Efficacy and Safety of Adjunctive IgM-enriched Immunoglobulin Therapy With a Personalized Dose Based on Serum IgM-titers vs. Standard Dose in Patients With Septic Shock. A Multicenter, Interventional, Randomized, Single-blinded, Two Arms Trial.
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 356
- 试验地点
- 1
- 主要终点
- All-cause mortality at day 28
研究概览
简要总结
In patients with septic shock, low levels of circulating immunoglobulins are common and they are kinetic, particularly of immunoglobulin M (IgM), seems to be related with clinical outcome. These observations, combined with the pivotal role of immunoglobulins on host immune response to infections, led to consider therapy with polyclonal intravenous immunoglobulins a promising option in patients with septic shock.
IgM-enriched preparations have been used since now most of all at a standard dose recommended by the producer although a more tailored approach may improve patients' outcomes.
This study hypothesizes that in patients with septic shock and low IgM immunoglobulins titers at shock onset, adjunctive treatment with a personalized dose of IgM-enriched immunoglobulins based on IgM serum titers of the patient may reduce mortality compared to a standard dose of IgM-enriched immunoglobulins. The study is designed as a multicentre, national, interventional, randomized, single-blinded, prospective, investigator-sponsored, two arms study. Patients will be randomly assigned to IgM titer-based treatment or flat treatment group in a 1:1 ratio. One group of patients will receive IgM-enriched immunoglobulins adjunctive treatment in a standard dose of 250mg/kg for 3 days. The other group will receive IgM-enriched immunoglobulins adjunctive treatment in a variable dose calculated taking note of the extent of IgM deficit, in order to achieve an IgM threshold value of 100 mg/dL or above. IgM preparation will be administered in this group up to the withdrawal of vasoactive drugs with a maximum allowed of 7 days. The confirmation of the efficacy of a tailored strategy for IgM-enriched immunoglobulin administration in reducing the mortality rate among patients with septic shock and low IgM titers will lead to a revision of the current clinical practice in the use of this adjunctive treatment.
详细描述
Rationale:
Several clinical studies have reported that serum immunoglobulins concentrations are generally low in patients with sepsis and that the level and kinetics of serum immunoglobulins, particularly immunoglobulin M (IgM), seem to be somehow related to patient outcome. Intravenous administration of immunoglobulin preparations seems to be a promising treatment option due to their pleiotropic effects on bacteria and the host response to infections.
In previous clinical experiences, IgM preparation has been mainly administered at the dosage recommended by Summary of Product Characteristics (250 mg/Kg/day for three consecutive days) regardless of the patient severity and without any adjustment based on immunoglobulins plasma concentration or other biomarkers. The recent understanding of the high heterogeneity in pathobiology led to recommend a more tailored approach in patients with sepsis by modulating therapies on the basis of specific clinical and biological markers. Therefore, nowadays the strategy of a fixed-dose should be revised.
Our study hypothesis is that a personalized administration of IgM-enriched immunoglobulin, calculated based on serum IgM-titers of the patient, will decrease mortality compared to standard IgM-enriched immunoglobulin treatment (fixed or flat dose).
Study objective:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
盲法说明
The study is conceived as single blinded: only the patients will be not aware of the group allocation.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age > 18 years;
- •Septic shock occurrence < 24 hours; septic shock is identified according to Sepsis-3 definition by a vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or greater and serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia in patients with sepsis
- •Sepsis is defined as a life threatening organ dysfunction identified as an acute change in total SOFA score ≥2 points consequent to the infection;
- •IgM-titers< 60mg/dl (or < 20% of the lower threshold value of local laboratory) within24hours from shock occurrence.
排除标准
- •Shock of uncertain diagnosis;
- •Hypersensitivity to IgM Preparation in use or its excipients;
- •Patients receiving intravenous immunoglobulins (e.g. IgG or IgM enriched preparations) for > 6 hours before enrolment;
- •Selective absolute IgA deficiency with antibodies to IgA;
- •Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available;
- •Clinical decision to withhold life-sustaining treatment or "too sick to benefit";
- •Neutrophil count <1.000/mm3;
- •Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition);
- •Patients with a known, chronic kidney dysfunction needing dialysis (creatinine ≥ 3.4 mg/dl or creatinine clearance ≤ 30 ml/min/1.73m2);
- •Body Mass Index (BMI) >40;
- •Participation in other clinical trials on adjunctive therapies for sepsis (during past 3 months);
- •Lack of withdrawal of informed consent.
研究组 & 干预措施
IgM titer-based treatment
The treatment with IgM preparation will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). The calculation of the dose is based on IgM single compartment distribution. The first dose of IgM preparation will be calculated on IgM serum concentration obtained within 24 hours after shock appearance to achieve serum titers above 100mg/dl. In the next days, the daily IgM preparation dose will be assessed individually on the basis of IgM serum titers assessment performed in the morning with the purpose of maintaining IgM serum titers above 100 mg/dl, up to discontinuation of vasoactive drugs or day 7 after enrolment. Daily, the calculated dose will be administered in 24 hours in continuous infusion with a maximum infusion rate of 0,4 ml/kg per hour (20mg/kg per hour). IgM preparation will be administered up to the withdrawal of vasoactive drugs with a maximum allowed of 7 days of therapy and a maximum dose of 350mg/Kg/day.
干预措施: IgM-enriched polyclonal immunoglobulins titer-based treatment (Drug)
IgM Flat treatment
The IgM treatment will be initiated as soon as possible after randomization (maximum allowed starting time 12h after randomization). The dose of IgM preparation will be 250mg/kg for 3 days, the dose will be administered in 24 hours in continuous infusion with a maximum infusion rate of 0,4 ml/kg (20mg/kg per hour) until reaching 250mg/kg.
干预措施: IgM-enriched polyclonal immunoglobulins Flat treatment (Drug)
结局指标
主要结局
All-cause mortality at day 28
时间窗: Day 28 from randomization
All-cause mortality at day 28, defined as the comparison of proportions of patients death for any cause at day 28 from randomization.
次要结局
- All-cause mortality at ICU discharge(ICU discharge, censored at day 28)
- All-cause mortality at hospital discharge(Hospital discharge, censored at day 90)
- Grade of organ dysfunction during ICU stay(From randomization to ICU discharge, censored at day 28)
- ICU free hours at day 28(From randomization to day 28)
- Hospital free days at day 90(From randomization to day 90)
- Ventilation free days at day 28(From randomization to day 28)
- Vasopressors free-days at day 28(From randomization to day 28)
- Antibiotic free days at day 28(From randomization to day 28)
- ICU acquired weakness(Day 7, 28 and 90 censored at hospital discharge)
- Occurrence of protocol related adverse events(From randomization to day 28)
- All-cause mortality at day 90(Day 90 from randomization)
- New organ dysfunction during ICU stay(From randomization to ICU discharge, censored at day 28)
研究者
Massimo Girardis
Professor
University of Modena and Reggio Emilia