Esmolol for the Treatment of Hypertension After Intracerebral Hemorrhage Study (ETHICHS) (ETHICHS)

A Randomized, Exploratory, Open-label, Phase IV, Blinded Endpoint, Multicenter and Prospective Study to Evaluate the Effect of the Addition of Esmolol on the Current Therapeutic Regimen Used for the Treatment of Hemorrhagic Stroke

Because of its pharmacokinetic characteristics, such as short half-life and its safety profile, esmolol hydrochloride is a beta blocker suitable for venous use in the form of continuous infusion. Strategies that improve the blood pressure control of patients with hemorrhagic stroke during the first hours of hospitalization are determinant in controlling the hematoma expansion and determining factor in its prognosis. This study was designed with the objective of evaluating the beneficial effects of combining esmolol hydrochloride with sodium nitroprusside for the blood pressure control of participants with hemorrhagic stroke.

Study Overview

• Status: Terminated
• Conditions: Hemorrhagic Stroke
• Intervention / Treatment: Drug: Brevibloc, 10 Mg/mL Intravenous Solution; Drug: Nitroprusside, Sodium

Detailed Description

Participants with parenchymal intracranial hemorrhage (diagnosis confirmed by computed tomography or magnetic resonance imaging), and:

• with systolic pressure > 150 mmHg,
• not contraindicated for treatment with beta-blockers,
• who can start the drug treatment within 6 hours of the stroke,
• having a target of ≤ 140 mmHg of systolic pressure within 1 hour after initiation of treatment.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 04022-002
    • Universidade Federal de Sao Paulo
  • Bahia
    • Salvador, Bahia, Brazil, 04011-032
      • Hospital Sao Rafael
  • Ceará
    • Fortaleza, Ceará, Brazil, 60150-160
      • Hospital Geral de Fortaleza
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30380-090
      • Hospital Madre Teresa
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre
  • São Paulo
    • Botucatu, São Paulo, Brazil, 18607-741
      • Hospital das Clínicas da Faculdade de Medicina de Botucatu
    • Ribeirão Preto, São Paulo, Brazil, 14015-130
      • Hospital das Clínicas de Riberião Preto

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signature of the TCLE by participant or companion.
2. Spontaneous intracerebral hemorrhage confirmed by computed tomography or magnetic resonance imaging and fit to be included in the study and initiate therapy with study medications within 6 hours after the event.
3. Intracerebral hemorrhage (volume < 30 cm3).
4. No immediate surgical indication.
5. Both sexes, aged above 18 years.
6. Systolic blood pressure (> 150 mmHg and < 220 mmHg) measured on two occasions with a minimum difference of 2 minutes.

Exclusion Criteria:

1. Cerebral hemorrhage secondary to structural lesions in the brain, vascular malformations, coagulopathies or traumatic brain injury, if known at the time of randomization.
2. Participant in deep coma, defined by the Glasgow Coma Scale score of 3 to 5.
3. Uncontrolled asthmatic or COPD participants, if known at the time of randomization.
4. Participants with Grade IV Heart Failure, defined as heart rate < 50 beats per minute.
5. Previous hemorrhagic stroke, if known at the time of randomization
6. Participants with Cerebral Vascular Stroke.
7. Participants who have presented previous ischemic cerebrovascular accident, if known at the time of randomization.
8. Chronic diseases with life expectancy less than 3 months.
9. Score ≥ 4 on the ICH score at the time of recruitment.
10. In use of anticoagulants in the last 48 hours, if known at the time of randomization.
11. Patients with contraindication to any of the study medications.
12. Intubation Orotraqueal on arrival at the service.
13. Pheochromocytoma, if known at the time of randomization.
14. Patients with hyperthyroidism, if known at the time of randomization.
15. Known pregnancy or breastfeeding . At the discretion of the investigator, an examination for confirmation may be requested.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Brevibloc, 10 Mg/mL Intravenous Solution; 10 mL/h every 5 minutes until reaching the pressure target	Drug: Brevibloc, 10 Mg/mL Intravenous Solution; 10 mL/h every 5 minutes until reaching the pressure target; Other Names: Brevibloc; Drug: Nitroprusside, Sodium; 0.5 ug/kg/min every 3 minutes until reaching the pressure target; Other Names: Nitroprus
ACTIVE_COMPARATOR: Nitroprusside, Sodium; 0.5 mcg / kg / min every 3 minutes until reaching the pressure target	Drug: Nitroprusside, Sodium; 0.5 ug/kg/min every 3 minutes until reaching the pressure target; Other Names: Nitroprus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate comparatively the drug test and the comparator drug	Variation of systolic and diastolic pressure during the time of use of the investigational products measured by ABPM (outpatient blood pressure monitoring).	7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare the percentage of participants	To compare the percentage of participants with controlled systolic pressure (goal ≤ 140 mmHg)	in the first hour of treatment between the groups.
Rankin Scale	To compare the ranks of the modified Rankin Scale (Applied by blind-investigator) between groups.	in 90 ± 4 days
NIH Stroke Scale (NIHSS) and Glasgow Coma Scale	Compare the variation in scores on the NIH Stroke Scale (NIHSS) and Glasgow Coma Scale (whichever comes first) between groups.	from admission to discharge or 7th day
MOCA scale	To compare the cognitive performance assessed between the groups.	in 90 ± 4 days
Hematoma volume expansion and perihematoma volume of cerebral edema	To compare the percentages of between admission tomography and control tomography after the end of infusion of investigational products	24 ± 4 hours
Severe hypotensive events with clinical consequences	To compare the frequency of severe hypotensive events with clinical consequencesrequiring corrective therapy with vasopressors during the use of investigational products between groups.	in 90 ± 4 days
Adverse events related with investigational product	To compare the frequency and intensity of adverse events related to the use of research products between groups.	in 90 ± 4 days
Severe cardiovascular events	Compare the frequency of severe cardiovascular events (acute myocardial infarction, cardiac arrest, arrhythmias, or the development of severe congestive heart failure) or major neurological complications (eg need for neurosurgery, intraventricular bypass placement, cerebral infarction, convulsive seizures, intoxication, neurological toxicity) within the first 90 days of follow-up between groups.	in 90 ± 4 days
Bradycardia	Compare the frequency and duration of major bradycardia (<50 beats per minute) between groups.	in 90 ± 4 days
QT interval variability	Compare the QT interval variability measured by Holter during the infusion period of the investigational products between the groups	during the infusion period
Frequency of changes in the ECO	Compare the frequency of changes in the Echocardiogram (Differences observed between the examination performed in the first 72 ± 4 hours and the return after 90 ± 3 days) between the groups.	in the first 72 ± 4 hours and the return after 90 ± 3 days
Frequency of changes in the level of BNP	To compare the frequency of changes in the level of B-type natriuretic peptide (BNP) measured at baseline times, 24 ± 4 and 72 ± 4 hours between groups.	at baseline times, 24 ± 4 and 72 ± 4 hours
Frequency of changes in baseline cardiac troponin levels	To compare the frequency of changes in baseline cardiac troponin levels, 24 ± 4 and 72 ± 4 hours	24 ± 4 and 72 ± 4 hours
Frequency of intra-cranial hypertension	To compare the frequency of intra-cranial hypertension diagnosed by measuring the diameter of the optic nerve sheath by transorbital ultrasound daily for 7 days or high, whichever occurs first between the groups.	7 days

Collaborators and Investigators

• Sponsor: Cristália Produtos Químicos Farmacêuticos Ltda.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 18, 2019
• Primary Completion (ACTUAL): October 31, 2021
• Study Completion (ACTUAL): October 31, 2021

Study Registration Dates

• First Submitted: November 13, 2018
• First Submitted That Met QC Criteria: November 13, 2018
• First Posted (ACTUAL): November 15, 2018

Study Record Updates

• Last Update Posted (ESTIMATE): February 9, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Hemorrhagic Stroke; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Adrenergic beta-1 Receptor Antagonists; Nitric Oxide Donors; Esmolol; Nitroprusside
• Other Study ID Numbers: CRT088

Drug and device information, study documents

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