Safety and Efficacy of Angiotensin (1-7) in Persons With Moderate to Severe Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

— ANGel T  

Official title:

A Randomized, Double-blind, Placebo Controlled Study of the Safety and Efficacy of Angiotensin (1-7) in Persons With Moderate to Severe Traumatic Brain Injury (TBI)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06282965
• Other study ID #: AngT-001
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: March 2024
• Est. completion date: September 2027

Study information

• Verified date: December 2023
• Source: University of Arizona
• Contact: Clinical Research Coordinator
• Phone: (520) 237-6845
• Email: traumaresearch[@]arizona.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The goal of this clinical trial is to test the safety of the drug Angiotensin (1-7) and learn whether it works well as a treatment in people who have suffered a moderate to severe traumatic brain injury (TBI). The main questions this trial aims to answer are: - Is Angiotensin (1-7) safe? - Does Angiotensin (1-7) improve mental functioning and reduce physical signs of brain damage in people who have suffered a moderate to severe TBI? Participants will: - Complete 21 days of study treatment consisting of a once-daily injection. - Provide blood samples. - Undergo two magnetic resonance imaging (MRI) scans of the brain. - Complete specific tasks and questionnaires that allow researchers to evaluate the participant's brain and psychological functioning. Researchers will compare three groups: two groups that receive different doses of Angiotensin (1-7) and one group that receives a look-alike treatment with no active drug. This will allow researchers to see if the drug has any negative effects and whether it improves mental functioning and physical signs of brain damage after a TBI.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 90
• Est. completion date: September 2027
• Est. primary completion date: September 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participant or representative willing to provide informed consent.
• Age 18 years or older at time of enrollment.
• Traumatically induced head injury resulting from insult to head from an external force.
• Clinical diagnosis of acute intracranial lesion based on neuroradiologist report. CT scan and report must be available.
• Moderate or severe traumatic brain injury (TBI) defined as Glasgow Coma Scale (GCS) score on trauma presentation of 12 or less. In general: Moderate TBI will be defined as loss of consciousness between 30 minutes and 24 hours and GCS between 9 and 12. Severe TBI will be defined as loss of consciousness > 24 hours and GCS = 9.
• Enrollment within 48 hours of TBI.

Exclusion Criteria:

• Time of injury cannot be determined.
• Neurosurgery within the last 30 days.
• History of neurodegenerative disease or disorder including dementia, Parkinson's disease, multiple sclerosis, seizure disorder, or brain tumors that would impact cognitive testing.
• Contraindication to having an MRI.
• Pregnant or lactating female.
• Female of childbearing potential or sexually active male who is not willing to use an acceptable method of birth control for the treatment period and 7 days after the last dose of the study drug.
• Participation in another clinical study involving investigational product within 30 days prior to study enrollment.
• If in the opinion of the investigator, candidate is unsuitable for participation in the study.

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury
• Wounds and Injuries

Intervention

Drug:
• Angiotensin (1-7)
The drug will be dissolved in 0.9% USP/NF grade sterile for injection saline (NaCl) and prepared in a concentration that aligns with the participant's weight.
• Sterile saline
Sterile solution of 0.9% NaCl in water.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Arizona	United States Department of Defense

References & Publications (27)

Bruhns RP, Sulaiman MI, Gaub M, Bae EH, Davidson Knapp RB, Larson AR, Smith A, Coleman DL, Staatz WD, Sandweiss AJ, Joseph B, Hay M, Largent-Milnes TM, Vanderah TW. Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury. Front Behav Neurosci. 2022 Aug 4;16:903980. doi: 10.3389/fnbeh.2022.903980. eCollection 2022. — View Citation

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Hay M, Vanderah TW, Samareh-Jahani F, Constantopoulos E, Uprety AR, Barnes CA, Konhilas J. Cognitive impairment in heart failure: A protective role for angiotensin-(1-7). Behav Neurosci. 2017 Feb;131(1):99-114. doi: 10.1037/bne0000182. Epub 2017 Jan 5. — View Citation

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Hellner K, Walther T, Schubert M, Albrecht D. Angiotensin-(1-7) enhances LTP in the hippocampus through the G-protein-coupled receptor Mas. Mol Cell Neurosci. 2005 Jul;29(3):427-35. doi: 10.1016/j.mcn.2005.03.012. — View Citation

Hoyer-Kimura C, Konhilas JP, Mansour HM, Polt R, Doyle KP, Billheimer D, Hay M. Neurofilament light: a possible prognostic biomarker for treatment of vascular contributions to cognitive impairment and dementia. J Neuroinflammation. 2021 Oct 15;18(1):236. doi: 10.1186/s12974-021-02281-1. — View Citation

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Janatpour ZC, Symes AJ. The extended renin-angiotensin system: a promising target for traumatic brain injury therapeutics. Neural Regen Res. 2020 Jun;15(6):1025-1026. doi: 10.4103/1673-5374.270304. No abstract available. — View Citation

Kelley BJ, Lifshitz J, Povlishock JT. Neuroinflammatory responses after experimental diffuse traumatic brain injury. J Neuropathol Exp Neurol. 2007 Nov;66(11):989-1001. doi: 10.1097/NEN.0b013e3181588245. — View Citation

Khellaf A, Khan DZ, Helmy A. Recent advances in traumatic brain injury. J Neurol. 2019 Nov;266(11):2878-2889. doi: 10.1007/s00415-019-09541-4. Epub 2019 Sep 28. — View Citation

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McGinn MJ, Povlishock JT. Pathophysiology of Traumatic Brain Injury. Neurosurg Clin N Am. 2016 Oct;27(4):397-407. doi: 10.1016/j.nec.2016.06.002. Epub 2016 Aug 10. — View Citation

Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM. Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone. Clin Cancer Res. 2009 Dec 1;15(23):7398-404. doi: 10.1158/1078-0432.CCR-09-1957. Epub 2009 Nov 17. — View Citation

Pham H, Schwartz BM, Delmore JE, Reed E, Cruickshank S, Drummond L, Rodgers KE, Peterson KJ, diZerega GS. Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy. Cancer Chemother Pharmacol. 2013 Apr;71(4):965-72. doi: 10.1007/s00280-013-2089-x. Epub 2013 Jan 31. — View Citation

Povlishock JT. The classification of traumatic brain injury (TBI) for targeted therapies. J Neurotrauma. 2008 Jul;25(7):717-8. doi: 10.1089/neu.2008.9964. No abstract available. — View Citation

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Regenhardt RW, Mecca AP, Desland F, Ritucci-Chinni PF, Ludin JA, Greenstein D, Banuelos C, Bizon JL, Reinhard MK, Sumners C. Centrally administered angiotensin-(1-7) increases the survival of stroke-prone spontaneously hypertensive rats. Exp Physiol. 2014 Feb;99(2):442-53. doi: 10.1113/expphysiol.2013.075242. Epub 2013 Oct 18. — View Citation

Rodgers KE, Oliver J, diZerega GS. Phase I/II dose escalation study of angiotensin 1-7 [A(1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer. Cancer Chemother Pharmacol. 2006 May;57(5):559-68. doi: 10.1007/s00280-005-0078-4. Epub 2005 Aug 12. — View Citation

Rudolph JL, Ramlawi B, Kuchel GA, McElhaney JE, Xie D, Sellke FW, Khabbaz K, Levkoff SE, Marcantonio ER. Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci. 2008 Feb;63(2):184-9. doi: 10.1093/gerona/63.2.184. — View Citation

Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol. 2013 Jan 18;216(2):R1-R17. doi: 10.1530/JOE-12-0341. Print 2013 Feb. — View Citation

Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, Godbout K, Parsons T, Baronas E, Hsieh F, Acton S, Patane M, Nichols A, Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002 Apr 26;277(17):14838-43. doi: 10.1074/jbc.M200581200. Epub 2002 Jan 28. — View Citation

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* Note: There are 27 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with adverse events	The number of participants with adverse events in each group will be compared in order to determine whether Angiotensin (1-7) is significantly associated with the occurrence of adverse events.	At 21 days
Primary	Performance on the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)	The Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) is a brief neuropsychological assessment consisting of eleven tasks. It is used to assess cognitive function. Errors in each task are summed for a total score ranging from 0 to 70. Higher scores represent greater cognitive dysfunction, with a score of 0 representing the least impairment and a score of 70 representing the greatest impairment.	90 days
Secondary	Cognitive functions after Angiotensin (1-7) treatment as measured by the Montreal Cognitive Assessment (MoCA)	Difference in performance for the treatment groups compared to controls on the Montreal Cognitive Assessment (MoCA). The range of possible scores is 0-30, with scores of 26 and above being considered normal.	90 days
Secondary	Function after Angiotensin (1-7) treatment, as measured by the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL)	Differences between the treatment groups and controls on the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL), a 23-item inventory to assess daily functioning by asking about the participant's performance of multiple activities in the past four weeks. Scores range from 0 to 78, with 0 indicating the greatest disability.	90 days
Secondary	Effects of Angiotensin (1-7) on acute CNS damage biomarker phosphorylated tau (p-tau)	Change in phosphorylated tau (p-tau), a biomarker which can predict cognitive decline, cognitive impairment, and dementia.	Enrollment to 21 days
Secondary	Effects of Angiotensin (1-7) on CNS damage biomarker phosphorylated tau (p-tau) after 90 days	Change in phosphorylated tau (p-tau), a biomarker which can predict cognitive decline, cognitive impairment, and dementia.	Enrollment to 90 days
Secondary	Effects of Angiotensin (1-7) on brain white matter integrity	Assessment of difference in white matter integrity calculated from MR images.	MRI baseline to 90 days
Secondary	Effects of Angiotensin (1-7) on length of hospital stay	Length of stay will be calculated as the difference between the admission and discharge dates.	Admission to discharge, average of 5 days
Secondary	Incidence and duration of delirium as assessed by the Confusion Assessment Method (CAM)	The Confusion Assessment Method (CAM) is used to diagnose delirium using an algorithm based on the following features: Acute onset and fluctuating course.; Inattention.; Disorganized thinking.; Altered level of consciousness.	Admission to discharge, average of 5 days
Secondary	Change in suicidal ideation and behavior as assessed by the Patient Health Questionnaire (PHQ-9)	The Patient Health Questionnaire (PHQ-9) is a brief questionnaire used to assess the severity of symptoms of depression. The range of possible scores is 0-27, with a higher score indicating greater depression severity.	Enrollment to 21 days, enrollment to 90 days