Beta Blocker Use In Traumatic Brain Injury Based On The High-Sensitive Troponin T Status (BBTBBT)

• ClinicalTrials.gov Identifier: NCT04508244
• Recruitment Status: Recruiting
• First Posted: August 11, 2020
• Last Update Posted: February 21, 2021
• Sponsor: Hamad Medical Corporation
• Information provided by (Responsible Party): Hamad Medical Corporation

Study Description

Brief Summary:

Beta blockers (BB) play an important role in protection of end organs that are susceptible for secondary injury by the Traumatic brain injury (TBI)-induced catecholamine surge. However, use of BBs in trauma patients is not yet the standard of care which necessitates clear scientific evidence and justification to be used especially in TBI patients. The BBTBBT study aims to determine whether early administration of propranolol based on the HSTnT status will improve the outcome of mild-to-severe TBI patients. Our primary hypothesis is that BBs are effective in reducing 10 and 30-day mortality in TBI patients.BBs are effective in reducing 10 and 30-day mortality in TBI patients.

Methods/Design: The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled trial, three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status.

Condition or disease	Intervention/treatment	Phase
Trauma; Brain Injuries; Stress Reaction; Beta Blockers; Troponin	Drug: Placebo; Drug: Propranolol	Phase 4

Detailed Description:

Traumatic brain injury (TBI) accounts for up to 30% of all injury-related deaths [1]. It also poses a significant morbidity and economic burden world-wide [2,3]. While there has been significant advances in trauma care overall, there are limited medical management options for head injury. Based on retrospective observational studies, TBI is associated with an increased risk of mortality. Some of these studies reported higher rate of mortality in TBI patients who had elevated serum troponin in comparison to those who had normal troponin, even in isolated TBI.

Few studies have evaluated the clinical significance of the release of serum cardiac troponins after trauma [4-7]. Some of these studies showed that elevated troponin could reflect the degree of severity of overall body injury, but in particular the severity of thorax trauma regardless of cardiac involvement [5,6]. Furthermore, elevated troponins were reported in acute non-traumatic head injury, including acute stroke (≈27%), and subarachnoid hemorrhage (≈20%) [4, 7]. However, the precise mechanism of elevated troponin is difficult to be determined due to the multitude of prevailing clinical circumstances which may influence troponin release. Moreover, the clinical significance and prognostic value of elevated troponins levels and immune response remain poorly explored in TBI patients. Earlier studies relied mainly on TnT or TnI and did not examine the newer high-sensitive TnT (HsTnT) which has more sensitivity and shorter time to detect myocardial damage. A recent meta-analysis showed that elevated troponins are commonly seen in critically-ill patients even in the absence of coronary artery disease [7,8,9] with a prevalence of 45% studies utilized conventional troponin assays ( TnT and TnI), [10] however, this figure reaches 62% with the use of HsTnT [11, 12]. From the therapeutic point of view, BBs use was reported to have better survival in blunt TBI patients [4, 14, 15,16]. Notably, BBs play an important role in protection of end organs that are susceptible for secondary injury by the TBI-induced catecholamine surge [4]. Upon the latter observation, the use of HsTnT test early in TBI cases may allow early stratification and therapy to possibly reduce mortality. However, this assumption needs further support through large clinical trials. Prospective studies that link the release of troponins and mortality in post-TBI patients are lacking. The use of BBs in patients with acute coronary myocardial injury is evidence-based, especially in the very early hours post myocardial injury. However, use of BBs in trauma patients is not yet the standard of care. The use of BBs needs to be clearly justified in TBI patients. Retrospectively, Salim et al [13] reported that patients with severe TBI who did not receive BBs had a mortality rate of 36% vs. 24% in those who were receiving BBs (p=0.036). Furthermore, if troponin I was elevated on admission, the hospital mortality increased to 48.5% in patients without BBs therapy vs. 22.4% in those who were using BBs (p=0.026).However, the two groups (with & without BB) were comparable for mortality, if the admission troponin values were not elevated (p=0.31). In brief, the utmost benefit in survival occurred in BBs use group based on the troponin positivity on admission. However, this study did not explain the specific underlying mechanism of troponin positivity. The BBTBBT study is a prospective, randomized, double-blinded, placebo-controlled trial, three-arm trial of BB use in mild-to-severe TBI patients based on the HsTnT status. We hypothesized that early administration of BBs has beneficial effect on the 10 and 30-day mortality in patients with mild-to-severe TBI based on the admission HsTnT status.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 771 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Prospective, randomized, double-blinded, placebo-controlled trial
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Beta Blocker Use In Traumatic Brain Injury Based On The High-Sensitive Troponin T Status: A Randomized Controlled Trial (BBTBBT)
• Actual Study Start Date: December 29, 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: TBI with positive troponin; Patients will receive IV propranolol for 6 days	Drug: Propranolol; 12 ampoules of 1 mg placebo solution (3 ampoules/day for 2 days; 2 ampoules/day for day-3 & 4 and 1 ampoule/day for day-5 & 6.; Other Name: inderal
Placebo Comparator: TBI with negative troponin (a); Patients will receive IV placebol for 6 days	Drug: Placebo; 12 ampoules of 1 mg placebo solution (3 ampoules/day for 2 days; 2 ampoules/day for day-3 & 4 and 1 ampoule/day for day-5 & 6.
Experimental: TBI with negative troponin (b); Patients will receive IV propranolol for 6 days	Drug: Propranolol; 12 ampoules of 1 mg placebo solution (3 ampoules/day for 2 days; 2 ampoules/day for day-3 & 4 and 1 ampoule/day for day-5 & 6.; Other Name: inderal

Outcome Measures

Primary Outcome Measures :

1. Mortality [ Time Frame: 10 days ]
   Number of participants who died from each study arm
2. Mortality [ Time Frame: 30 days ]
   Number of participants who died from each study arm

Secondary Outcome Measures :

1. Duration of hospital stay [ Time Frame: 3 months ]
   number of days in the hospital
2. Functional status [ Time Frame: 3 months ]
   Glasgow Outcome scale (range 1-8); higher scores mean a better outcome

Other Outcome Measures:

1. Injury severity indicators [ Time Frame: 48 hours ]
   correlation between blood biomarkers and head CT scan findings

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• All adults (≥18 -65 years)
• both genders
• mild-to-severe blunt TBI (head AIS 1-5 and/ GCS 4-15) patients requiring hospital admission

Exclusion Criteria:

• Patients <18 and> 65 yrs old
• penetrating trauma
• non-survivable injuries (head AIS=6 & GCS=3)
• uncontrolled bleeding on arrival to ED
• pregnant women
• prisoners
• patients with heart rate (HR) ≤70, systolic blood pressure (SBP) ≤100 mmHg (or MAP <70 mmHg) not responding to initial management or required to be maintained on vasopressors on arrival .
• Patients who will undergo hypothermia therapy,
• any penetrating injury to head, thorax or abdomen,
• history of bronchial asthma
• patients posted for emergency surgery during the first 6 hrs.

Contacts and Locations

Contacts

Contact: Ayman El-Menyar, MD; 44396130; aelmenyar@hamad.qa

Contact: Mohammad Asim, PhD; masim1@hamad.qa

Locations

Qatar

Hamad General Hospital; Recruiting

Doha, Qatar

Contact: Ayman El-Menyar, MD

Sponsors and Collaborators

Hamad Medical Corporation

Investigators

• Principal Investigator: Ayman El-Menyar, MD; Hamad Medical Corporation

More Information

Publications:

Faul M, Xu L, Wald MM, Coronado VG. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2010.

Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil. 2014 May;95(5):986-995.e1. doi: 10.1016/j.apmr.2013.10.032. Epub 2014 Jan 21. Review.

Mock C, Lormand JD, Goosen J, Joshipura M, Peden M. Guidelines for essential trauma care. Geneva, World Health Organization, 2004. Retrieved from: http://www.who.int/violence_injury_prevention/publications/services/en/guidelines_traumacare.pdf

Al-Otaiby MA, Al-Amri HS, Al-Moghairi AM. The clinical significance of cardiac troponins in medical practice. J Saudi Heart Assoc. 2011 Jan;23(1):3-11. doi: 10.1016/j.jsha.2010.10.001. Epub 2010 Oct 20.

Mahmood I, El-Menyar A, Dabdoob W, Abdulrahman Y, Siddiqui T, Atique S, Arumugam SK, Latifi R, Al-Thani H. Troponin T in Patients with Traumatic Chest Injuries with and without Cardiac Involvement: Insights from an Observational Study. N Am J Med Sci. 2016 Jan;8(1):17-24. doi: 10.4103/1947-2714.175188.

Edouard AR, Felten ML, Hebert JL, Cosson C, Martin L, Benhamou D. Incidence and significance of cardiac troponin I release in severe trauma patients. Anesthesiology. 2004 Dec;101(6):1262-8.

Hasanin A, Kamal A, Amin S, Zakaria D, El Sayed R, Mahmoud K, Mukhtar A. Incidence and outcome of cardiac injury in patients with severe head trauma. Scand J Trauma Resusc Emerg Med. 2016 Apr 27;24:58. doi: 10.1186/s13049-016-0246-z. Erratum in: Scand J Trauma Resusc Emerg Med. 2016;24:79.

Smith A, John M, Trout R, Davis E, Moningi S. Elevated cardiac troponins in sepsis: what do they signify? W V Med J. 2009 Jul-Aug;105(4):29-32.

Lim W, Cook DJ, Griffith LE, Crowther MA, Devereaux PJ. Elevated cardiac troponin levels in critically ill patients: prevalence, incidence, and outcomes. Am J Crit Care. 2006 May;15(3):280-8; quiz 289.

Poe S, Vandivier-Pletsch RH, Clay M, Wong HR, Haynes E, Rothenberg FG. Cardiac Troponin Measurement in the Critically Ill: Potential for Guiding Clinical Management. J Investig Med. 2015 Dec;63(8):905-15. doi: 10.1097/JIM.0000000000000239.

Salim A, Hadjizacharia P, Brown C, Inaba K, Teixeira PG, Chan L, Rhee P, Demetriades D. Significance of troponin elevation after severe traumatic brain injury. J Trauma. 2008 Jan;64(1):46-52. doi: 10.1097/TA.0b013e31815eb15a.

Bukur M, Mohseni S, Ley E, Salim A, Margulies D, Talving P, Demetriades D, Inaba K. Efficacy of beta-blockade after isolated blunt head injury: does race matter? J Trauma Acute Care Surg. 2012 Apr;72(4):1013-8. doi: 10.1097/TA.0b013e318241bc5b. Erratum in: J Trauma Acute Care Surg. 2012 Jun;72(6):1725. Mosheni, Shahin [corrected to Mohseni, Shahin].

Schroeppel TJ, Fischer PE, Zarzaur BL, Magnotti LJ, Clement LP, Fabian TC, Croce MA. Beta-adrenergic blockade and traumatic brain injury: protective? J Trauma. 2010 Oct;69(4):776-82. doi: 10.1097/TA.0b013e3181e981b8.

Ko A, Harada MY, Barmparas G, Thomsen GM, Alban RF, Bloom MB, Chung R, Melo N, Margulies DR, Ley EJ. Early propranolol after traumatic brain injury is associated with lower mortality. J Trauma Acute Care Surg. 2016 Apr;80(4):637-42. doi: 10.1097/TA.0000000000000959.

El-Menyar A, Asim M, Latifi R, Bangdiwala SI, Al-Thani H. Predictive value of positive high-sensitivity troponin T in intubated traumatic brain injury patients. J Neurosurg. 2018 Dec 1;129(6):1541-1549. doi: 10.3171/2017.7.JNS17675.

El-Menyar A, Goyal A, Latifi R, Al-Thani H, Frishman W. Brain-Heart Interactions in Traumatic Brain Injury. Cardiol Rev. 2017 Nov/Dec;25(6):279-288. doi: 10.1097/CRD.0000000000000167. Review.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

El-Menyar A, Asim M, Bahey AA, Chughtai T, Alyafai A, Abdelrahman H, Rizoli S, Peralta R, Al-Thani H. Beta blocker use in traumatic brain injury based on the high-sensitive troponin status (BBTBBT): methodology and protocol implementation of a double-blind randomized controlled clinical trial. Trials. 2021 Dec 7;22(1):890. doi: 10.1186/s13063-021-05872-8.

• Responsible Party: Hamad Medical Corporation
• ClinicalTrials.gov Identifier: NCT04508244
• Other Study ID Numbers: IRGC-05-SI-18-293
• First Posted: August 11, 2020
• Last Update Posted: February 21, 2021
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: data sharing agreement should be signed with the MRC and legal affair at HMC

• 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 Hamad Medical Corporation:

propranolol; troponin; biomarkers; myocardial injury; brain injury; trauma; qatar

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Fractures, Stress; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Fractures, Bone; Propranolol; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents