Clinical trial NCT03976180: High-flow Oxygen for Vaso-occlusive Pain Crisis
Official title: 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;
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease
vaso-occlusive pain crisis
HFNO
ACS
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Fisher and Paykel Healthcare
name: Orkyn'
First posted: 2019-06-05
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a comparative randomized controlled superiority open-label multi-arm multi-stage (MAMS) trial. The study will use a multi-arm multi-stage (MAMS) trial design with three stages and four arms (one control arm and three intervention arms).

* "Pilot" stage: a formal safety/feasibility testing. Research arms will only continue to recruitment in the next stage if they have been shown to be both safe and feasible, although patient data from all patients and all stages will be included in the final analyses.
* "Activity" stage: an interim comparison of activity using the rate of VOC resolution without complication at day-5 as primary endpoint. At the end of this stage, an interim analysis will be used in order to select the most promising experimental treatment and compare it to control in the subsequent stage ("pick the winner" strategy).
* "Efficacy" stage: final comparison with secondary ACS at day-14 as the primary endpoint.
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* 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;
* Informed consent;
* Patient affiliated to social security

Exclusion Criteria:

* The presence at inclusion of a primary ACS. Primary ACS is defined by the combination at time of inclusion 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 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;
* Chronic transfusion program;
* Known cerebral vasculopathy or past medical history of stroke;
* Known ischemic heart disease or typical chest angina;
* Patient who is currently enrolled in other investigational drug study;
* Previous participation in this study.
* Known legal incapacity,
* Prisoners or subjects who are involuntarily incarcerated
* Anatomical factors precluding placement of a nasal cannula

Primary outcomes:
measure: Rate of cardiac and neurologic related events (Pilot Stage)
timeFrame: At the end end of the "pilot stage" and up to 28 days
measure: Rate of vaso-occlusive pain crisis (VOC) resolution without complication (Activity stage)
timeFrame: Day 5
measure: Rate of secondary acute chest syndrome (ACS)(Efficacy Stage)
timeFrame: Day 14
Secondary outcomes:
measure: Volume of transfused red blood cells and volume of exsanguinated blood
timeFrame: Between day-1 (randomization) and day-14
measure: Pain intensity evaluated by categorical pain score
timeFrame: Between day-1 (randomization) and day-14
measure: Pain intensity evaluated by visual analogue scale
timeFrame: Between day-1 (randomization) and day-14
measure: VOC duration
timeFrame: Day-14
measure: VOC-free days
timeFrame: Day-14
measure: Reticulocyte count
timeFrame: Day-2 and Day-5
measure: Arterial blood gas
timeFrame: Up to 24 hours
measure: Cumulative doses of intravenous and subcutaneous opioids
timeFrame: Between day-1 (randomization) and day-14
measure: Number of complicated VOC
timeFrame: Day-14
measure: Duration of hospital stay
timeFrame: Day-28
measure: Number of re-hospitalizations or emergency department consultations for VOC or ACS
timeFrame: Up to 28 days
measure: Number of death (Mortality)
timeFrame: Day-28
Other outcomes:
Locations:
city: Créteil
country: France
facility: Henri Mondor
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Armand Mekontso
role: STUDY_CHAIR
References: