A Trial of BUN/Cr-based Hydration Therapy to Reduce Stroke-in-evolution and Improve Short-term Functional Outcomes for Dehydrated Patients With Acute Ischemic Stroke-version 2.

English Synopsis

I. Title of Study:

A trial of BUN/Cr-based hydration therapy to reduce stroke-in-evolution and improve short-term functional outcomes for dehydrated patients with acute ischemic stroke-version 2.

II. Indication:

We use blood urea nitrogen (BUN)/blood creatinine (Cr) ratio≧15 as a dehydration biomarker. This clinical trial aims to determine if more aggressive intravenous fluid supplement instead of present treatment would yield a better outcome in patients with acute ischemic stroke and a BUN/Cr ratio≧15.

III. Phase of Development:

Phase III, randomized double-blind control trial.

IV. Study Rationale:

We have recently reported a novel finding that the blood urea nitrogen (BUN)/creatinine (Cr) ratio, a marker of hydration status, was an independent predictor of early neurological deterioration among patients who had suffered acute ischemic stroke. Pilot study was then designed to determine if providing hydration therapy, specifically intravenous saline infusion, to patients with a blood urea nitrogen/creatinine ratio (BUN/Cr) ≥15 improves outcomes after acute ischemic stroke. The results showed that patients with a presenting BUN/Cr ≥ 15 who received saline hydration therapy experienced a better functional outcome compared with similar patients who received standard therapy.

V. Study Objectives:

Primary objective: To compare the effectiveness of BUN/Cr-based hydration therapy with standard treatment in early neurological improvement (ENI) rate at 72 hours for dehydrated subjects with acute ischemic stroke Secondary objectives: To compare the benefit of BUN/Cr-based hydration therapy with standard treatment after three months using measure of modified Rankin scale (mRS)

VI. Study Design:

Duration of Treatment: 12 hours Number of Planned Patients: 288 subjects Investigational Product: normal saline

Endpoints:

1. Primary endpoint: To compare the ENI rate between group at 72 hours. ENI is defined as the improvement of the NIHSS score by 2 or more points or a score of 1 or 0 at 72 hours after the onset of stroke.
2. Secondary endpoints: To compare the rate of favorable functional outcome at 3 months. Scores <=1 on the mRS are considered to indicate a favorable outcome.

Criteria for Evaluation

Inclusion criteria:

1. Acute ischemic stroke diagnosed by the clinical presentations and brain imaging is confirmed by a stroke care specialist.
2. has a measurable neurologic deficit according to the National Institutes of Health Stroke Scale (NIHSS)
3. the time between the onset of neurological symptoms and starting therapy are less than 24 hours
4. admission BUN/Cr≧15

Exclusion criteria:

1. no informed consent obtained
2. initial NIHSS >10
3. prepared for or received fibrinolytic therapy
4. prepared for or received surgical intervention with 14 days
5. congestive heart failure according to past history or Framingham criteria
6. history of liver cirrhosis or severe liver dysfunction (ALT or AST > x 3 upper normal limit)
7. admission blood Cr >2 mg/dl
8. initial blood pressure SBP<90 mmHg
9. fever with core temperature >=38°C
10. indication of diuretics for fluid overload
11. any conditions needed more aggressive hydration or blood transfusion
12. cancer under treatment
13. life expectancy or any reasons for follow-up < 3 months

Statistical Methods:

The primary objective is efficacy using the binary endpoint of ENI. Descriptive statistics on continuous measurements will include means, medians, standard deviations, and ranges, while categorical data will be summarized using frequency counts and percentages. For the primary endpoint of ENI rate, the proportion of subjects with ENI response will be summarized by treatment group. The proportions of ENI will be compared between BUN/Cr-based hydration therapy (Arm A) and Standard therapy (Arm B) using two proportion Z test. The secondary objectives of this study are to evaluate the benefit of BUN/Cr-based hydration therapy after three months using measure of modified Rankin scale. For the secondary endpoint comparisons between groups, independent t-test will be considered.

Duration of the Study: 3 years (or From 01/09/2020 to 31/08/2023) End of Study : When total 288 participants are enrolled or meet the criteria of early termination.