Human Recombinant Interferon Gamma-1b for the Prevention of Hospital-acquired Pneumonia in Critically Ill Patients: a Double-blind, International, Phase 2, Randomized, Placebo-controlled Trial - the PREV-HAP Study
试验速览
- 阶段
- 2 期
- 入组人数
- 109
- 试验地点
- 18
- 主要终点
- To demonstrate the efficiency of rHuIFN-γ for the prevention of hospital-acquired pneumonia
研究概览
简要总结
PREV-HAP study is part of a larger project entitled 'Host-targeted Approaches for the Prevention and the treatment of Hospital-Acquired Pneumonia' (HAP2), funded by the European Union's H2020 research and innovation programme under grant agreement N°847782. HAP2 aims to develop stratified host-directed drugs and biomarkers to enhance the prevention and the treatment of HAP and develop precision medicine in infectious diseases. Its ambition is to revolutionize the management of HAP: capitalising on the novel concept of critical-illness related immunosuppression altering the host-pathogens interactions, the aim is to propose a complete reappraisal of the physiopathology of HAP based on the concept of respiratory dysbiosis.
The main hypothesis of the PREV-HAP study is that human recombinant Interferon gamma 1b (rHuIFN-γ, Imukin) treatment can restore immunity in critically ill patients and prevent Hospital-Acquired Pneumonia.
The hypothesesis is that the in vivo investigations of the host-pathogens interactions can be used for the stratification of patients into high/low risk and responders/non-responders to host-targeted prevention of hospital-acquired infections.
The involvement of a state of critical-illness related immunosuppression in the susceptibility to hospital-acquired pneumonia is widely accepted, and an emerging trend is that the development of drugs for the treatment of this acquired immunosuppression will prevent infection and enhance outcomes of hospitalized patients.
It has been demonstrated that the productions of IFN-γ by immune cells are decreased in critically ill patients, and that these defects are associated with the susceptibility to HAP. rHuIFN-γ has neither been tested nor is recommended as adjunctive treatment of patients with HAP. Based on these specific factors identified in the host response, it is proposed in this study to use rHuIFN-γ as novel preventive approach for HAP.
详细描述
200 adult patients hospitalized in intensive care units, under mechanical ventilation in three European countries will be included in the trial, and will be randomized in 2 arms :
Arm 1 (rHu-IFNγ):
• Recombinant Interferon gamma 1b (IMUKIN®, from Clinigen®): 100 µg/0,5ml subcutaneous injections from day 1 to day 9 (5 injections, i.e. 1 injection of 100 µg every 48h),
Arm 2 (Placebo):
• Recombinant Interferon gamma 1b placebo: 5 subcutaneous injections from day 1 to day 9 (i.e. 1 injection of 0,5ml every 48h).
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patients (18yr to 85yr).
- •Hospitalized in intensive care unit for less than 48 hours.
- •Receiving invasive mechanical ventilation at the time of inclusion.
- •One or more acute organ failure at the time of inclusion among: neurological (Glasgow coma scale <13 before sedation), hemodynamic (norepinephrine, epinephrine, or any other vasopressor at a dose of ≥ 0.1 μg per kilogram of body weight per minute or ≥0.5 mg per hour for at least 6 hours), respiratory (PaO2 / FiO2< 200) and/or renal (creatininemia > 2 fold higher than the basal value and/or oliguria < 0.5 mL/kg/hour for at less 12 hours).
- •Informed consent from a legal representative, or emergency procedure (when possible according to national regulation, see below). As is not possible to obtain the patient consent prior the inclusion (comatose patients), patient consent for the study continuation will be obtained as soon as deemed possible.
- •Person insured under a health insurance scheme.
排除标准
- •Pregnant women (serum or urine test), breastfeeding women
- •Patient under legal protection (incl. under guardianship or trusteeship)
- •Hypersensitivity to the active substance (interferon gamma-1b) or known hypersensitivity to related products, such as another interferon, or to any of the following excipients: Mannitol, Disodium succinate hexahydrate, Succinic acid, Polysorbate 20
- •Severe hepatic insufficiency ( Child Pugh score B or C)
- •Liver cytolysis with hepatic enzymes (AST and/or ALT) > 5N
- •Severe chronic renal insufficiency (MDRD Creatinine Clearance < 10 ml/min/1.73m2)
- •Immunosuppression (hematologic cancer, aplasia, chemotherapy/radiotherapy for cancer within 3 months prior to the inclusion, known infection Human immunodeficiency virus, concomitant use of any anti-graft rejection drug).
- •Coma after resuscitated cardiac arrest
- •Cervical spinal cord injury
- •Participation to a drug interventional study within 1 month prior to the inclusion
- •Hospital-acquired pneumonia before inclusion in the study during the current hospitalization.
- •Sustained hyperlactatemia > 5 mmol/L.
研究组 & 干预措施
Recombinant Interferon gamma 1b (IMUKIN®)
干预措施: Recombinant Interferon gamma 1b (IMUKIN®) (Drug)
Recombinant Interferon gamma 1b placebo
干预措施: Recombinant Interferon gamma 1b placebo (Drug)
结局指标
主要结局
To demonstrate the efficiency of rHuIFN-γ for the prevention of hospital-acquired pneumonia
时间窗: Day 28
Rate of the composite outcome at day 28 made of at least one item among the following: all cause mortality and/or hospital-acquired pneumonia
次要结局
- All-cause mortality [efficiency of rHu-IFN-γ, on pneumonia-associated morbidity and mortality reduction](Day 28 and Day 90)
- Rate of HAP [efficiency](Day 28)
- Bacterial ecology of the 1st episode of HAP [efficiency](Day 28)
- Rate of ventilator-associated tracheobronchitis [efficiency](Day 28)
- Occurence of Acute Respiratory Distress Syndrome [efficiency](Day 28)
- Duration of antimicrobial therapy [efficiency](Day 28)
- Duration of mechanical ventilation [efficiency](Day 90)
- Duration of ICU hospitalization [efficiency](Day 90)
- Rate of SAEs and SUSARs [tolerance](Day 15)
- Rate of leukocytosis [tolerance](Day 15)
- Rate of neutropenia [tolerance](Day 15)
- Rate of lymphopenia [tolerance](Day 15)
- Rate of thrombopenia [tolerance](Day 15)
- Rate of liver cytolysis [tolerance](Day 15)
- Rate of pancreatitis [tolerance](Day 15)
- Rate of patients with episode of fever [tolerance](Day 15)
- Rate of patients with episode of headache [tolerance](Day 15)
- Rate of patients with episode of nausea [tolerance](Day 15)
- Rate of allergic reaction [tolerance](Day 15)
- Incidence of injection site reaction [tolerance](Day 15)
- Rate of myalgia [tolerance](Day 15)
- Rate of arthralgia [tolerance](Day 15)
- Rate of back pain [tolerance](Day 15)
- Economic efficiency of rHu-IFN-γ in the prevention of pneumonia(Day 90)
- To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using The Short Form (36) Health Survey(Day 90)
- To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using the Hospital Anxiety and Depression scale (HADS)(Day 90)
- To determine the suitability of rHu-IFN-γ from the patients' and relatives' perspectives using Satisfaction With Life Scale (SWLS)(Day 90)
- To determine the acceptability of rHu-IFN-γ from the patients' and relatives' perspectives(Day 90)