Clinical trial NCT06439615: Baricitinib for the Lung Injury Following Spontaneous SAH
Official title: The Treatment Effect of Baricitinib for the Secondary Pulmonary Complications Following Spontaneous Subarachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Spontaneous Subarachnoid Hemorrhage
Keywords: Spontaneous subarachnoid hemorrhage
Baricitinib
Inflammation
Complications
Acute respiratory distress syndrome
Pneumonia
Outcome
Lead sponsor: Tang-Du Hospital
Sponsor class: OTHER
First posted: 2024-06-03
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The present study is a randomized, parallel control, and double-blind trial designed to assess the efficacy of baricitinib in reducing the occurrence of pulmonary complications in patients with spontaneous subarachnoid hemorrhage (SAH). The research protocol incorporates an adaptive design, allowing for modifications to key elements such as the sample size enrolled during interim analysis.

Detailed description: Subarachnoid hemorrhage (SAH) is an acute cerebrovascular disorder resulting from the rupture of intracranial vessels, primarily caused by factors such as the rupture of intracranial aneurysms (accounting for approximately 75%-80% of SAH cases), arteriovenous malformations, and abnormal vasculature.

Pulmonary complications, including pneumonia and acute respiratory distress syndrome (ARDS), frequently manifest in a significant number of subarachnoid hemorrhage (SAH) patients, significantly impacting their prognosis. The pathogenesis of these complications can be partially attributed to an exaggerated inflammatory response during the acute phase following SAH. The incidence of cerebrovascular spasm and mortality rates significantly increase in SAH patients with pulmonary complications, thereby resulting in a poorer long-term prognosis. However, the current strategy for preventing or managing pulmonary complications after SAH is not sufficiently effective.

The JAK-STAT signaling pathway, a pivotal stress-induced inflammatory cascade triggered subsequent to SAH, is characterized by its rapid response to external stimuli. Baricitinib, a JAK inhibitor developed by Eli Lilly Company, exerts significant anti-inflammatory effects in diverse pathological processes and finds extensive application in patients with rheumatoid arthritis, COVID-19, and alopecia areata. However, it remains uncertain whether early administration of baricitinib can mitigate the incidence of secondary pulmonary complications and enhance the prognosis of SAH by suppressing the exaggerated inflammatory response during the acute phase following SAH.

The current multicenter clinical trial is designed as a randomized, parallel control, and double-blind study to assess the efficacy of baricitinib in reducing pulmonary complications among patients with SAH. SAH Patients admitted to participating clinical centers with a Hunt-Hess score of Ⅲ-Ⅳ will undergo continuous screening based on predefined selection criteria. The enrolled subjects will be randomly allocated into an experimental group and a control group, receiving either Baricitinib (4mg/day for 3 days) in addition to conventional treatment or placebo in addition to conventional treatment, respectively. The primary outcome is the incidence of pneumonia within 14 days after SAH. While the secondary outcome including the incidence of ARDS and other pulmonary complications within 14 days, the incidence of serious adverse events within 14 days, the proportion of patients requiring assisted ventilation measures within 14 days, the mortality rate within 14/30/90 days, as well as the neurological outcome at 30/90 days.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 and ≤80 years old;
2. Diagnosed with spontaneous subarachnoid hemorrhage through imaging or lumbar puncture;
3. Hunt-Hess score of Ⅲ-Ⅳ;
4. Acute onset, admitted to the hospital within 24 hours of onset

Exclusion Criteria:

1. Presence of lung diseases before initiation of study treatment such as chronic obstructive emphysema, bronchiectasis, lung cancer, tuberculosis, or a history of lung surgery;
2. Presence of autoimmune diseases, immune system dysfunction, or blood system dysfunction (absolute lymphocyte count (ALC) less than 0.5×109 cells/L, absolute neutrophil count (ANC) less than 1×109 cells/L, or hemoglobin value less than 8 g/dL) before the onset of the disease;
3. Secondary SAH (such as traumatic SAH), or combined craniocerebral trauma, intraparenchymal hemorrhage, or peripheral organ trauma;
4. Evidence of fever or infection already present at the time of admission;
5. History of previous craniocerebral surgery, previous cerebral hemorrhage, craniocerebral injury, cerebral infarction, intracranial tumor, or presence of neurological dysfunction before the onset of the disease;
6. Presence of contraindications for baricitinib treatment, including severe liver damage, renal dysfunction (creatinine clearance rate \<30ml/min), hypercholesterolemia, or known drug allergies;
7. Taking JAK inhibitors or other immunosuppressive drugs before the onset of the disease;
8. Expected survival time less than 2 weeks;
9. Females who are pregnant or breastfeeding;
10. Currently participating in other interventional clinical studies;
11. Patients who refuse to sign the consent form or refuse to accept follow-up.

Primary outcomes:
measure: The incidence of pneumonia
timeFrame: up to 14 days
Secondary outcomes:
measure: The incidence of ARDS
timeFrame: up to 14 days
measure: The incidence of other pulmonary complications
timeFrame: up to 14 days
measure: The incidence of assisted ventilation measures
timeFrame: up to 14 days
measure: The incidence of Systemic Inflammatory Response Syndrome(SIRS)
timeFrame: up to 14 days
measure: Mortality rate
timeFrame: up to 90 days
measure: The incidence of serious adverse events (SAE)
timeFrame: up to 14 days
measure: The neurological functional outcome
timeFrame: up to 90 days
measure: The cognitive impairment after SAH
timeFrame: up to 90 days
Other outcomes:
Locations:
Study officials:
affiliation: Department of Neurosurgery, Tangdu Hospital
name: Yan Qu, PhD MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Robba C, Busl KM, Claassen J, Diringer MN, Helbok R, Park S, Rabinstein A, Treggiari M, Vergouwen MDI, Citerio G. Contemporary management of aneurysmal subarachnoid haemorrhage. An update for the intensivist. Intensive Care Med. 2024 May;50(5):646-664. doi: 10.1007/s00134-024-07387-7. Epub 2024 Apr 10.
citation: Chai CZ, Ho UC, Kuo LT. Systemic Inflammation after Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci. 2023 Jun 30;24(13):10943. doi: 10.3390/ijms241310943.
citation: Kahn JM, Caldwell EC, Deem S, Newell DW, Heckbert SR, Rubenfeld GD. Acute lung injury in patients with subarachnoid hemorrhage: incidence, risk factors, and outcome. Crit Care Med. 2006 Jan;34(1):196-202. doi: 10.1097/01.ccm.0000194540.44020.8e.
citation: Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med. 2002 Aug;28(8):1012-23. doi: 10.1007/s00134-002-1382-7. Epub 2002 Jul 6.
citation: RECOVERY Collaborative Group. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. Lancet. 2022 Jul 30;400(10349):359-368. doi: 10.1016/S0140-6736(22)01109-6.
citation: Taylor PC, Laedermann C, Alten R, Feist E, Choy E, Haladyj E, De La Torre I, Richette P, Finckh A, Tanaka Y. A JAK Inhibitor for Treatment of Rheumatoid Arthritis: The Baricitinib Experience. J Clin Med. 2023 Jul 6;12(13):4527. doi: 10.3390/jcm12134527.
citation: Ely EW, Ramanan AV, Kartman CE, de Bono S, Liao R, Piruzeli MLB, Goldman JD, Saraiva JFK, Chakladar S, Marconi VC; COV-BARRIER Study Group. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir Med. 2022 Apr;10(4):327-336. doi: 10.1016/S2213-2600(22)00006-6. Epub 2022 Feb 3.
citation: Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich C, Rooney T, Schlichting D, Macias WL, de Bono S, Tanaka Y. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017 Feb 16;376(7):652-662. doi: 10.1056/NEJMoa1608345.