Effects and Mechanisms of Celecoxib on Intracerebral Hemorrhage

A phase IIa human clinical trial will be performed to clarify the safety and efficacy of using usual dose of celecoxib (200 mg/day) for 21 days starting within 6 hours after onset of ICH. Totally 60 patients will be enrolled prospectively, and the case number was estimated by statistical methods for the percentage of participants with increased perihematomal edema volume shown in the previous clinical trial (Lee et al., 2013) (estimated by G-power software, settings as: exact test, one sample test, α = 0.05, power = 0.95). Patients will be randomly assigned as treatment group or control group as 1:1 distribution.

Intervention: Celecoxib 200 mg per dose, started within 6 h after onset, then one dose per day for 21 days in the treatment group. The low dose of Celecoxib will be used to minimize the side effect of Celecoxib. No trial medication will be given for the control group. Pregnancy will be excluded at enrollment and prevented throughout the treatment period in female cases at reproductive ages.

Evaluations:

1. Brain CT:

1. Initial brain CT: for initial hematoma volume (length \* width \* height /2) 2. Brain CT on day 2 for final hematoma volume and hematoma expansion 3. Brain CT on day 7±1 for perihematomal edema and hematoma resolution 2. Neurological functions: NIHSS score, GCS score, modified Rankin scale (mRS) on day 1, 2, 7±2, 14±2, 21±2, and mRS at 3 months 3. Renal function (creatinine) on day 1, then once per week during day 2-7, day 8-14 and 15-21 4. Gastrointestinal bleeding evens within 21 days 5. Myocardial infarction evens within 21 days 6. Blood sampling on day 1, 7±2, and 21±2

Patient enrollment: If the patient's consciousness is not clear before the enrollment of this study, his (her) family can decide the enrollment for this patient. Once the patient regains his (her) consciousness, we will reconfirm with the patient about the enrollment of this study.

Data checks: The data recorded of this study will be double-checked for their accuracy and compared with predefined ranges to avoid typing error.

Plan for missing data: Missing data include those data which are reported as missing, unavailable, uninterpretable, or considered missing because of data inconsistency or out-of-range results. This study will try to minimize missing data by limiting the collection of data to essential information and minimizing the number of follow-up visits, develop a documentation of this study for the methods to screen the participants and the procedures to follow up, appropriate training for all personnel related to this study, and data will be reviewed as close to real-time as possible.

Statistical analysis plan: The continuous variables between Celecoxib group and control group will be compared using Mann-Whitney U test if these data are not with normal distribution, or t-test if these data are with normal distribution. Categorical data will be compared using Fisher's exact test.

• Hematoma expansion volume [Time frame: Day 2]
• Percentage of participants with hematoma expansion (33% relative or 12.5 mL absolute volume increase) [Time frame: Day 2]
• Perihematomal edema increase volume [Time frame: Day 2, 7±1]
• Hematoma and perihematomal edema expansion volume [Time frame: Day 2, 7±1]
• Hematoma and perihematomal edema expansion percentage [Time frame: Day 2, 7±1]
• Change in National Institutes of Health Stroke Scale (NIHSS) [Time frame: Day 21±2]
• Percentage of participants with adverse events (AEs) [Time frame: Day 1-21]
• modified Rankin scale (mRS) score [Time frame: 3-month]