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Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury (BFF)

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ClinicalTrials.gov Identifier: NCT03496545
Recruitment Status : Recruiting
First Posted : April 12, 2018
Last Update Posted : August 29, 2019
Sponsor:
Information provided by (Responsible Party):
Judy Ch'ang, MD, University of California, San Francisco

Brief Summary:
The purpose of this study is to evaluate the antipyretic effect of bromocriptine in critically-ill patients with acute neurologic injury and fever from infectious and non-infectious etiologies.

Condition or disease Intervention/treatment Phase
Subarachnoid Hemorrhage Subdural Hematoma Traumatic Brain Injury Ischemic Stroke Fever Intracerebral Hemorrhage Drug: Bromocriptine Drug: Acetaminophen Phase 1 Phase 2

Detailed Description:

In patients with acute neurologic injury such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke, fever has been found to be an independent predictor of poor outcome including increased mortality rates, longer hospital stays, depressed level of consciousness, and worse functional outcomes. Our current antipyretic therapy of acetaminophen and sometimes nonsteroidal anti-inflammatory drugs are not very effective and external cooling requires sedatives and other medications to prevent shivering and pain. Bromocriptine is a dopamine D2 receptor agonist which acts at the hypothalamus, a specific area of the brain that regulates body temperature. Fevers of both central and infectious etiologies must be regulated through the hypothalamus and we have evidence that bromocriptine has an antipyretic effect at the hypothalamus; thus, we hypothesize that bromocriptine could be used safely and more broadly to treat all fevers in the acute setting and not just refractory central fevers in this patient population.

Here, we propose to evaluate the acute antipyretic effects of bromocriptine in this critically-ill population through a pilot, open label, blinded endpoint, randomized controlled trial. In both enrolling centers, University of California, San Francisco Medical Center Parnassus (UCSF) and Zuckerberg San Francisco General Hospital, every patient who is admitted to the neurointensive care unit for an anticipated stay of greater than 48 hours with a diagnosis of subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), traumatic brain injury (TBI), subdural hematoma (SDH), and ischemic stroke will be screened and consented. If they have a temperature reading ≥ 38.3 ºC, the investigational pharmacy will randomize them to the control arm of acetaminophen or the intervention arm of acetaminophen and bromocriptine for 48 hours. We will continuously measure their temperature and other vitals data. Retrospectively, we will review imaging and labs ordered to work up infectious etiologies of fever. The ICU nurse will do a 5 minute assessment every shift during the 48 hour study period for side effects. The temperature data will be analyzed between the two study arms.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: open label, blinded endpoint, randomized (1:1) controlled trial with two arms: control - acetaminophen and intervention - acetaminophen and bromocriptine.
Masking: Single (Outcomes Assessor)
Masking Description: The data analyst who will analyze the data from each patient will be masked to what medication(s) the patients received.
Primary Purpose: Treatment
Official Title: Efficacy of Bromocriptine to Reduce Body Temperature in Febrile Critically-ill Adults With Acute Neurologic Disease: an Open-label, Blinded Endpoint, Randomized Controlled Trial
Actual Study Start Date : November 30, 2018
Estimated Primary Completion Date : July 1, 2020
Estimated Study Completion Date : July 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fever

Arm Intervention/treatment
Acetaminophen
standard of care - acetaminophen 650mg every 4 hours PO/NG/FT (per oral, nasogastric tube, feeding tube) for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC.
Drug: Acetaminophen
acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours
Other Name: Tylenol

Experimental: Bromocriptine
bromocriptine 5mg every 4 hours PO/NG/FT for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC.
Drug: Bromocriptine
bromocriptine 5mg every 4 hours PO/NG/FT and acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours
Other Name: parlodel

Drug: Acetaminophen
acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours
Other Name: Tylenol




Primary Outcome Measures :
  1. Temperature burden [ Time Frame: Average temperature in degrees Celsius above 37°C over 48 hours ]
    Total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication


Secondary Outcome Measures :
  1. Incidence of bromocriptine-induced adverse events - symptomatic hypotension, nausea and headache [ Time Frame: Nursing assessment at every shift during 48 hour study period after first drug administration ]
    Episodes of symptomatic hypotension, defined as decrease in supine systolic and diastolic pressures of greater than 20mm and 10mm Hg respectively with patient reported accompanying symptoms of light headedness or dizziness and incidence of nausea and headache.

  2. Total time that temperature is ≥ 38.3ºC [ Time Frame: Temperature in degrees Celsius up to 48 hours ]
    How many hours where the temperature is ≥ 38.3ºC during the 48 hours of control versus intervention administration

  3. Total Time to first temperature < 37.5ºC [ Time Frame: Temperature in degrees Celsius assessed at 48 hours ]
    How many minutes to hours does it take after initial control versus intervention administration for the temperature to reach < 37.5ºC



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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • age ≥18 years old
  • weight ≥ 40 kg
  • one reading of body temperature ≥ 38.3 ºC
  • diagnosis of subarachnoid hemorrhage, intracerebral hemorrhage, traumatic brain injury, subdural hematoma, or ischemic stroke
  • admission to the Intensive Care Unit at UCSF Medical Center or Zuckerberg San Francisco General Hospital.

Exclusion Criteria:

  • bromocriptine or acetaminophen hypersensitivity or allergy
  • known contraindication to bromocriptine— known ergot alkaloid hypersensitivity, known history of syncopal migraine
  • contraindication to nasogastric tube or swallowing pills
  • current diagnosis of acute liver failure, acute liver injury, or prior diagnosis of cirrhosis. acute presentation (< 26 weeks), evidence of coagulation abnormality: international normalized ratio (INR) ≥ 2; evidence of liver damage: alanine aminotransferase (ALT) of 10 x normal value; and any degree of mental status alteration
  • currently being treated with intra or extravascular therapeutic hypothermia - or where therapeutic hypothermia treatment is anticipated during study period
  • hyperthermic syndromes: heat stroke, evidence of thyrotoxicosis, malignant hyperthermia, neuroleptic malignant syndrome, or other drug-induced hyperthermia
  • administration of acetaminophen or acetaminophen containing medications within 9 hours prior to fever presentation
  • administration of non-steroidal anti-inflammatory drugs (NSAIDs) within 6 hours prior to fever presentation or aspirin > 300mg less than 1 hour prior to fever presentation.
  • pregnancy
  • extracorporeal blood circuit therapies: replacement therapy, extracorporeal life support (ventricular assist device, extracorporeal membrane oxygenation) during study period
  • anticipated ICU stay < 48 hours'
  • creatinine clearance ≤ 30
  • severe cardiovascular disease (especially unstable angina or severe valvular disease)
  • patients already taking bromocriptine for other indications

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03496545


Contacts
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Contact: Judy H Ch'ang, MD 415-502-1453 judy.chang@ucsf.edu
Contact: Anthony S Kim, MD, MAS 415-476-3733 anthony.kim@ucsf.edu

Locations
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United States, California
Zuckerberg San Francisco General Hospital and Trauma Center Recruiting
San Francisco, California, United States, 94110
Contact: Judy H Ch'ang, MD    415-502-1453    judy.chang@ucsf.edu   
Contact: Anthony S Kim, MD, MAS    415-476-3733    anthony.kim@ucsf.edu   
University of California, San Francisco Medical Center - Parnassus Recruiting
San Francisco, California, United States, 94143
Contact: Judy H Ch'ang, MD    415-502-1453    judy.chang@ucsf.edu   
Contact: Anthony S Kim, MD, MAS    415-476-3733    anthony.kim@ucsf.edu   
Sub-Investigator: Hildegarde Schell-Chapele, PhD, RN         
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Judy H Ch'ang, MD University of California, San Francisco
  Study Documents (Full-Text)

Documents provided by Judy Ch'ang, MD, University of California, San Francisco:
Informed Consent Form  [PDF] February 6, 2019


Publications:

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Responsible Party: Judy Ch'ang, MD, Clinical Instructor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03496545     History of Changes
Other Study ID Numbers: 18-24766
First Posted: April 12, 2018    Key Record Dates
Last Update Posted: August 29, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to make IPD available to other researchers as this data is very specific to this study.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Judy Ch'ang, MD, University of California, San Francisco:
fever
central fever
neurogenic fever
hyperthermia
bromocriptine
subarachnoid hemorrhage
SAH
subdural hematoma
SDH
intracerebral hemorrhage
ICH
traumatic brain injury
TBI
ischemic stroke
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Subarachnoid Hemorrhage
Cerebral Hemorrhage
Hematoma, Subdural
Hemorrhage
Fever
Hematoma
Wounds and Injuries
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Craniocerebral Trauma
Trauma, Nervous System
Body Temperature Changes
Signs and Symptoms
Intracranial Hemorrhages
Intracranial Hemorrhage, Traumatic
Acetaminophen
Bromocriptine
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Antipyretics