Clinical trial NCT05289700: Hyperbaric-oxygen Therapy (HBOT) Versus Placebo for Treating Vaso-Occlusive Crisis (VOC) in Sickle Cell Disease (SCD)
Official title: Multicentric, Double-blind, Randomised Controled Trial of Hyperbaric-oxygen Therapy (HBOT) Versus Placebo for Treating Vaso-Occlusive Crisis (VOC) in Sickle Cell Disease (SCD) After 8 Years Old
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Sickle Cell Disease
Hyperbaric Oxygen Therapy
Vaso-occlusive Crisis
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
Collaborators: name: University Hospital, Toulouse
name: Hospices Civils de Lyon
First posted: 2022-03-21
Enrollment: 100
Sex: ALL
Minimum age (years): 8
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Intervention is a treatment with Hyperbaric Oxygen Therapy in Hyperbaric chamber. Placebo is entry in hyperbaric chamber but without oxygen and with a minimal pression. Within 4 hrs (or at the latest 12 hrs) of their initial consultation at their hospital's ED, patients who have agreed to participate in the study will be randomised between the HBOT intervention group (2 ATA, 95 min, FIO2=1) and the placebo group (1.3 ATA, 95 min, FIO2=0.21). Patients undergo a first session (HBOT/placebo) in the hyperbaric chamber and then return to their ward.
Primary purpose: TREATMENT

Brief summary: This is a randomised, controlled, double-blind, placebo trial of HBOT (intervention) superiority in the treatment of VOC in SCD, to demonstrate the effectiveness of HBOT for the decrease in pain level in the treatment of SCD-VOC.

Detailed description: Background: Sickle cell disease (SCD) is one of the most common genetic diseases in the world, affecting approximately 310,000 births each year and causing \>100,000 deaths. Vaso-occlusive crisis (VOC) is the most frequent complication of SCD, leading to bone pain, thoracic pain and/or abdominal spasms and is the main cause of death in patients with SCD. It is linked to sickling which is often triggered by internal and external environmental conditions such as acidosis, cold, dehydration, hyperthermia, infection and especially hypoxia. Sickling is initially reversible if local oxygenation supply and conditions are improved.

Rationale: The use of hyperbaric oxygen therapy (HBOT) should enable the patient's tissues to receive the extra oxygen necessary by increasing the amount of dissolved O2 in blood which in turn would limit sickling. A pilot study of 9 patients showed the potential positive effects of HBOT on VOC induced pain. International guidelines indicate that SCD-induced VOC is one of the potential indications for HBOT, even though the evidence available is weak.

Aim and objectives: To demonstrate the analgesic effect of HBOT for VOC and to analyse the procedure's safety, impact on the biological markers of SCD-induced VOC, progression of SCD and cost-effectiveness.

Methodology: This study will be a multicentric, double-blind, randomised controlled trial. Any patient presenting at one of the participating centres' Emergency Departments (EDs) with VOC is eligible to be evaluated, included and randomized. Inclusion criteria: Patients aged 8 years or over with a major SCD, having a VOC non-responsive to level 2 analgesics (WHO classification), with or without Acute Chest Syndrome (ACS). Exclusion criteria: Pregnancy, indication for artificial ventilation, proven contraindication for HBO, blood velocity \> 200 cm/sec previously measured with transcranial Doppler, previous history of stroke, patient requiring more than 2 l/min of normobaric oxygen in order to achieve an SpO2 (peripheral oxygen saturation) ≥ 92%. Patients with exclusion criteria, although precluded from the randomisation process, will however be eligible to undergo the HBOT intervention and become part of the cohort. Measurements and procedures: In all cases, included patients will receive usual care for VOC, including hydration, analgesics (patient-controlled analgesia with morphine), normobaric oxygen therapy and where medically indicated, antibiotic therapy and/or transfusions. Within 4 to 12 hours of their initial consultation at their hospital's ED, patients who have agreed to participate in the study will be randomised between the HBOT intervention group (2 Atmosphere Absolute pressure \[ATA\], 95 min, FIO2 = 1) and the placebo group (1.3 ATA, 95 min, FIO2 = 0.21). Patients will undergo a first session in the hyperbaric chamber and then return to their ward. The second (and third) session (for both groups) will systematically take place within 24 h (max. 36 h) of the first session. If the visual analogue scale (VAS) pain score is ≤ 2 without the use of level 3 analgesics at the standard dosage, subsequent sessions will be cancelled. Difference in the visual analogue scale (VAS) pain score before and after HBOT and other outcomes will be compared between the intervention and placebo groups. A superiority of HBOT compared placebo group in VOC should be demonstrated, with decrease of pain, length of stay and cost.

Expected results and their impact: Expected benefits of HBOT are the reduction of: pain experienced, duration of the crisis, number of transfusions required, the number of morphine doses, reduction of length of stay and reduction in the frequency of ACSs and VOCs.

Eligibility criteria: Inclusion Criteria:

* Patients aged 8 or over;
* Diagnosed with a major SCD disorder (SS, SC, Hb O Arab, Sβ0 and Sβ+ -thalassemias);
* Presentation of a Vaso-Occlusive Crisis (VOC), with or without Acute Chest Syndrome,
* Unresponsive to level 2 analgesics (WHO classification)
* Which fulfils the criteria necessary for consultation at an ED;
* Ability to carry out the Valsalva manoeuvre;
* Ability to give informed consent and sign a written informed consent form (consent and signature of legal guardian authorised).

Exclusion Criteria:

* Pregnancy;
* Indication for artificial ventilation (non-invasive ventilation/oro-tracheal intubation);
* Proven contraindication for HBOT established by a physician responsible for hyperbaric medicine;
* Anomaly in the results of prior transcranial Doppler (TCD) ultrasound (\> 200 cm/sec) or a previous history of stroke (but TCD will not be performed for the study);
* Patients requiring more than 2 l/min of normobaric oxygen in order to maintain an SpO2 ≥ 92%.

Primary outcomes:
measure: Change from baseline of visual analogue scale (VAS) pain score
timeFrame: Baseline (before HBOT session ; H0) and 6th hour after the start of the HBOT session (H6)
measure: Change from baseline of a number of patients with composite outcome (VAS pain score >4 and/or mean morphine dosage > 1mg/h IV)
timeFrame: Baseline (before HBOT session ; H0) and 6th hour after the start of the HBOT session (H6)
Secondary outcomes:
measure: Change from baseline of the mean morphine dosage treatment (mg/h IV) at H6
timeFrame: Baseline (before HBOT session ; H0) and 6th hour after the start of the HBOT session (H6)
measure: Change from baseline of the mean morphine dosage treatment (mg/h IV) at H24
timeFrame: Baseline (before HBOT session ; H0) and 24th hour after the start of the HBOT session (H24)
measure: time to discontinuation of IV opioids
timeFrame: From admission date until discharge date (up to 1 month)
measure: length of hospital stay
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number of patients experiencing relief from pain (ie reduction of VAS>30%) at Hour 6
timeFrame: 6th hour after the start of the HBOT session (H6)
measure: Number of patients experiencing relief from pain (ie reduction of VAS>30%) at Hour 24
timeFrame: 24th hour after the start of the HBOT session (H24)
Other outcomes:
measure: Patient's "global impression of change"
timeFrame: 6th hour (H6) and 24th hour (H24) after the start of the HBOT session
measure: time until end of VOC (Vaso-occlusive crisis)
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number of transfusion therapies during hospitalization
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number and type of complications
timeFrame: From inclusion date, up to one year after baseline (HBOT session)
measure: Lactate Dehydrogenase dosage in blood sample
timeFrame: From admission date until discharge date (up to 1 month)
measure: C-reactive protein (CRP) in blood sample
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number of patients with readiness discharge
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number of new hospitalisations
timeFrame: During one year after hospitalisation
measure: treatment costs
timeFrame: From admission date until discharge date (up to 1 month)
measure: Number of patients with death
timeFrame: During one year after hospitalisation
Locations:
city: Lyon
country: France
facility: Hospices civils de Lyon
city: Toulouse
country: France
facility: Centre de compétences Sd drépanocytaires
city: Geneva
country: Switzerland
facility: HUG
Study officials:
References: