A randomized, placebo-controlled, double-blind clinical trial evaluating the safety and efficacy of parecoxib in hospitalized patients with spontaneous subarachnoid hemorrhage
- Conditions
- spontaneous subarachnoid hemorrhage
- Interventions
- Drug: Placebo
- Registration Number
- 2024-519436-17-00
- Lead Sponsor
- Fakultni Nemocnice U Sv Anny V Brne
- Brief Summary
The primary endpoint is the percentage of patients in the experimental and placebo groups whose clinical outcome according to the modified Rankin Scale (mRS) is graded as favorable (mRS 0-3) or unfavorable (mRS 4-6) 6 months after the first dose of the investigational drug/placebo.
- Detailed Description
Spontaneous subarachnoid hemorrhage (SAH) is a specific type of hemorrhagic stroke with a worldwide incidence ranging from 0.5 to 28 per 100,000 population, with large regional variations. Despite improvements in diagnosis, treatment and care, SAH remains a disease with high mortality and morbidity. According to the literature, one third of patients die within the first few days after SAH, and most survivors have cognitive impairment or long-term disability. The overall clinical outcome depends on the severity of early brain injury (EBI), cerebral edema, hydrocephalus, development of delayed ischemic neurological deficit (DIND), epileptic seizures, and other complications. The pathophysiological cascades responsible for the development of these complications remain poorly understood. However, numerous studies support the important role of aseptic cerebrovascular inflammation induced by blood and blood breakdown products in the subarachnoid space after SAH. The increased interest in the development of cerebrovascular inflammation after SAH is confirmed by the increasing number of clinical and experimental studies devoted to this topic. Cerebrovascular aseptic inflammation as a potential treatment target is also mentioned in current guidelines for the management of patients after SAH.
The results of experimental studies formed the basis for the clinical evaluation of the effects of NSAIDs after SAH. The effects of several commonly used NSAIDs, particularly dexketoprofen, ibuprofen, diclofenac, indomethacin, or dipyrone, have been evaluated in prospective and retrospective clinical trials over the past decade. In addition to reducing pro-inflammatory markers such as IL6, lowering body temperature and platelet aggregation, the administration of NSAIDs has been associated with reduced mortality and improved clinical outcomes. Despite the beneficial effects of some NSAIDs, more robust studies are still lacking, except for one study that evaluated the effect of meloxicam in patients after SAH. This study was a randomized, double-blind, placebo-controlled trial. It showed a trend towards a better outcome with a lower incidence of vasospasm or mortality in patients after SAH.
Despite encouraging experimental results, no clinical trials have yet evaluated the anti-inflammatory and other potentially beneficial effects of cyclooxygenase-2 (COX-2) inhibitors. COX-2 inhibitors, or coxibs, belong to the group of NSAIDs that selectively inhibit the COX-2 enzyme, which is responsible for developing inflammation and pain. A planned clinical study will evaluate the effects of parecoxib, a specific COX-2 inhibitor in the NSAIDs group, on overall clinical outcome and development of complications in patients following spontaneous SAH.
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 112
Signed informed consent.
Age: 18-85 years
Weight > 50 kg.
Spontaneous SAH diagnosed on native brain CT within 48 hours of first symptoms due to rupture of a bulge in one of the cerebral arteries confirmed by on DSA or CT angiography (Fisher grade 1 to 4) OR Spontaneous SAH without source by CT AG, DSA or MRI with Fisher grade 3 and 4.
For women capable of becoming pregnant (see definition from CTFG contraceptive guidelines): use of the following highly reliable contraceptive method within 3 months of study completion: adherence to sexual abstinence or progesterone-containing contraceptives with ovulation inhibition (oral administration, injection) or intrauterine device non-hormonal or hormonal or bilateral tubal occlusion or partner vasectomy. Men: adherence to sexual abstinence or use of an adequate contraceptive method (i.e., condom) in the event of sexual intercourse within 3 months of study completion.
Symptoms of SAH without blood findings on the initial native CT scan of the brain.
Severe hepatic insufficiency (serum albumin level <25 g /l or Child-Pugh score 10).
History of active peptic ulcer or gastrointestinal bleeding.
History of inflammatory bowel disease.
Systolic blood pressure ≥ 160 mmHg.
History of congestive heart failure (NYHA II-IV).
History of coronary artery disease, peripheral arterial insufficiency.
Participation in another clinical trial (at least 5 half-lives apart before administration of the investigational medicinal product).
SAH due to a cause other than ruptured aneurysm, e.g. A-V malformation, traumatic SAH.
Pregnancy and breastfeeding (pregnancy test).
Known hypersensitivity to the components of the product.
History of allergic reaction to the active substance or to sulfonamides.
Concomitant treatment with another non-steroidal anti-inflammatory drug, aspirin or corticosteroids (at least 5 half-lives apart before administration of the investigational medicinal product).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control - Placebo Placebo A placebo is a substance administered to a participant as a comparison without any pharmacological effect. However, unlike conventional medicines, it does not contain any active ingredients. In this clinical trial, the placebo is an isotonic sodium chloride solution. The placebo is injected into a peripheral or central venous catheter within 12 hours of the patient's enrollment in the study (from when informed consent is signed). Placebo 100 mL per dose will continue to be administered every 12 hours for five days. Participants will be followed for six months for any adverse events and changes in subjective status. In the event of adverse effects, patients will be followed until resolution. After that, their participation in this clinical trial will be terminated. The total duration of the patient's participation in the clinical trial will be six months. Active - Parecoxib Parecoxib Parecoxib 40 mg/100 ml will be injected into a peripheral or central venous catheter within 12 hours of the patient's inclusion in the study (from when informed consent is signed). Parecoxib 40 mg/100 ml is administered every 12 hours for 5 days. The maximum daily dose is 80 mg. In patients with moderate hepatic impairment (Child-Pugh score 7-9), parecoxib is started at 20 mg/50 mL and continued at this dose every 12 hours. The maximum daily dose is 40 mg. Participants will be monitored for six months for adverse events and changes in subjective status. In the event of adverse events, patients will be followed until resolution. After that, their participation in this clinical trial will be terminated. The total duration of the patient's participation in the clinical trial will be six months.
- Primary Outcome Measures
Name Time Method The primary outcome measure is the percentage of patients in the active and control groups whose outcome is categorized as favorable (mRS 0-3) or unfavorable (mRS 4-6) according to the modified Rankin Scale (mRS). The primary outcome measure is the percentage of patients in the active and control groups whose outcome is categorized as favorable (mRS 0-3) or unfavorable (mRS 4-6) according to the modified Rankin Scale (mRS).
- Secondary Outcome Measures
Name Time Method The secondary monitored parameter is the percentage of patients in the active and control groups whose outcome, according to the modified Rankin scale (mRS), is divided into favourable (mRS 0-3) or unfavourable (mRS 4-6). The secondary monitored parameter is the percentage of patients in the active and control groups whose outcome, according to the modified Rankin scale (mRS), is divided into favourable (mRS 0-3) or unfavourable (mRS 4-6).
Number of patients with vasospasms confirmed on TCD / CT AG / MR AG / DSA Number of patients with vasospasms confirmed on TCD / CT AG / MR AG / DSA
Number of patients with delayed ischemic neurological deficit Number of patients with delayed ischemic neurological deficit
Number of deaths Number of deaths
Length of hospitalization in ICU Length of hospitalization in ICU
Total length of hospitalization Total length of hospitalization
Number of patients with acute hydrocephalus Number of patients with acute hydrocephalus
Number of patients with chronic hydrocephalus with V-P shunt implantation Number of patients with chronic hydrocephalus with V-P shunt implantation
Number of patients with fever above 38 degrees Celsius Number of patients with fever above 38 degrees Celsius
Evaluation of the systemic inflammatory response (assessed daily during hospitalization) meeting at least 2 parameters: heart rate > 90/min., leukocytosis > 12x109/l) or leukopenia < 9x109, respiratory rate > 20/min. or PaCO2 < 32 mm Hg (4.3 kPa), body temperature < 36.0 °C or > 38.0 °C Evaluation of the systemic inflammatory response (assessed daily during hospitalization) meeting at least 2 parameters: heart rate > 90/min., leukocytosis > 12x109/l) or leukopenia < 9x109, respiratory rate > 20/min. or PaCO2 < 32 mm Hg (4.3 kPa), body temperature < 36.0 °C or > 38.0 °C
The comparison of the patients in the treatment and placebo arm with pain according to the Visual Analogue Scale, a numerical scale from 0 to 10 points, where increasing pain is indicated by a higher score. The comparison of the patients in the treatment and placebo arm with pain according to the Visual Analogue Scale, a numerical scale from 0 to 10 points, where increasing pain is indicated by a higher score.
Evaluation of prostaglandins (COX-2, PGH2, PGI2, PGE2, PGD2, PF2a, TXA2) and pro-inflammatory cytokines (TNF, IL-1, IL-4, IL-6, IL-8, IL-12) in the cerebrospinal fluid in the case of the below-mentioned external ventricular drainage after 2 days and in the serum regardless of the established cerebrospinal fluid drainage after two days to day 10 from initial symptoms Evaluation of prostaglandins (COX-2, PGH2, PGI2, PGE2, PGD2, PF2a, TXA2) and pro-inflammatory cytokines (TNF, IL-1, IL-4, IL-6, IL-8, IL-12) in the cerebrospinal fluid in the case of the below-mentioned external ventricular drainage after 2 days and in the serum regardless of the established cerebrospinal fluid drainage after two days to day 10 from initial symptoms
C-reactive protein (CRP), procalcitonin (PCT) and white blood cell count C-reactive protein (CRP), procalcitonin (PCT) and white blood cell count
This evaluation will compare the number of patients in the treatment and placebo arms who undergo cerebrospinal fluid drainage. This evaluation will compare the number of patients in the treatment and placebo arms who undergo cerebrospinal fluid drainage.
Evaluation of quality of life (SF-36 score) Evaluation of quality of life (SF-36 score)
Number of patients with inflamation based on source of bleeding Number of patients with inflamation based on source of bleeding
Percentage of patients in the experimental and placebo groups with the occurrence of serious adverse events (SAE) (assessed during hospitalization, at discharge, 3 and 6 months after the first dose) supplemented by evaluation in individual subgroups according to the source of bleeding. Percentage of patients in the experimental and placebo groups with the occurrence of serious adverse events (SAE) (assessed during hospitalization, at discharge, 3 and 6 months after the first dose) supplemented by evaluation in individual subgroups according to the source of bleeding.
Percentage of patients in the experimental and placebo groups with an increase in blood creatine phosphokinase (CPK), an increase in blood lactate dehydrogenase (LDH), an increase in alanine transaminase (ALT), an increase in aspartate transaminase (AST), and an increase in blood urea level > 5x ULN; separate analysis for subgroups by source of bleeding. Percentage of patients in the experimental and placebo groups with an increase in blood creatine phosphokinase (CPK), an increase in blood lactate dehydrogenase (LDH), an increase in alanine transaminase (ALT), an increase in aspartate transaminase (AST), and an increase in blood urea level > 5x ULN; separate analysis for subgroups by source of bleeding.
Trial Locations
- Locations (3)
Fakultni Nemocnice Ostrava
🇨🇿Ostrava, Czechia
Fakultni Nemocnice U Sv Anny V Brne
🇨🇿Brno-Stred, Czechia
University Hospital Olomouc
🇨🇿Olomouc, Czechia
Fakultni Nemocnice Ostrava🇨🇿Ostrava, CzechiaTomáš HrbáčSite contact+420597375402tomas.hrbac@fno.cz