A Phase 2, Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Repertaxin in the Prevention of Primary Graft Dysfunction After Lung Transplantation
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 114
- 试验地点
- 6
- 主要终点
- PaO2/FiO2 Ratio at ICU Admission (Time 0) and 24 Hours
研究概览
简要总结
The objective of this clinical study was to evaluate whether CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) inhibition with repertaxin leads to reduced severity of primary graft dysfunction, as the result of improved functional and clinical outcomes in lung transplantation patients.
The safety of repertaxin in the specific clinical setting was also evaluated.
The ability of repertaxin to reduce target cells (polymorphonuclear leukocyte [PMN]) infiltration into the graft was evaluated to confirm its mechanism of action.
详细描述
This was a phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-group (two arms) study.
A total of 100 patients accepted and listed for lung transplantation, who met all of the study inclusion and none of the exclusion criteria described in Sections 9.3.1 and 9.3.2 of this report, were planned to be enrolled in the study. These patients were randomly assigned in a 1:1 ratio to receive either repertaxin or placebo, by continuous intravenous infusion for a period of 48 hours to start approximately 2 hours before reperfusion of the (first) transplanted lung occurred.
The experimental treatment was additional to the standard treatment of lung transplant recipients.
An initial 'loading dose' of repertaxin of 4.488 mg/kg body weight/hour was to be administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.
Placebo was to be volume matched saline. Total infusion volume was not to exceed 500 mL/24 hours. Study medication was to be provided as clear glass class I ampoules, each containing 10 mL of the following products: repertaxin (33 mg/mL aqueous injectable solution) and placebo (9 mg/mL aqueous injectable solution of NaCl).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
盲法说明
All personnel involved and patients participating in the study were to remain blinded to the patient randomization codes with the exception of those involved in packaging and labelling the study medication. After the database lock of data recorded in the main part of the study, corresponding to the Month 1 follow-up visit of the last patient in, the blind code was broken and the study continued in an open fashion.
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
- •Patients accepted and listed for transplantation due to irreversible, progressive disabling, end-stage pulmonary disease;
- •Ages 18 to 65 years;
- •Body weight 30 to 95 kg (inclusive) (i.e. up to 95.99 kg);
- •Planned isolated (single and bi-lateral) lung transplant from a non-living donor with brain death. This included lobar lung transplant involving excision and sizing of a cadaver donor lobe to meet the thoracic dimension of the recipient before being transplanted;
- •Normal renal function at the time of transplant as per calculated creatinine clearance (Clcr) 60 mL/min. Creatinine clearance was calculated according to the Cockcroft-Gault formula;
- •Patient was willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations;
- •Patient gave written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent could be withdrawn by the patient at any time without prejudice to their future medical care.
排除标准
- •Recipients of an intended multiple organ transplant, including heart-lung and liver-lung transplantation;
- •Recipients of a lung from a living lobar donor;
- •Recipients of a lung from a non-heart beating donor;
- •Re-do lung transplantation;
- •Recipients requiring mechanical ventilation at the time of transplant;
- •Recipients with an extra-respiratory tract site of infection (positive blood culture(s) and/or fever associated with other signs of systemic sepsis syndrome). The criterion was not meant to exclude bacteraemic cystic fibrosis patients with or without fever, unless they presented with other signs of sepsis;
- •Recipients with hepatic dysfunction (bilirubin exceeding 3 mg/dL and/or transaminases >3X upper limit of normal [ULN]) at the time of transplant;
- •Hypersensitivity to:
- •Ibuprofen or to more than one non steroidal anti-inflammatory drug (NSAID);
- •Medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib;
- •Patients simultaneously participating in any other studies involving a study drug to be administered concomitantly with the investigational product and/or a study drug intended to prevent ischemia/reperfusion injury;
- •Planned use of anli-CD3 monoclonal antibody (Orthoclone OKT3) or alemtuzumab (Campath) induction immunosuppression;
- •Planned use of sirolimus in the first 3 months after transplantation;
- •Pregnant or breast-feeding women (NB: pregnancy was lo be avoided in patients or partners during the first month of participation in the study; no other specific warnings were described, considering even stricter general recommendations concerning pregnancy in transplanted patients, the treatment course of the investigational product, its pharmacokinetic profile, and the lack of significant adverse effects on mating performance and fertility in animal studies).
研究组 & 干预措施
Repertaxin
Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. Each ampoule contained 10 mL of either repertaxin or placebo.The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. An initial 'loading dose' of Repertaxin of 4.488 mg/kg body weight/hour was administered over 30 minutes followed by a maintenance dose of 2.772 mg/kg body weight/hour lasting 47.5 hours.The loading and maintenance doses were administered using the same dosing solution (Repertaxin 12.65 mg/ml), but with the pump rate altered to provide an infusion rate of approximately 0.35 mUkg/hour and 0.22 ml/kg/hour, respectively.
干预措施: Repertaxin (Drug)
Placebo
Both repertaxin and placebo were aqueous solutions packaged into identical clear glass Type I ampoule single dose units. The dosing solution for infusion was prepared aseptically at the designated Pharmacy within each center and dispensed as 12.65 mg/mL solution in appropriate size infusion bags. ampoule contained 10 mL of either repertaxin or placebo. An initial 'loading dose' of 9 mg/ml sodium chloride (NaCl) solution was administered over 30 minutes, followed by a maintenance dose lasting 47.5 hours.
干预措施: Placebo (Other)
结局指标
主要结局
PaO2/FiO2 Ratio at ICU Admission (Time 0) and 24 Hours
时间窗: At T0 (time of ICU admission) and 24 hours post-ICU admission
The PaO2/FiO2 ratio was calculated to assess the severity of hypoxemia, or low blood oxygen levels. A low PaO2/FiO2 value has been associated with increased mortality and hospital stay in patients admitted to the intensive care unit (ICU). It was calculated by dividing the partial pressure of oxygen in arterial blood (PaO2) by the fraction of inspired oxygen (FiO2). A normal P/F ratio was typically above 300, and a lower ratio indicates a greater severity of hypoxemia. As the Pa02/Fi02 ratio was dependent on altitude, data were corrected for altitude in the analyses of corrected data. The correction factor is defined as (Pressure at Denver)/(Pressure at sea level) = 633/760 = 0.8329; PaO2 values were corrected as follows: Corrected value = measured value/0.8329
次要结局
- PaO2/FiO2 Ratio (ICU Admission Then 24 Hours up to Extubation or up to 72 Hours)(At ICU admission (T0), 24, 48 and 72 hours post-ICU admission)
- Number of Patients With Different Primary Graft Dysfunction (PGD) Scores (0-3, and Missing Data)(At ICU admission (T0), 24, 48 and 72 hours post-ICU admission)
- Time to Freedom From Mechanical Ventilation(At 24, 48, 72 hours post ICU admission)
- Probability of Death During Intensive Care Unit (ICU) Stay at Different Timepoints(At 24, 48, 72 hours post ICU admission)
- Number of Patients Dead Within 30 Days Post-transplant(Up to 30 days post-transplant)
- Pulmonary Function Tests (FEV1=Forced Expiratory Volume in One Second and FVC=Forced Vital Capacity) at Month 1, 6 and 12 Post-transplant Evaluated According to Estenne et al.(2002).(At months 1, 6 and 12 post-transplant)
- Number of Patients With Different Bronchiolitis Obliterans Syndrome (BOS) Scores (0-3) Assessed at Months 6 and 12 Post-transplant(At Months 6 and 12 post-transplant)
- Number of Patients With at Least One Acute Rejection Episode at Months 1, 6 and 12 Post-transplant(At months 1, 6 and 12 post-transplant)
- Patient Survival up to 12 Months Post-transplant(at Months 3, 6, 9 and 12 post-transplant)
- Number of Patients With at Least One Adverse Events Within the First Month(to month 1)
- Number of Patients With at Least One Adverse Events From Month 1 to Month 12(from month 1 to month 12)