A Randomized Placebo-controlled Safety and Dose-finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 178
- 试验地点
- 3
- 主要终点
- Ventilator Free Survival
研究概览
简要总结
In this study invetigators propose to administer clazakizumab to patients with life-threatening COVID-19 infection manifest by pulmonary failure and a clinical picture consistent with a cytokine storm syndrome. This is a double-blinded randomized multi-center trial designed as a phase II dose-finding three arm trial with seamless adaptive transition to a phase III efficacy trial. For phase II, patients were randomized 1:1:1 ratio to three study arms and received clazakizumab at a dose of 12.5 mg, 25 mg or placebo.
Based on interim analysis, the low dose arm was dropped and the phase III portion of the study continued to enroll patients randomized 1:1 to high dose clazakizumab or placebo.
Based on interim analysis, the remaining 10 subjects at NYU will be randomly assigned to a 1:1 ratio to two arms that will receive clazakizumab at a dose of 25 mg or placebo. The NYU site will serve as the central data management site for other centers who undertake this protocol. Other sites will enroll patients based on the two arm 1:1 randomization. 60 patients at outside sites are expected to enroll.
详细描述
The limited understanding of the clinical behavior of patients infected with SARS-CoV-2 (the viral organism responsible for COVID-19 disease) is evolving on a daily basis. Reports from China indicate that a subset of patients with the worst clinical outcomes may manifest cytokine storm syndrome. Hypotheses that excess cytokines may trigger a secondary hemophagocytic lymphhistiocytosis (sHLH) have been proposed. Indeed, cytokine profiles consistent with this picture were observed in Chinese patients with severe pulmonary involvement. Specifically, elevated ferritin and interleukin-6 (IL-6) were associated with fatalities among the infected patients. A role for targeted anti-inflammatory and anti-cytokine therapies in the treatment of pulmonary hyperinflammation has been proposed.
Clazakizumab is a genetically engineered humanized IgG1 monoclonal antibody (mAb) that binds with high affinity to human IL-6. This investigational agent is currently being studied as a treatment for chronic active antibody mediated rejection of renal allografts.
In this study investigators propose to administer clazakizumab to patients with life-threatening pulmonary failure secondary to COVID-19 disease.
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
- Double (Participant, Investigator)
盲法说明
This study is double-blind and therefore neither the Investigator, the subject, the Sponsor and its representatives, nor other designated study site personnel involved in running of the study will be aware of the identification of the investigational drug administered to each subject.
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
- •In order to be eligible to participate in this study, the patients must meet all of the following criteria:
- •At least 18 years of age
- •Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time RT-PCR using nasopharyngeal swab sample, or equivalent test available to be performed by the NYU Langone clinical laboratory). Effort will be made to have the confirmatory test result <72 hours prior to enrollment however given overall clinical demand this may not be feasible in all cases.
- •Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a P/F ratio of <200), OR SpO2 < 90% on 4L (actual or expected given higher O2 requirement) OR increasing O2 requirements over 24 hours, PLUS 2 or more of the following predictors for severe disease:
- •CRP > 35 mg/L Ferritin > 500 ng/mL D-dimer > 1000 mg/mL Neutrophil-Lymphocyte Ratio > 4 LDH > 200 U/L Increase in troponin in patient w/out known cardiac disease
- •Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient.)
- •Women of childbearing potential must be willing and able to use at least one highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as:
- •combined (estrogen and progestogen containing) hormonal contraception combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal)
- •progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
- •intrauterine device (IUD)
- •intrauterine hormone-releasing system (IUS)
- •vasectomized partner
- •bilateral tubal occlusion
- •true abstinence. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception.
- •Men must be willing to use a double-barrier contraception from enrollment until at 5 months after the last dose of study drug, if not abstinent.
排除标准
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Evidence of irreversible injury deemed non-survivable even if the pulmonary failure recovers (for example severe anoxic brain injury)
- •Known active inflammatory bowel disease
- •Known active, untreated diverticulitis
- •Known untreated bacteremia
- •Pregnancy. (The protocol will exclude pregnant subjects given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study subjects be excluded on this basis).
- •Known hypersensitivity to the clazakizumab
研究组 & 干预措施
Clazakizumab 25 mg
干预措施: Clazakizumab 25 mg (Drug)
Clazakizumab 12.5 mg
干预措施: Clazakizumab 12.5 mg (Drug)
Placebo
干预措施: Placebo (Other)
结局指标
主要结局
Ventilator Free Survival
时间窗: 28 days
Ventilator Free Survival is defined as the total number of patients who were alive and ventilator free at 28 days.
Number of Serious Adverse Events Associated With High and Low Dose of Clazakizumab
时间窗: 60 days
次要结局
- Number of Clazakizumab-expected Adverse Events(60 days)
- Overall Patient Survival(60 days)
- Number of Participants With Change in Clinical Status(28 days)
- Number of Participants With a Change in Clinical Status(60 days)