An Autologous and Antigen-specific Cell-based Therapy of Vitamin D3-treated and Myelin-derived Peptide Loaded Tolerogenic Dendritic Cells in Subjects With Progressive Forms of Multiple Sclerosis: a Phase IIa, Open-label, Self-controlled, Multi-center Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 14
- 试验地点
- 3
- 主要终点
- Efficacy (Change in EDSS score)
研究概览
简要总结
The investigators propose to design and conduct a phase IIa clinical trial to treat patients with progressive forms of multiple sclerosis (MS) by vaccination with tolerogenic dendritic cells (tolDC), generated using Good Manufacturing Practices (GMP). Hereby, the investigators want to demonstrate the efficacy and safety of administrating clinical-grade vitamin D3-treated tolDC loaded with myelin-derived peptides to patients with progressive forms of MS. In vitro generation of dedicated and stable immunomodulatory DC followed by in vitro loading of antigens to ensure tolerance and safety of DC-directed therapy is a promising strategy with the potential to induce long term tolerance.
详细描述
This is an open-label, self-controlled, multi-center phase IIa clinical trial designed to evaluate the proof-of-concept for both efficacy and safety of tolDC-based therapy. The primary objective is to determine whether treatment with tolDC is effective (using a surrogate primary outcome-change in EDSS score) and safe (the occurrence and severity of adverse events). Secondary evaluations will include the clinical outcomes (assessed using 9HPT, SDMT and number and severity of relapses) and MRI-based markers. Participants will serve as their own controls, with data from 24 weeks pre-treatment period (documented by their neurologist). Following six tolDC administrations, a 24-weeks follow-period will take place. Furthermore, participants can enroll voluntarily into an optional additional follow-up phase of 52 weeks. Completion of screening assessments and confirmation of eligibility criteria should take no longer than 8 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient is ≥ 18 years old, and ≤65 years of age, at time of screening visit
- •Diagnosis of MS according to the 2017 McDonald Criteria or more recent criteria
- •Progressive MS by 2014 Lublin MS phenotypic criteria
- •EDSS 2,0 - ≤7,5
- •No clinical evidence of relapses in the past 2 years
- •Ability to understand and the willingness to sign a written informed consent document. Patients must have signed informed consent to participate in the trial.
- •Appropriate venous access
- •Use of adequate contraceptive measures or not of childbearing potential
排除标准
- •Previous treatment with alemtuzumab, autologous hematopoietic stem cell transplantation or cladribine in the past 3 years.
- •Prior treatment with any investigational agent within 3 months, or 5 half-lives, whichever is longer.
- •Current and ongoing treatment with an approved DMT for MS
- •Treatment with S1P receptor modulators, natalizumab, dimethylfumarate, teriflunomide within the last 3 months prior to study enrolment; last treatment with B cell depleting monoclonal antibodies at least 6 months prior to enrollment and normal CD19 B cell counts at time of enrollment
- •Pregnancy or planning pregnancy in the next 12 months and breast feeding
- •Drug or alcohol abuse
- •Inability to undergo MRI assessments
- •History of or actual signs of immunodeficiency or malignancies (with the exception of treated basal cell carcinoma)
- •Concurrent clinically relevant cardiac, immunological, pulmonary, neurological, renal or other major disease that could impact safety or outcome measures.
- •Active or chronic infection with hepatitis B, C, HIV, syphilis or tuberculosis
- •Splenectomy
- •Dementia or severe psychiatric, cognitive or behavioral problems or other comorbidity that could interfere with the compliance to the protocol.
研究组 & 干预措施
Intradermal Arm: tolerogenic dendritic cells (tolDC)
Each vaccine (15x10E6cells in 500 µL solution with 5% human albumin supplemented with 10% DMSO and 4% glucose) will be administered through intradermal injection at 5 sites (100 µL/site) in the posterior cervical region, targeting lymphatic drainage into both superficial and deep cervical lymph nodes (5-10 cm from the cervical lymph nodes). Injection sites will alternate between left and right sides of the neck for each administration timepoint.
干预措施: Tolerogenic dendritic cells (tolDC) (Biological)
结局指标
主要结局
Efficacy (Change in EDSS score)
时间窗: 62 weeks
To evaluate the efficacy of tolDC administration, the change in Expanded Disability Severity Scale (EDSS) will be employed. The participants' disability level well be checked during every visit. The EDSS consists of a 10-point scale of disease severity ranging from 0, i.e. no disability, to 10, i.e. death from MS. The impact on disability progression will be analyzed by the proportion of participants free from confirmed disability progression, defined by sustained changes in the EDSS score. Disease progression criteria: * 1.0 point in participants with a screening EDSS of 0-5.0 * 0.5 point in those with a screening EDSS of 5.5-6.0
Efficacy (Change in EDSS score)
时间窗: 62 weeks
To evaluate the efficacy of tolDC administration, the change in Expanded Disability Severity Scale (EDSS) will be employed. The participants' disability level well be checked during every visit. The EDSS consists of a 10-point scale of disease severity ranging from 0, i.e. no disability, to 10, i.e. death from MS. The impact on disability progression will be analyzed by the proportion of participants free from confirmed disability progression, defined by sustained changes in the EDSS score. Disease progression criteria: * 1.0 point in participants with a screening EDSS of 0-5.0 * 0.5 point in those with a screening EDSS of 5.5-6.0
Incidence of treatment-emergent adverse events (safety and tolerability)
时间窗: 62 weeks
Tolerability and safety of tolDC administration will be assessed by recording the incidence, severity, and relationship to study treatment of adverse events throughout the trial. Participants will be monitored by the treating neurologist for the occurrence and outcomes of AEs, SAEs, relapses and study discontinuations. Full physical examinations, vital signs, and blood and urine samples (only in case of women of childbearing age for pregnancy test) will be recorded at screening, during tolDC administration and during follow-up. An assessment of severity grading of AEs will follow the WHO toxicity grading scale (1= mild, 2= moderate, 3= severe, 4= potentially life threatening).
次要结局
- T2 lesion volume on MRI(62 weeks)
- Total Brain Volume on MRI(62 weeks)
- Brain Atrophy on MRI(62 weeks)
- Symbol Digit Modalities test (SDMT)(62 weeks)
- 9 Hole Peg Test (9HPT)(62 weeks)
- Biomarkers(62 weeks)
- 9 Hole Peg Test (9HPT)(62 weeks)
- Symbol Digit Modalities test (SDMT)(62 weeks)
- T2 lesion volume on MRI(62 weeks)
- Total Brain Volume on MRI(62 weeks)
- Brain Atrophy on MRI(62 weeks)
- Biomarkers(62 weeks)