Propranolol on Post Stroke Immune Status and Infection

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiovascular Diseases; Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Propranolol; Immunologic Factors; Beta Blocker
• Intervention / Treatment: Drug: Propranolol; Drug: Ceftriaxone

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 Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Fu-Dong Shi, Ph.D; Phone Number: +8615822011530; Email: fshi@tmu.edu.cn

Study Locations

• China
  • Beijing, China, 100070
    • Beijing Tiantan Hospital
    • Contact: Fu-Dong Shi, MD,PhD
  • Tianjin, China, 300052
    • Tianjin Medical University General Hospital
    • Contact: Fu-Dong Shi, MD,PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age: 60 years older and less than 90 years.
2. 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.
3. Clinical signs consistent with the diagnosis of stroke, including impairment of language, motor function, cognition, and/or gaze, vision, or neglect.
4. 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.
5. MRI or CT scan confirmed stroke.
6. 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.
7. TOAST: Large-artery atherosclerosis.
8. Signed and dated informed consent by the subject, legally authorized representative, or surrogate obtained.

Exclusion Criteria:

1. Time of symptom onset that cannot be reliably assessed.
2. Subjects considered as candidates for immediate surgical intervention by the neurosurgery service.
3. Pregnancy or parturition within previous 30 days or active lactation.
4. 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.
5. Use of beta blockers (propranolol, metoprolol, sotalol, carvedilol, bisoprolol, atenolol, esmolol) or antibiotics within 30 days.
6. Use of reserpine within the last 30 days.
7. Pre-stroke dementia or disability.
8. 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.
9. Severe liver, kidney disease, or malignancy, life expectancy is less than 14 days.
10. Bronchial asthma or COPD.
11. Cardiogenic shock.
12. Severe or acute heart failure.
13. Degree II-III atrioventricular block.
14. Sinus bradycardia (heart rate ≤75/min).
15. Known anergic to propranolol or amoxicillin.
16. Current participation in other interventional clinical trials.
17. Immunosuppressant therapy or known immunosuppression.
18. Inability to undergo neuroimaging with magnetic resonance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of pneumonia	Stroke-associated pneumonia diagnosed in accordance to a defined algorithm.	Up to 7 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Tianjin Medical University General Hospital

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): June 1, 2022
• Primary Completion (ANTICIPATED): June 1, 2024
• Study Completion (ANTICIPATED): June 1, 2024

Study Registration Dates

• First Submitted: April 19, 2022
• First Submitted That Met QC Criteria: May 11, 2022
• First Posted (ACTUAL): May 16, 2022

Study Record Updates

• Last Update Posted (ACTUAL): May 16, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Treatment; Infection; Stroke; Propranolol
• Additional Relevant MeSH Terms: Vascular Diseases; Stroke; Cardiovascular Diseases; Ischemic Stroke; Infections; Nervous System Diseases; Brain Diseases; Cerebrovascular Disorders; Central Nervous System Diseases; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Anti-Bacterial Agents; Propranolol; Ceftriaxone
• Other Study ID Numbers: IRB2022-YX-001

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