First in Human Study for the Assessment of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Multiple Ascending Intravenous Doses of LIS1 in Kidney Transplanted Patients
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Safety of the treatment with LIS1: Graft rejection
研究概览
简要总结
This first in human study aims at evaluating LIS1, a stabilized solution of purified anti-T lymphocytes polyclonal glyco-humanized swine IgG with immunosuppressive activity, in regards of safety, T cell depletion, and pharmacokinetics / pharmacodynamics in 10 kidney transplant recipients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- •Participants must be listed for kidney transplantation,
- •AD cohort participants: First transplantation, Panel Reactive Antibody (PRA) < 20%, negative Donor Specific Antibody (DSA), no anti-HLA antibodies, Epstein-Barr Virus positive (EBV+) serology,
- •TD cohort participants: First transplantation, 0-50 % PRA, negative DSA, negative flow cytometry crossmatch (FCXM) for any patients with anti-HLA antibodies on screening is mandatory, Epstein-Barr Virus positive (EBV+) serology
- •Participants must weigh at least 50 kg and have a Body Mass Index (BMI) 18.0 ≤ BMI < 35.0 kg/m2,
- •White Blood Cells > 3000/mm3, platelets > 75000/mm3,
- •Female participants (WOCBP) must have a negative pregnancy test at screening and use a highly effective birth control until 90 days after the last administration of study drug,
- •Non-vasectomized male subjects having a female partner of childbearing potential must agree to the use of a highly effective method of contraception until 90 days after the last administration of study drug,
- •Participants must be capable of giving signed informed consent.
排除标准
- •Patients with an active cancer or a history of kidney cancer,
- •Patients who have previously been exposed to other anti-lymphocyte globulins,
- •Patients with previous organ transplantation,
- •Patients with a history of specific viral infection that would contraindicate depleting antibody therapy (Hepatitis B and C, HIV),
- •Patients with a positive HIV and/or Hepatitis B and C tests
- •Patients who have uncontrolled concomitant bacterial or viral infections (unresolved during screening), mycosis and/or parasitosis,
- •Patients with a significant liver function impairment: enzyme (AST and/or ALT) values must not exceed 1.5 times upper limit of normal,
- •Patients with positive testing for tuberculosis (using QuantiFERON-TB test), Patients with CMV D+/R- constellation at transplant,
- •Patients with seronegative EBV prior to transplantation,
- •Patients who have previously been exposed to antibodies of swine origin,
- •Expanded Criteria Donor (ECD) defined as donor older than 60 years,
- •Participants who have participated in another research study involving an investigational product in the previous 3 months,
- •Patients with cardiovascular or severe respiratory comorbidities (severe chronic respiratory failure, severe pulmonary fibrosis, obesity-ventilation syndrome, severe idiopathic pulmonary arterial hypertension) not allowing general anesthesia,
- •Patients with type 1 diabetes,
- •Participants who are pregnant, breast feeding or planning pregnancy during the study,
- •Participants who have any form of substance abuse (drug, alcohol...), any other health abnormalities (psychiatric disorders) or condition that according to the investigator's opinion might endanger patient during his/her participation in the study.
研究组 & 干预措施
Ascending Dose Cohort
The AD cohort will be first recruited and will include 5 patients: 1 patient per dose, sequentially recruited, the recruitment of the next dose level patient will be assessed by Data Safety Monitoring Board :
- Patient 1: 0.6 mg/Kg/day
- Patient 2: 1 mg/Kg/day
- Patient 3: 3 mg/Kg/day
- Patient 4: 6 mg/Kg/day
- Patient 5: 8 mg/Kg/day
Once the 5 AD patients complete LIS1 treatment, the sponsor and the DSMB will rule on the LIS1 dose to obtain an optimal CD3+ cells depletion, with a good safety profile and will determine the therapeutic dose.
干预措施: LIS1 (Biological)
Therapeutic Dose Cohort
The TD cohort will be recruited once the therapeutic dose is defined. This cohort will be divided in 2 subgroups of respectively 2 and 3 patients sequentially recruited.
DSMB will review the safety and efficacy profile of the first 2 patients (Subgroup1) and decide:
- To continue at the same dose and recruit the next 3 patients of Subgroup 2
- To recruit the next 3 patients with a lower dose, estimated from AD as bringing efficient depletion
- To recruit the next patient with a higher dose (+2 mg/kg), if the depletion is not considered satisfactory and if the safety profile is considered acceptable
- To end the trial if LIS1 toxicity is too important vs its efficacy in CD3+ depletion.
If the decision to increase the dose after the first two TD patients is made, an additional DSMB review will be planned after patient 8. The DSMB will decide to maintain the dose for the last 2 patients or to get back to the previous dose
干预措施: LIS1 (Biological)
结局指标
主要结局
Safety of the treatment with LIS1: Graft rejection
时间窗: up to 3 months after the transplant
Clinical safety parameters (4): Graft rejection (yes/no).
Safety of the treatment with LIS1: CRP
时间窗: up to 3 months after the transplant
Laboratory parameters (1): C-Reactive Protein (CRP, mg/L).
Pharmacodynamics (depletion of T lymphocytes) of LIS1
时间窗: up to 3 months after the transplant
Absolute T lymphocyte counts (10\^9/L).
Safety of the treatment with LIS1: Re-admission
时间窗: up to 3 months after the transplant
Clinical safety parameters (6): Re-admission after patient discharge (yes/no).
Safety of the treatment with LIS1: Infection
时间窗: up to 3 months after the transplant
Clinical safety parameters (5): Viral infections (namely Cytomegalovirus \[CMV\], BK virus) (yes/no).
Safety of the treatment with LIS1: Hospitalization
时间窗: up to 3 months after the transplant
Clinical safety parameters (7): Prolonged stay in hospital for \>4 weeks (days).
Safety of the treatment with LIS1: aPTT
时间窗: up to 3 months after the transplant
Laboratory parameters (3): activated Partial Thromboplastin Time (aPTT, seconds).
Safety of the treatment with LIS1: Body temperature
时间窗: up to 3 months after the transplant
Clinical safety parameters (3): Body temperature (Celsius degrees).
Safety of the treatment with LIS1: Complete Blood Count (CBC)
时间窗: up to 3 months after the transplant
Laboratory parameters (4): Platelets (10\^9/L), white blood cells (10\^9/L), absolute neutrophil count (10\^9/L), absolute lymphocyte count (10\^9/L), absolute monocyte count (10\^9/L), absolute eosinophil count (10\^9/L), absolute basophil count (10\^9/L).
Safety of the treatment with LIS1: Blood pressure
时间窗: up to 3 months after the transplant
Clinical safety parameters (1): Systolic and diastolic blood pressure (mm Hg).
Safety of the treatment with LIS1: Pulse rate
时间窗: up to 3 months after the transplant
Clinical safety parameters (2): Pulse rate (beats per minute \[bpm\]) .
Safety of the treatment with LIS1: LDH
时间窗: up to 3 months after the transplant
Laboratory parameters (2): Lactate Dehydrogenase (LDH, µkat/L).
次要结局
- Biology of LIS1 (1): electrolytes plasma concentration(up to 3 months after the transplant)
- Pharmacodynamics of LIS1 (2): cytokines(up to 3 months after the transplant)
- Biology of LIS1 (3): total plasma proteins(up to 3 months after the transplant)
- Immunogenicity of LIS1(up to 3 months after the transplant)
- Pharmacokinetics of LIS1 (1): swine IgG(up to 3 months after the transplant)
- Biology of LIS1 (2): urea and creatinine(up to 3 months after the transplant)
- Biology of LIS1 (4): plasmatic proteins(up to 3 months after the transplant)