Propranolol on Post Stroke Immune Status and Infection

Sponsor

Tianjin Medical University General Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05375240

Collaborator

(none)

Enrollment

Locations

Arms

Anticipated Duration (Months)

22.5

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Stroke-associated pneumonia (SAP) is one of the important risk factors influencing poor outcomes and death in stroke patients. Over the past two decades, accumulating evidence suggests that post-stroke brain injury mobilizes the adrenergic system, which induces post-stroke immunosuppression and SAP. This study is designed to test the safety and efficacy of an adrenergic β-receptor blocker, propranolol, with or without combination of antibiotics, in reducing SAP in stroke patients. The underlying immune mechanisms will be investigated.

Condition or Disease	Intervention/Treatment	Phase
Stroke Cerebrovascular Disorders Ischemic Stroke Brain Diseases Central Nervous System Diseases Nervous System Diseases Cardiovascular Diseases Propranolol Beta Blocker Molecular Mechanisms of Pharmacological Action Immunologic Factors Physiological Effects of Drugs	Drug: Propranolol Drug: Ceftriaxone	Phase 2

Detailed Description

Stroke patients meeting the inclusion criteria will be randomly assigned at a 1:1:1 ratio into groups of standard treatment (blank-controlled), propranolol, or propranolol + ceftriaxone.

Patients will be given 10.0mg*3/day oral/nil propranolol alone or combined with 2.0g/day intravenous ceftriaxone over the course of 7 consecutive days. Neurological functions of these patients will be assessed at the baseline, day 7, 14, 30, and 90 after randomization. Head magnetic resonance imaging (MRI) will be performed at baseline and 7 days after randomization. Chest computed tomography (CT) will be performed within 7 days following randomization. Abdomen CT will be performed simultaneously with CT chest to evaluate spleen volume. For patients requiring acute endotracheal intubation upon admission, bronchoalveolar lavage fluid will be harvested at baseline and 7 days post-randomization. For all patients, 15 mL intravenous blood will be collected at baseline, days 3 and 7 after randomization. Bronchoalveolar lavage fluid and blood will be used to explore the peripheral and pulmonary immune status of patients. Urinary tract infection will be evaluated within 14 days based on routine urine test and bacterial culture.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

45 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Blank-controlled, Open Label Study of the Safety and Efficacy of Propranolol in Reducing Stroke Associated Pneumonia and Urinary Tract Infection

Anticipated Study Start Date :

Jun 1, 2022

Anticipated Primary Completion Date :

Jun 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Blank-control group Patients will receive standard treatment.
Experimental: Oropranolol group Propranolol will be administered at a dose of 10mg*3/day over a course of 7 consecutive days after stroke onset.	Drug: Propranolol Propranolol will be given at a dose of 10 mg orally, 3 times per day, for 7 consecutive days after stroke onset.
Experimental: Propranolol + ceftriaxone group Propranolol will be administered at a dose of 10mg*3/day combined with 2g/day ceftriaxone over a course of 7 consecutive days after stroke onset.	Drug: Propranolol Propranolol will be given at a dose of 10 mg orally, 3 times per day, for 7 consecutive days after stroke onset. Drug: Ceftriaxone Intravenously 2.0g/day for 7 consecutive days.

Arm

Intervention/Treatment

No Intervention: Blank-control group

Patients will receive standard treatment.

Experimental: Oropranolol group

Propranolol will be administered at a dose of 10mg*3/day over a course of 7 consecutive days after stroke onset.

Drug: Propranolol

Propranolol will be given at a dose of 10 mg orally, 3 times per day, for 7 consecutive days after stroke onset.

Experimental: Propranolol + ceftriaxone group

Propranolol will be administered at a dose of 10mg*3/day combined with 2g/day ceftriaxone over a course of 7 consecutive days after stroke onset.

Drug: Propranolol

Propranolol will be given at a dose of 10 mg orally, 3 times per day, for 7 consecutive days after stroke onset.

Drug: Ceftriaxone

Intravenously 2.0g/day for 7 consecutive days.

Outcome Measures

Primary Outcome Measures

Incidence of pneumonia [Up to 7 days]
Stroke-associated pneumonia diagnosed in accordance to a defined algorithm.

Secondary Outcome Measures

Assessment of clinical outcome by National Institute of Healthy Stroke Scale [Up to 90 days]
National Institute of Healthy Stroke Scale(0-42 score),higher scores mean a worse outcome.
Assessment of clinical outcome by modified Barthel Index [Up to 90 days]
Modified Barthel Index（0-100 score),higher scores mean a better outcome.
Assessment of clinical outcome by modified Rankin Scale [Up to 90 days]
Modified Rankin Scale(0-5 score),higher scores mean a worse outcome.
Assessment of clinical outcome by Glasgow Coma Scale [Up to 90 days]
Glasgow Coma Scale(0-15),higher scores mean a better outcome.
Incidence of urinary tract infection [Up to 14 days]
Urinary tract infection diagnosed with defined criteria.
Incidence of sepsis [Up to 14 days]
Sepsis diagnosed with defined criteria.
Alterations of spleen volume [Up to 7 days]
Spleen volume will be evaluated within 7 days via abdomen CT scan.
Single cell sequencing results of immune cells from blood and bronchoalveolar lavage fluid [Up to 7 days]
Single cell sequencing of immune cells from blood and bronchoalveolar lavage fluid will be conducted at baseline and 7 days after stroke onset.
Concentration of soluble protein in blood and bronchoalveolar lavage fluid [Up to 7 days]
Soluble proteins in blood and bronchoalveolar lavage fluid will be evaluated by O-link at baseline and 7 days after stroke onset
Counts of lymphocytes in blood [Up to 7 days]
Counts of lymphocytes will be evaluated by flow cytometry at baseline, day 3, and day 7 post stroke onset

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age: 60 years older and less than 90 years.
Onset of new neurological deficits within 24 hours at the time of randomization and propranolol treatment can be initiated within 24 hours of symptom onset.
Clinical signs consistent with the diagnosis of stroke, including impairment of language, motor function, cognition, and/or gaze, vision, or neglect.
Initial NIHSS score of 11 or greater or Total GCS score (aggregate of verbal, eye, and motor response scores) of 5 or greater and no more than 12 at time of enrollment.
MRI or CT scan confirmed stroke.
Inability to tolerate normal diet or fluids because of: a. impaired consciousness levels; b. failed clinical bedside swallowing assessment performed by a trained and qualified assessor; c. "nil orally" orders, nasogastric tubes, modified diet or requiring compensatory feeding techniques.
TOAST: Large-artery atherosclerosis.
Signed and dated informed consent by the subject, legally authorized representative, or surrogate obtained.

Exclusion Criteria:

Time of symptom onset that cannot be reliably assessed.
Subjects considered as candidates for immediate surgical intervention by the neurosurgery service.
Pregnancy or parturition within previous 30 days or active lactation.
Coagulation disorders (platelet count less than 50x109/L, elevated baseline APTT or INR>1.3) or use of anti-coagulant drugs within the last 24 hours.
Use of beta blockers (propranolol, metoprolol, sotalol, carvedilol, bisoprolol, atenolol, esmolol) or antibiotics within 30 days.
Use of reserpine within the last 30 days.
Pre-stroke dementia or disability.
Admission with any of following signs: 1). Fever>38℃; 2). Signs of pneumonia in chest CT scan; 3). White blood cell count>12000 or <4000 /μL; 4). Cough, sputum or dyspnea; 5). Respiratory rate>25.
Severe liver, kidney disease, or malignancy, life expectancy is less than 14 days.
Bronchial asthma or COPD.
Cardiogenic shock.
Severe or acute heart failure.
Degree II-III atrioventricular block.
Sinus bradycardia (heart rate ≤75/min).
Known anergic to propranolol or amoxicillin.
Current participation in other interventional clinical trials.
Immunosuppressant therapy or known immunosuppression.
Inability to undergo neuroimaging with magnetic resonance.