A Multicentre, Prospective, Randomized, Multi-arm, Multi-stage Clinical Trial of High-flow Oxygen for Vaso-occlusive Pain Crisis in Adult Patients With Sickle Cell Disease;
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 350
- 试验地点
- 2
- 主要终点
- Rate of vaso-occlusive pain crisis (VOC) resolution without complication (Activity stage)
研究概览
简要总结
Sickle cell disease (SCD) is characterized by recurrent vaso-occlusive pain crisis (VOC), which may evolve to acute chest syndrome (ACS), the most common cause of death among adult patients with SCD. Currently, there is no safe and effective treatment to abort VOC or prevent secondary ACS. Management of VOC mostly involve a symptomatic approach including hydration, analgesics, transfusion, and incentive spirometry, which was investigated in a very limited number of patients (<30).
The polymerisation of HbS is one major feature in the pathogenesis of vaso-occlusion. Among factors determining the rate and extent of HbS polymer formation, the hypoxic stimulus is one of the most potent and readily alterable. Current guidelines recommend oxygen therapy in patients with VOC in order to maintain a target oxygen saturation of 95%. Low-flow nasal oxygen (LFNO) is routinely used to achieve this normoxia approach, particularly in patients at risk of secondary ACS because they may experience acute desaturation. In contrast, various case series suggest a potential beneficial role of intensified oxygen therapy targeting hyperoxia for the management of VOC, particularly with the use of hyperbaric oxygen, but the latter is difficult to implement in routine clinical practice.
A recent high-flow nasal oxygen (HFNO) technology allows the delivery of humidified gas at high fraction of inspired oxygen (FiO2) through nasal cannula. The FiO2 can be adjusted up to 100% (allowing hyperoxia that may reverse sickling) and the flow can be increased up to 60 L/min (which generates positive airway pressure and dead space flushing, that may prevent evolution of VOC towards ACS by alleviating atelectasis and opioid-induced hypercapnia). In patients with acute respiratory failure, HFNO has been shown to improve patient's comfort, oxygenation, and survival as compared to standard oxygen or non-invasive ventilation.
The aim of the present study is to test the efficacy and safety of HFNO for the management of VOC and prevention of secondary ACS. The investigators will use a multi-arm multi-stage (MAMS) design to achieve these goals. HFNO will be delivered through AIRVO 2 (Fisher and Paykel Healthcare, New Zealand), a device that incorporates a turbine allowing its use in hospital wards.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
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;
- •Patient with major sickle cell disease syndrome (SS, SC, Sβ0 or Sβ+);
- •VOC as defined by acute pain or tenderness, affecting at least one part of the body, including limbs, ribs, sternum, head (skull), spine, and/or pelvis, that requires opioids and is not attributable to other causes;
- •Intermediate-to-high risk for secondary ACS derived from the PRESEV score (Bartolucci et al, EBioMedicine 2016) as follows: a reticulocyte count >216 G/L OR at least two of the followings : i) spine and/or pelvis CPS >1; ii) leucocyte count >11G/L; iii) hemoglobin ≤ 9 g/dL; in case of long-term treatment by hydroxyurea, only one of the above mentioned criteria will be needed, given its effects on hemoglobin, leucocyte and reticulocytes counts;
- •Informed consent;
- •Patient affiliated to social security
排除标准
- •The presence at inclusion of a primary ACS. Primary ACS is defined by the combination at time of randomization of a clinical sign [chest pain or auscultatory abnormality (crepitants and/or bronchial breathing)] with a new pulmonary infiltrate (on chest film, thoracic scan, or lung ultrasound);
- •VOC with need of parenteral opioids lasting longer than 72 hours at time of inclusion;
- •Known pregnancy or current lactation; Women of child bearing potential will be tested for pregnancy before inclusion;
- •Known cerebral vasculopathy or past medical history of stroke, due to Moya Moya or persisting visible macrovessel stenosis/occlusion;
- •Known ischemic heart disease or typical chest angina;
- •Patient who is currently enrolled in other investigational drug study;
- •Known legal incapacity,
- •Prisoners or subjects who are involuntarily incarcerated
- •Anatomical factors precluding placement of a nasal cannula
结局指标
主要结局
Rate of vaso-occlusive pain crisis (VOC) resolution without complication (Activity stage)
时间窗: Day 5
VOC will be considered terminated when at least 3 of the following 4 criteria are met at two consecutive assessments: i) absence of fever for 8 hours; ii) absence of pain progression and no requirement of intravenous infusion of opioid analgesics for the last 8 hours; iii) the patient is able to walk or move without pain; iv) absence of spontaneous pain with a CPS (categorical pain score) of 1 or less
Rate of secondary acute chest syndrome (ACS)(Efficacy Stage)
时间窗: Day 14
Defined as the proportion of patients with secondary ACS during the 14 days following randomization. Secondary ACS is defined as the combination after randomization of a clinical sign \[chest pain or auscultatory abnormality (crepitants and/or bronchial breathing)\] with a new pulmonary infiltrate (on chest film, thoracic scan, or lung ultrasound).
Rate of cardiac and neurologic related events (Pilot Stage)
时间窗: At the end end of the "pilot stage" and up to 28 days
This endpoint will be assessed at the end of the "pilot stage" and throughout the entire study for cumulative safety information. Research arms will only continue to recruitment in the next stage if they have been shown to be both safe (\<5 cardiac or neurologic related events, in the arm during the pilot phase as defined by one of the following: acute coronary syndrome, acute ischemic stroke, or seizure) and feasible (\<8 definitive discontinuations before day-2 due to patient's intolerance), although patient data from all patients and all stages will be included in the final analyses.
次要结局
- VOC duration(Day-14)
- Pain intensity evaluated by visual analogue scale(Between day-1 (randomization) and day-14)
- Reticulocyte count(Day-2 and Day-5)
- Cumulative doses of intravenous and subcutaneous opioids(Between day-1 (randomization) and day-14)
- Number of complicated VOC(Day-14)
- Pain intensity evaluated by categorical pain score(Between day-1 (randomization) and day-14)
- VOC-free days(Day-14)
- Duration of hospital stay(Day-28)
- Number of re-hospitalizations or emergency department consultations for VOC or ACS(Up to 28 days)
- Volume of transfused red blood cells and volume of exsanguinated blood(Between day-1 (randomization) and day-14)
- Number of death (Mortality)(Day-28)
- Arterial blood gas(Up to 24 hours)