E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing Remitting Multiple Sclerosis (RRMS) |
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E.1.1.1 | Medical condition in easily understood language |
Diagnosis of relapsing-remitting multiple sclerosis (RRMS). In this type of MS, flare-ups of the disease occur. Between these flare-ups, there are periods of recovery or remission. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Safety objective (Part A and B) To assess the safety and tolerability of CLS12311 in patients with RRMS
Efficacy objective (Part B) To provide proof-of-concept for the efficacy of CLS12311 in reducing the number of new lesions on brain magnetic resonance imaging (MRI) as a measure for inflammatory disease activity in patients with RRMS |
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E.2.2 | Secondary objectives of the trial |
Safety objectives (Part A and B) To assess the safety and tolerability of each dose group of CLS12311
Efficacy objective (Part B) To define the optimal dose of CLS12311 to reduce new disease activity on brain MRI in RRMS patients
Exploratory objective (Part A and B) To understand the mechanism/s of action of tolerance induction with peptide-coupled RBCs and to identify biomarkers for measuring immune tolerance induction |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A and Part B General inclusion criteria (to be assessed at the beginning of the baseline period based on patient interview and medical history): 1. RRMS according to the 2017 McDonald criteria 2. Male or female patients (assigned at birth) aged 18-55 years 3. Disease duration (since diagnosis) <10 years 4. EDSS at baseline 0-5.5 5. ≥1 relapse or new CEL/T2 in previous 12 months (only Part B) 6. Untreated patients or patients being off therapy for the time periods listed under exclusion criterion No. 2. Patients are either not eligible to receive approved therapies or have explicitly chosen not to receive such therapies after being adequately informed by the investigators 7. Only for sexually active female patients of childbearing potential (sexually mature, pre-menopausal and not surgically sterile): the patient is willing to use a highly effective method of contraception (defined in the study protocol) throughout the complete treatment phase or at least for 4 weeks after the last dose of CLS12311 8. Male patients willing to use contraception (condoms) throughout the complete treatment phase or at least for 4 weeks after the last dose of CLS12311 unless surgically sterile 9. Basic immunization against SARS-CoV-2, i.e. both doses of two-dose vaccines (or one dose of a vaccine and a SARS-CoV-2 infection before or after vaccination) OR a dose of a single-dose vaccine
Part B Specific qualification criteria (to be assessed during the baseline period): 10. ≥ 2 cumulative new brain lesions (as defined above) on two MRI scans performed during baseline phase |
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E.4 | Principal exclusion criteria |
Part A and B General exclusion criteria (to be assessed at the beginning of the baseline period based on patient interview and medical history): 1. Patients with an active chronic disease (or stable but treated with immunomodulatory/-suppressive therapy) of the immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Crohn’s disease, ulcerative colitis, etc.) or with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug-induced immune deficiency) 2. Prior treatment with any of the medications below within the specified time-frame: a. glatiramer acetate, interferon-beta within 4 weeks prior to screening visit 1 b. dimethylfumarate, diroximel-fumarate within 4 weeks prior to screening visit 1 c. teriflunomide within 4 weeks prior to screening visit 1, provided accelerated elimination procedure (eg. cholestyramine) was performed and teriflunomide plasma level are below 0.02 mg/L before randomization d. fingolimod, ozanimod within 12 weeks prior to screening visit 1, provided normal lymphocyte counts (see exclusion criterion No. 18) e. siponimod, ponesimod within 8 weeks prior to screening visit 1, provided normal lymphocyte counts (see exclusion criterion No. 18) f. natalizumab within 12 weeks prior to screening visit 1 g. ocrelizumab, ofatumumab, rituximab, alemtuzumab, cladribine, mitoxantrone within 52 weeks prior to screening visit 1 h. plasma exchange, intravenous immunoglobulin within 8 weeks prior to screening visit 1 i. azathioprine, methotrexate, cyclophosphamide or any other continuous immunosuppressive therapy within 24 weeks prior to screening visit 1 j. any other immunosuppressive monoclonal antibody treatment within 24 weeks prior to screening visit 1 k. Prior autologous hematopoietic stem cell transplantation l. Corticosteroid treatment for MS relapse within 4 weeks prior to screening visit 1 m. Patients who participated in the ETIMSred trial 3. History of HIV, chronic or active Hepatitis C, chronic or active Hepatitis B or prior Syphilis, which has not been sufficiently treated 4. Long-COVID19 Syndrome 5. History of splenectomy or chronic liver disease 6. History of coronary artery disease, chronic heart failure, aortic stenosis 7. Current anticoagulation therapy 8. Uncontrolled grade II hypertension (≥160 systolic and/or ≥100 diastolic blood pressure; according to ISH global practice guidelines) despite treatment or without treatment 9. History of stroke 10. Pregnant female confirmed by a positive pregnancy test or breast-feeding 11. History of alcohol or drug abuse within the 1 year prior to screening visit 1 12. History of or existing malignancy within the last 5 years prior to enrolment except history of basal cell carcinoma and melanoma in situ 13. History of or existing relevant central nervous system disorder (other than MS) 14. Allergy to gadolinium-based contrast agents 15. Any other disease or condition, which could interfere with the participation in the study according to the study protocol, or with the ability of the patients to cooperate and comply with the study procedures
Specific exclusion criteria (to be assessed during the baseline period): 16. Anemia, defined as hemoglobin levels ≤12.5 g/dl (7.25 mmol/l) for female and ≤13.5 g/dl (8.37 mmol/l) for male participants (may be repeated if 11.5 -12.5 g/dl in females and 12.5 - 13.5 g/dl in males) 17. Erythrocyte count <4.0 E12/L in female and <4.5 E12/L in male patients (may be repeated if >3.8 E12/L in female and >4.3 E12/L in male) 18. Lymphopenia with total lymphocyte counts ≤ 1000/µl (may be repeated if >800/µl) 19. Positive HIV testing 20. Positive results of baseline period testing for serological markers for hepatitis B, C, and Syphilis indicating acute or chronic infection 21. Patient is not eligible for blood donation according to local regulation 22. Having one or more of the following laboratory results: a. Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 (may be repeated if eGFR is 45-59 mL/min/1.73 m2) b. ALT or AST > 3 x upper limit of normal (ULN; may be repeated if 3.1-4 x ULN) c. Total bilirubin greater than 2 x ULN (may be repeated if 2.1 - 3 x ULN), with the exception for patients with Gilbert’s disease d. Platelet count ≤ 100E9/L (may be repeated if 80-100E9/L) e. Abnormalities in hepatic synthetic function tests (PT time, INR, PTT, albumin) as judged by the Investigator to be clinically significant |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety (Part A and B) • Safety and tolerability of CLS12311 measured by the number and severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) and/or worsening of disease by clinical (relapses) and imaging (number and size of brain lesions)
Efficacy (Part B only) • The cumulative number of new brain lesions on the MRI scans developed in the treatment phase between weeks 16 and 24 compared to the pre-treatment number of new brain MRI lesions developed between weeks -8 and 0 for any dose.
New lesions on brain MRI are defined as being: • Contrast enhancing lesions on the reference scan at weeks -8 and 16 or • new/enlarging T2 lesions on scan at: • week 0 compared to scan at week -8 • week 24 compared to scan at week 16
MRIs will be assessed centrally by independent readers. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Safety endpoints (Part A and B): • Number and severity of TEAEs and TESAEs in each dose group • Number of confirmed relapses in the treatment phase in each dose group • Changes in clinical measures of disease severity (EDSS, 9-HPT, T25FW, SDMT) following CLS12311 administration in each dose group (Part A only EDSS)
Efficacy endpoints (Part B): • Number of new lesions on brain MRI (as defined above) in weeks 16-24 in the three dose groups • Efficacy of CLS12311 in reducing the number of new brain MRI lesions (as defined above) in defined subgroups, e.g. stratified for HLA or immunological parameters
Exploratory immunological and biomarker measures (Part A and B): • Percentage of patients in each dose group showing a reduction of antigen-specific T cells against the protein(s) they responded to at study entry • Changes in predefined serum biomarkers of disease activity and in other markers related to tolerance induction • Mechanistic profiling of serum and blood cells will be performed by measuring specific biomarkers of tolerance, tissue damage and inflammation as well as broad-based methods including but not limited to multi-analyte measurements, transcriptomics and proteomics. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Part A: open-label, ascending dose Part B: randomized, dose-blind |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Switzerland |
Czechia |
Germany |
Italy |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |