive function, quality of life, neuroimaging outcomes, and serum biomarkers. The trial is expected to run from October 2022 to June 2027, with participant involvement lasting approximately 122 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease progression, and absence of relapses in the past 12 months. Following randomization, participants will receive either cladribine or placebo. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the protocol. These visits will include assessments of neurological status, imaging studies, and laboratory tests. The end-of-study visit will occur at week 122, where final evaluations will be conducted to assess the primary and secondary endpoints.
Participants are expected to adhere to the study protocol, including the use of contraception for women of childbearing potential and men, as well as abstaining from donating eggs or semen during the study and for six months after the last dose. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.
Treatment
The clinical trial involves the administration of **cladribine**, marketed under the name BIODRIBIN, as the experimental medication. Cladribine is provided in a **solution for infusion** form, with a concentration of 1 mg/ml. The pharmaceutical form is specifically designed for **subcutaneous injection**. The maximum daily dose of cladribine is 10 mg, with a total maximum dose of 1.8 mg/kg over the treatment period. The treatment duration is set for a maximum of 26 weeks. Cladribine is a synthetic purine nucleoside, and its chemical origin is confirmed. The primary objective of the trial is to evaluate the efficacy and safety of cladribine in patients with secondary progressive multiple sclerosis (SPMS), focusing on the slowing of brain volume loss compared to placebo.
The non-experimental treatment used in this study is a **placebo**, specifically 0.9% physiological saline (sodium chloride). This placebo is utilized to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocations. The placebo is administered in a manner consistent with the experimental treatment to ensure comparability. The use of a placebo is critical in assessing the true efficacy of cladribine by providing a baseline for comparison. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to maintain the integrity of the study results.
Efficacy
The efficacy of subcutaneously administered **cladribine** in patients with secondary progressive multiple sclerosis (SPMS) will be assessed through a series of predefined endpoints. The primary efficacy endpoint is the slowing of brain volume loss relative to placebo, measured as the percent brain volume change from the last cladribine dose at week 26 to the end of the study at week 122. Secondary efficacy endpoints include the time to 24-week confirmed composite progression of disability, which is defined by an increase in the Expanded Disability Status Scale (EDSS) score, the time of the Timed 25-Foot Walk, and the 9-Hole Peg Test. Additional secondary endpoints involve changes from baseline in cognitive function assessed by CANTAB, CVLT, and SDMT, as well as quality of life measured by MSQeL-54. Neuroimaging parameters such as the number of gadolinium-enhancing lesions, new T2 lesions, QSM rim+ lesions, volume of T1 lesions (black holes), and volume of the cervical spinal cord in T1 will also be evaluated. Furthermore, serum levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and the presence of oligoclonal bands will be analyzed. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent to participate in the study 2. Diagnosis of SPMS based on the 2017 McDonald criteria, with a relapsing-remitting course at the onset of the disease 3. History of progressive neurological deterioration within at least 24 months: Increase in EDSS score by at least 1 point if EDSS ≤ 5 and by at least 0.5 point if EDSS> 5. A summary written by the researcher explaining why he thinks the patient has progressive disease for at least 24 months. 4. No clinical relapses in the last 12 months 5. Baseline EDSS ≥ 3.5 and ≤ 7.5 6. Age 30-65 years 7. Time from first symptoms at least 10 years 8. For women of childbearing potential: a written declaration of discontinuation of heterosexual intercourse or use of contraception in the study and for at least 6 months after the last dose as defined below: a. The woman must stop heterosexual intercourse or use a contraceptive method with a failure rate <1% per year during treatment. Women are also not allowed to donate eggs during this period. b. A woman of childbearing potential is a woman who has had her first menstrual period, is premenopausal (uninterrupted period of at least 12 months without menstruation) and is not permanently sterile due to surgery (removal of the ovaries, fallopian tubes and / or uterus) or any other reason. found by the researcher. c. Examples of contraception with a failure rate <1% per year are bilateral tubal ligation, partner sterilization, hormonal contraception to suppress ovulation, hormone-secreting IUDs or copper IUDs. d. Hormonal contraception must be used in conjunction with a barrier method. e. Temporary abstinence, such as using a calendar method, is not an acceptable form of contraception. 9. For men: a written declaration to stop heterosexual intercourse in the study and for at least 6 months after the last dose, or to use condoms and contraception in female partners during this period as described above. In addition, statements on not donating semen during the study and for 6 months after the last dose of the drug. 10. Possibility of meeting the requirements of the test protocol in the opinion of the researcher.
Exclusion Criteria
- Lack of consent to participate in the study 2. History of cladribine treatment regardless of indication 3. Hypersensitivity to any component of the investigational drug 4. The need to use other immunomodulating or immunosuppressive drugs, including drugs used in secondary progressive MS, e.g. interferon beta-1b, mitoxantrone, siponimod 5. Contraindications for performing magnetic resonance imaging 6. Pregnancy and the period of breastfeeding 7. Lack of consent to the use of effective methods of contraception as defined in the inclusion criteria 8. Diseases of the nervous system (brain or spinal cord tumors, stroke or spinal cord, brain or spinal cord injury, encephalomyelitis, vitamin B12 deficiency, other than multiple sclerosis demyelinating diseases of the central nervous system) 9. Serious accompanying diseases (e.g. cancer, liver and / or kidney failure, heart failure II and III according to NYHA) or other diseases which, in the opinion of the investigator, could threaten the patient's safety in the study or prevent compliance with the requirements of the study protocol 10. Disease relapse <12 months after screening visit 11. Chronic treatment with steroids or immunosuppressants (e.g. azathioprine, methotrexate, cyclosporine) <6 months prior to study entry 12. Disease-modifying therapies: a. Interferons, glatiramer acetate, and dimethyl fumarate must be withdrawn prior to inclusion in the study; they do not require a transition period; b. teriflunomide, fingolimod, natalizumab must be discontinued at least 6 weeks prior to study enrollment; for teriflunomide, the SmPC dropout procedure must be followed if the patient requires enrollment in the study between 2-4 weeks after withdrawal;c. ocrelizumab, mitoxantrone, and alemtuzumab must be discontinued for at least 12 months prior to study enrollment. 13. Relapsing-remitting MS 14. Primary progressive form of MS 15. HBV or HCV infection (positive HBV, positive anti-HBc antibodies or positive anti-HCV antibodies) 16. HIV infection or HIV screening positive (anti-HIV 1/2 antibodies, p24 antigen) 17. Active or latent tuberculosis: a positive QuantiFERON TB Gold (QFT) test during screening or in the 3 months prior to screening (inconclusive test should be repeated; two inconclusive tests are considered positive) 18. Other infections that may worsen with cladribine therapy. 19. Lymphopenia during screening (<1,000 / μl), neutrocytopenia (<1,500 / μl) or thrombocytopenia (<150,000 / μl) 20. Clinical significant abnormalities in the ECG examination according to the researcher's opinion 21. Alcohol or drug abuse in the last 12 months 22. Positive serum pregnancy test during screening 23. History of bone marrow or other organ transplantation 24. Treatment with immunoglobulins or plasmapheresis within the 3 months prior to randomization 25. Treatment with another Investigational medicinal product or medical device in the 6 months prior to randomization 26. At least one abnormal test: a.Creatinine> 1.5 x ULN (ULN; may be repeated if 1.5-2.0 x ULN) b. ALT or AST> 2 x ULN (may be repeated if 1.5-3 x ULN) c. Total Bilirubin> 1.5 x ULN (may be repeated if 1-3 x ULN) d. Hemoglobin <9.5 g / dL (can be repeated if 9-9.4 g / dL) 27. Patient is not fully vaccinated against COVID-19, i.e. at least 6 weeks have not elapsed since the last dose of vaccination. 28. Vaccination with any vaccine within less than 6 weeks 29. The patient has not been screened for neoplasms or the tests performed suggest neoplasm or further tests for neoplasm (chest X-ray PA + side for women and men, mammography or ultrasound of breasts for women, cytology for women, PSA for men). 30. Lack of measurable serum levels of anti-varicella / herpes zoster antibodies. 31. Anticoagulant therapy (oral or parenteral) or anti-platelet therapy other than acetylsalicylic acid.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 01 Oct 2022 | 188 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BIODRIBIN, 1 mg/ml, roztwór do infuzji | Test | ROZTWÓR DO INFUZJI | SUBCUTANEOUS INJECTION | 10 | 26 | PRD802229 |
0.9% physiological salinesodium chloride | Placebo | N/A | — | — | — | N/A |