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Subarachnoid HemorrhagePhase 1/2BFFNCT03496545

Efficacy of Bromocriptine For Fever Reduction in Acute Neurologic Injury

A Phase 1/2 study testing Bromocriptine 5 MG and Acetaminophen 650 MG in people with Subarachnoid Hemorrhage and Subdural Hematoma, run by University of California, San Francisco at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 100 years
What is being tested?
Bromocriptine 5 MG and Acetaminophen 650 MG
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
47 participants
Where
2 sitesUnited States
Study dates
30 Nov 2018to 2 Nov 2019
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 14Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • Zuckerberg San Francisco General Hospital and Trauma Center

    San Francisco, California, 94110

  • University of California, San Francisco Medical Center - Parnassus

    San Francisco, California, 94143

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Bromocriptine 5 MG, Acetaminophen 650 MG
Keywords
fever, central fever, neurogenic fever, hyperthermia, bromocriptine, subarachnoid hemorrhage, SAH, subdural hematoma, SDH, intracerebral hemorrhage, ICH, traumatic brain injury, TBI, ischemic stroke
Medical subject headings
Subarachnoid Hemorrhage, Hematoma, Subdural, Brain Injuries, Traumatic, Ischemic Stroke, Fever, Cerebral Hemorrhage, Hyperthermia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bromocriptine 5 MGDrug

    Also called parlodel

    Bromocriptine 5 mg every 4 hours PO/NG/FT

  • Acetaminophen 650 MGDrug

    Also called Tylenol

    Acetaminophen 650 mg every 4 hours PO/NG/FT for 48 hours

Study groups in NCT03496545
Study groupRoleWhat they receive
AcetaminophenActive comparatorStandard 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.
Receives: Drug: Acetaminophen 650 MG
Bromocriptine and AcetaminophenExperimentalBromocriptine 5mg every 4 hours PO/NG/FT for 48 hours and acetaminophen 650mg every 4 hours PO/NG/FT for 48 hours, initiated within 1 hour after temperature reading ≥ 38.3ºC.
Receives: Drug: Bromocriptine 5 MG; Drug: Acetaminophen 650 MG

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Temperature Burden

    Mean total body temperature burden above 37°C over 48 hours during which patient receives either control or intervention medication.

    Measured: over 48 hours

Secondary outcomes (3)
  1. Incidence of Adverse Events - Symptomatic Hypotension, Nausea and Headache

    Episodes of symptomatic hypotension, including 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.

    Measured: Nursing assessment at every shift during 48 hour study period after first drug administration

  2. Total Time That Temperature is ≥ 38.3ºC

    Time in minutes where the temperature is ≥ 38.3ºC during the 48 hours of control versus intervention administration.

    Measured: 48 hours

  3. Total Time to First Temperature < 37.5ºC

    Time in minutes it took after medication administration for the temperature to reach < 37.5ºC.

    Measured: 48 hours

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Apr 2018
  2. Study start30 Nov 2018
  3. Primary completion2 Nov 2019
  4. Study completion2 Nov 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
open label, blinded endpoint, randomized (1:1) controlled trial with two arms: control - acetaminophen and intervention - acetaminophen and bromocriptine.
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
47 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03496545
Sponsor's protocol ID
18-24766
Acronym
BFF
Status last verified
Jun 2021
First submitted
17 Mar 2018
Last updated
24 Jun 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: There is no plan to make IPD available to other researchers as this data is very specific to this study.

Publications

  • Mullins ME, Empey M, Jaramillo D, Sosa S, Human T, Diringer MN. A prospective randomized study to evaluate the antipyretic effect of the combination of acetaminophen and ibuprofen in neurological ICU patients. Neurocrit Care. 2011 Dec;15(3):375-8. doi: 10.1007/s12028-011-9533-8.

    PubMed 21503807
  • Polson J, Lee WM; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology. 2005 May;41(5):1179-97. doi: 10.1002/hep.20703. No abstract available.

    PubMed 15841455
  • Meyfroidt G, Baguley IJ, Menon DK. Paroxysmal sympathetic hyperactivity: the storm after acute brain injury. Lancet Neurol. 2017 Sep;16(9):721-729. doi: 10.1016/S1474-4422(17)30259-4.

    PubMed 28816118
  • Weimar C, Ziegler A, Konig IR, Diener HC. Predicting functional outcome and survival after acute ischemic stroke. J Neurol. 2002 Jul;249(7):888-95. doi: 10.1007/s00415-002-0755-8.

    PubMed 12140674
  • Sung CY, Lee TH, Chu NS. Central hyperthermia in acute stroke. Eur Neurol. 2009;62(2):86-92. doi: 10.1159/000222778. Epub 2009 Jun 12.

    PubMed 19521083
  • Jiang JY, Gao GY, Li WP, Yu MK, Zhu C. Early indicators of prognosis in 846 cases of severe traumatic brain injury. J Neurotrauma. 2002 Jul;19(7):869-74. doi: 10.1089/08977150260190456.

    PubMed 12184856
  • Axelrod YK, Diringer MN. Temperature management in acute neurologic disorders. Neurol Clin. 2008 May;26(2):585-603, xi. doi: 10.1016/j.ncl.2008.02.005.

    PubMed 18514828
  • Maher J, Hachinski V. Hypothermia as a potential treatment for cerebral ischemia. Cerebrovasc Brain Metab Rev. 1993 Winter;5(4):277-300.

    PubMed 8110595
  • Ginsberg MD, Sternau LL, Globus MY, Dietrich WD, Busto R. Therapeutic modulation of brain temperature: relevance to ischemic brain injury. Cerebrovasc Brain Metab Rev. 1992 Fall;4(3):189-225.

    PubMed 1389956
  • Durukan A, Marinkovic I, Strbian D, Pitkonen M, Pedrono E, Soinne L, Abo-Ramadan U, Tatlisumak T. Post-ischemic blood-brain barrier leakage in rats: one-week follow-up by MRI. Brain Res. 2009 Jul 14;1280:158-65. doi: 10.1016/j.brainres.2009.05.025. Epub 2009 May 18.

    PubMed 19450568
  • Dietrich WD, Alonso O, Halley M, Busto R. Delayed posttraumatic brain hyperthermia worsens outcome after fluid percussion brain injury: a light and electron microscopic study in rats. Neurosurgery. 1996 Mar;38(3):533-41; discussion 541. doi: 10.1097/00006123-199603000-00023.

    PubMed 8837806
  • Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab. 1987 Dec;7(6):729-38. doi: 10.1038/jcbfm.1987.127.

    PubMed 3693428
  • Rabinstein AA, Sandhu K. Non-infectious fever in the neurological intensive care unit: incidence, causes and predictors. J Neurol Neurosurg Psychiatry. 2007 Nov;78(11):1278-80. doi: 10.1136/jnnp.2006.112730.

    PubMed 17940175
  • Marik PE. Fever in the ICU. Chest. 2000 Mar;117(3):855-69. doi: 10.1378/chest.117.3.855.

    PubMed 10713016
  • Samudra N, Figueroa S. Intractable Central Hyperthermia in the Setting of Brainstem Hemorrhage. Ther Hypothermia Temp Manag. 2016 Jun;6(2):98-101. doi: 10.1089/ther.2016.0004. Epub 2016 Mar 16.

    PubMed 26982342

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Bromocriptine 5 MG and Acetaminophen 650 MG in people with Subarachnoid Hemorrhage and Subdural Hematoma, run by University of California, San Francisco at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 24 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Jun 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Temperature Burden (time frame: over 48 hours). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03496545, which also lists 29 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2021.

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