Evaluation of the Safety and Efficacy of Parecoxib in Patients With Subarachnoid Hemorrhage (PARISAH)

A Randomized, Placebo-controlled, Double-blind Clinical Trial Evaluating the Safety and Efficacy of Parecoxib in Hospitalized Patients With Spontaneous Subarachnoid Hemorrhage

Because of the important role of inflammation in the pathophysiology of SAH, it was hypothesized that its pharmacological manipulation might improve the prognosis of patients. In recent years, the effects of several groups of anti-inflammatory drugs on the development of complications after SAH have been described. Initially promising, glucocorticoids, thought to reduce cerebrovascular inflammation, brain swelling, and headache, failed in clinical trials. Studies have not provided clear evidence of the beneficial effects of these drugs in patients after SAH. Therefore, the administration of glucocorticoids is not currently part of the recommended practice. In addition, glucocorticoid treatment is associated with adverse effects that worsen outcomes, including hyperglycemia, infection, and the risk of gastrointestinal bleeding.

Study Overview

• Status: Not yet recruiting
• Conditions: Neurological Complication
• Intervention / Treatment: Drug: Parecoxib; 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.

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Lucie Tesárková; Phone Number: +420 543 185 174; Email: lucie.tesarkova@fnusa.cz
• Study Contact Backup: Name: Klara Kostelanska, PhD; Phone Number: +420 543 185 526; Email: klara.kostelanska@fnusa.cz

Study Locations

• Czechia
  • Czech Republic
    • Brno, Czech Republic, Czechia, 602 00
      • St. Anne's University Hospital Brno
      • Contact: Klara Kostelanska, PhD; Phone Number: +420 543 185 526; Email: klara.kostelanska@fnusa.cz
      • Contact: Peter Solar, MD; Phone Number: + 420 543 182 703; Email: peter.solar@fnusa.cz
      • Principal Investigator: Peter Solar, M.D., Ph.D.
      • Sub-Investigator: Radim Jancalek, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent
• Age: 18-85 years
• Weight> 50 kg
• Spontaneous SAH diagnosed on a native CT brain max. 48 hours after the first symptoms
• Spontaneous SAH caused by rupture of the cerebral aneurysm confirmed on DSA or CT angiography (Fisher grade 1 to 4) OR Spontaneous SAH without a source on CT AG, DSA or MRI with Fisher grade 3 and 4
• For women capable of becoming pregnant (see definitions from the CTFG guideline for contraception): use of the following highly reliable contraceptive method within 3 months after the end of the study: adherence to sexual abstinence or contraception containing progesterone with inhibition of ovulation (oral administration, injection) or non-hormonal intrauterine device or hormonal or bilateral tubal occlusion or partner vasectomy. Males: adherence to sexual abstinence or use of an adequate contraceptive method (i.e. condom) in case of sexual intercourse within 3 months after the end of the study.

Exclusion Criteria:

• Symptoms of SAH without the finding of blood on the initial native CT scan of the brain
• SAH from a cause other than a ruptured aneurysm, e.g. A-V malformation, traumatic SAH
• Pregnancy and breastfeeding (pregnancy test)
• Known hypersensitivity to the components of the product
• Allergic reaction to the active substance or sulfonamides in the anamnesis
• Concomitant treatment with other non-steroidal anti-inflammatory drugs, aspirin or corticosteroids (at least five half-lives before administration of the medicinal product under investigation)
• Severe hepatic insufficiency (serum albumin level <25 g/l or Child-Pugh score less than 10).
• Active peptic ulcer or bleeding from the gastrointestinal tract in the anamnesis
• Inflammatory bowel disease in the anamnesis
• Congestive heart failure (NYHA II-IV) in history.
• Proven ischemic heart disease, peripheral arterial insufficiency.
• Participation in another clinical study (a gap of at least five half-lives before administration of the medicinal product under investigation).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active - 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.	Drug: Parecoxib; Parecoxib (Dynastat) 40 mg solution for injection is for intravenous administration. Parecoxib may be given as an intravenous injection for 30 minutes directly into a vein or through an intravenous infusion set.
Placebo Comparator: Control - 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.	Drug: Placebo; Placebo intravenous injection can be administered quickly and directly into a vein or through an intravenous infusion set.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Influence of parecoxib on outcome of patients with SAH	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).	180 days ± 14 days after first dose of parecoxib/placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Influence of parecoxib on outcome of patients with SAH	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).	Discharge from hospital and 90 days ± 7 days after first dose of parecoxib/placebo
Occurrence of symptomatic vasospasms (vasospasms confirmed on TCD / CT AG / MR AG / DSA	Number of patients with vasospasms confirmed on TCD / CT AG / MR AG / DSA	Six, eight and ten days after the application of the first dose of the evaluated medicinal product /placebo.
Incidence of delayed ischemic neurological deficit (DIND)	Number of patients with delayed ischemic neurological deficit	Six, eight and ten days, three and six months after the application of the first dose of the evaluated medicinal product /placebo.
Mortality	Number of deaths	During the treatment and post treatment period of hospitalization, 90 days ± 7 days and 180 days ± 14 days
Length of hospitalization in ICU	Length of hospitalization in ICU	3 months
Total length of hospitalization	Total length of hospitalization	3 months
Occurrence of acute hydrocephalus	Number of patients with acute hydrocephalus	During the treatment and post treatment period of hospitalization
Occurrence of chronic hydrocephalus	Number of patients with chronic hydrocephalus with V-P shunt implantation	During the treatment and post treatment period of hospitalization, 90 days ± 7 days, 180 days ± 14 days
Occurrence of fevers	Number of patients with fever above 38 degrees Celsius	During the treatment and post treatment period of hospitalization
Occurrence of inflammation	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	During the treatment and post treatment period of hospitalization
Evaluation of pain according to Visual Analogue Scale	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.	During the treatment and post treatment period of hospitalization, discharge from hospital, 90 days ± 7 days and 180 days ± 14 days after first dose of parecoxib/placebo
Evaluation of prostaglandins and pro-inflammatory cytokines in the cerebrospinal fluid in the case of the below-mentioned external ventricular drainage after 2 days and in the serum	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	0, 2, 4, 6, 8 and 10 days after implantation of drainage
Evaluatioon of laboratory markers of inflammatory response in peripheral blood	C-reactive protein (CRP), procalcitonin (PCT) and white blood cell count	Two, four, six, eight and ten days after the application of the first dose parecoxib/placebo
Evaluation of the functionality of the blood-cerebrospinal fluid barrier every 2 days if cerebrospinal fluid drainage is necessary.	This evaluation will compare the number of patients in the treatment and placebo arms who undergo cerebrospinal fluid drainage.	0, 2, 4, 6, 8 and 10 days after implantation of drainage
Quality of life measured through questionnaires	Evaluation of quality of life (SF-36 score)	Discharge from hospital, 90 days ± 7 days and 180 days ± 14 days after the application of the first dose parecoxib/placebo
Evaluation of the difference in efficacy parameters between subgroups according to the source of bleeding	Number of patients with inflamation based on source of bleeding	After discharge from hospital, six days after administration of the 1st dose of parecoxib/placebo
Serious adverse events	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.	During hospitalization, at discharge, 90 days ± 7 days, 180 days ± 14 days after the first dose of parecoxib/placebo
Hepatotoxicity	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.	Before the 1st dose of parecoxib/placebo, 1., 3. and 5. day of treatment and 10. day of hospitalization

Collaborators and Investigators

• Sponsor: St. Anne's University Hospital Brno, Czech Republic
• Collaborators: Masaryk University; CZECRIN - Czech Clinical Research Infrastructure Network
• Investigators: Principal Investigator: Peter Solar, St. Anne´s University Hospital Brno

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: August 19, 2024
• First Submitted That Met QC Criteria: August 26, 2024
• First Posted (Actual): August 30, 2024

Study Record Updates

• Last Update Posted (Actual): August 30, 2024
• Last Update Submitted That Met QC Criteria: August 26, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: inflammation; NSAIDs; subarachnoidal hemorrhage
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Subarachnoid Hemorrhage; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Cyclooxygenase 2 Inhibitors; Parecoxib
• Other Study ID Numbers: PAR-FNUSA-2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No