A Pilot, Open Label, Phase II Clinical Trial of Nebulised Recombinant Tissue-Plasminogen Activator (Rt-PA)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 35
- 试验地点
- 1
- 主要终点
- Efficacy - PaO2/FiO2 Ratio
研究概览
简要总结
Some patients infected with COVID-19 develop a severe form of a lung disease called acute respiratory distress syndrome (ARDS). In these patients, the lungs become severely inflamed because of the virus. The inflammation causes fluid from nearby blood vessels to leak into the tiny air sacs in the lungs, making breathing increasingly difficult. This fluid forms small clots in the air sacs. In some patients, these clots do not disappear in a timely fashion. Furthermore, the small clots in the air sacs obstruct the air and oxygen getting deep into the lungs, interfering with ventilation. The trial recruited patients with COVID-19 induced ARDS. Eligible patients (or if patients lack capacity, their legal representative) were provided with an information sheet and informed consent was sought. Eligibility was mainly assessed via routine clinical assessments. Patients received a nebulised version of a type of drug called tissue plasminogen activator (rt-PA) that was inhaled using a nebuliser. This is normally a drug used to break down blood clots. In the nebulised form, we hypothesised that it may be useful for stopping clots forming in the lungs. The study ran two cohorts sequentially. In cohort 1, 9 consented patients received nebulised rtPA in addition to SOC. As an observational arm, matched historical controls who received SOC were also recruited at a ratio of 2 controls to every 1 treatment arm patient, resulting in 18 historical controls. After the first wave of COVID-19 cases decreased in August 2020 in the UK, it became difficult to continue recruiting, so recruitment was closed for cohort 1. With a second surge in early 2021, cohort 2 opened with the aim to recruit more patients to provide more data on the safety of rt-PA. In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment without compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised. 26 patients were recruited in total, 12 in the IMV arm and 14 in the NIV/NIRS arm. To evaluate drug efficacy, the improvement of oxygen levels over time and safety were monitored throughout. Blood samples were taken to measure markers of clotting and inflammation in both cohorts. From the end of the treatment phase, both groups were followed up in accordance with SOC up to a maximum of 28 days, starting from the day of first dose of rt-PA.
详细描述
This is a phase II, open label, uncontrolled, repeated dose, pilot trial of nebulised rt-PA in patients with COVID-19 ARDS.
The study recruited patients requiring either invasive mechanical ventilation (IMV) or non-invasive ventilation/non-invasive respiratory support (NIV/NIRS) between April 2020 and February 2021. Eligible patients (or if patients lacked capacity, their legal representative) were provided with an information sheet and informed consent was sought. Eligibility was assessed via routine clinical assessments, which may have been done prior to consent. The only exceptions were pregnancy tests (blood or urine), and possibly any assessments that were not done as per routine care. If required, these would have been done following consent, and all screening assessments must have been done during the 24-hour period before dosing with rt-PA.
In the rt-PA treatment group of cohort 1, 9 consented patients received nebulised rt-PA in addition to standard of care (SOC). Out of the 9 patients, 6 were on the IMV arm and another 3 were on the NIV arm. As an observational arm, matched historical controls who received only SOC were also recruited at a ratio of 2 controls to every 1 treatment arm patient, to ensure that any changes were not entirely due to disease resolution. A total of 18 patients were recruited to the historical matched control arm of cohort 1. Therefore a total of 27 patient constituted cohort 1.
For patients in the treatment group, 10 mg of rt-PA dissolved in 5 ml of diluent was given every 6 hrs for 3 days. This was extended to up to 14 days with a subsequent protocol amendment. Dose modifications were not permitted. Efficacy was described as the change in PaO2/FiO2 ratio from baseline, daily during treatment, end of treatment, 3 days post end of treatment and 5 days post end of treatment.
With a second surge of COVID-19 in early 2021, cohort 2 was opened to recruit more patients to provide additional data on the safety of rt-PA. Fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rt-PA was utilised. Patients on IMV received 60mg daily over three doses for up to 14 days. NIV patients received 60mg daily over 3 doses for two days, followed by 40mg daily over two doses for up to 12 days. A total of 26 patients were recruited in cohort 2, 12 on the IMV arm and 14 on the NIV/NIRS arm.
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
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 1
Patients in the rt-PA group received the first dose as soon as possible after registration.
Initial dosing regime: 10 mg of rt-PA dissolved in 5 ml of diluent given every 6 hrs (resulting in a total daily dose of 40mg) for a maximum of 66 hrs, in addition to standard of care for COVID-19 acute respiratory distress syndrome (ARDS). Following protocol amendment, dosing duration was increased from 3 days to up to 14 days of rt-PA treatment. Six patients were receiving Invasive mechanical ventilation and 3 were receiving non-invasive ventilation.
干预措施: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 1 (Drug)
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 IMV
In cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised.
Patients on IMV received 60mg daily over three doses for up to 14 days
干预措施: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 IMV (Drug)
Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - cohort 2 NIV
n cohort 2, fewer timepoints were collected, which allowed for more rapid recruitment while at the same time not compromising safety monitoring. A more flexible dosing regimen for rtPA was utilised.
Patients on NIV received 60mg daily for over 3 doses for two days, followed by 12 days receiving 40mg daily over two doses.
干预措施: Nebulised recombinant tissue-Plasminogen Activator (rt-PA) - Cohort 2 NIV (Drug)
结局指标
主要结局
Efficacy - PaO2/FiO2 Ratio
时间窗: Day 14 and last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days)
PaO2/FiO2 measured at multiple timepoints: baseline, during treatment, end of treatment, 3 days post end of treatment and 5 days post end of treatment. For Cohort 1, all available values were extracted per day and summarised every 4 hours (± 2h). For Cohort 2, up to six values were extracted per days including the worst ratio over the preceding day; Cohort 2 included only the lowest value for the day. PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure to fractional inspired oxygen. It is a widely used clinical indicator of hypoxaemia and is used to classify severity of acute respiratory distress syndrome. Limited data was observed due to patient discharge or death: Day 14 is presented below, and the last value available on treatment regardless of the duration of treatment (death or discharge may have occurred within 14 days) was summarised post-hoc. Summarized values were rounded to the nearest integer.
Safety- Participants With Major Bleeding Events Directly Attributable to Study Drug
时间窗: 28 days
Number of patients with major bleeding events assessed as related to the study drug summarised in each group.
Safety- Participants With Serious Adverse Events Causally Related to Treatment
时间窗: 28 days
Number of Participants with serious adverse events causally related to treatment. Adverse events (other than bleeding events) were not recorded in the study.
Safety- Participants With Decrease in Fibrinogen Levels to < 1gm/L
时间窗: 28 days
Number of participants with a decrease in fibrinogen levels to \< 1gm/L during the treatment period and 48 hours after the last dose.
次要结局
- Clinical Status as Determined by a 7-point WHO Ordinal Scale(Day 28)
- Number of Days of New Mechanical Ventilation Use During in the First 28 Days(28 days)
- Lung Compliance(Last value available on treatment (which could occur up to 14 days, death or discharge may have occurred within 14 days))
- Sequential Organ Failure Assessment (SOFA) Score(28 days (day 14 presented))
- Number of Oxygenation Free Days(up to 28 days or death or discharge, whichever occurred first)
- Number of Ventilator Free Days(up to 28 days or death or discharge, whichever occured first)
- Intensive Care Stay(28 days)
- Number of Days of Non-invasive Ventilation Use(Day 28)
- In-hospital Mortality(28 days)