Angiotensin (1-7) for Traumatic Brain Injury
(ANGel T Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: University of Arizona
Disqualifiers: Neurosurgery, Neurodegenerative diseases, Pregnancy, others
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?
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.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
What evidence supports the effectiveness of the drug Angiotensin (1-7) for treating traumatic brain injury?
How is the drug Angiotensin (1-7) unique for treating traumatic brain injury?
Angiotensin (1-7) is unique because it works by activating the Mas receptor, which helps reduce inflammation and protect brain cells after a traumatic brain injury. Unlike other treatments, it is administered subcutaneously (under the skin) and has shown potential in improving recovery by reducing brain damage and enhancing cognitive function in animal studies.12346
Eligibility Criteria
This trial is for adults who've had a moderate to severe traumatic brain injury (TBI) with a Glasgow Coma Scale score of 12 or less. They must be enrolled within 48 hours of the injury and have a CT scan confirming an acute intracranial lesion. Consent from the participant or representative is required.Inclusion Criteria
I had a serious head injury with a low consciousness score.
I am willing to sign the consent form.
I am 18 years old or older.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive a once-daily injection of Angiotensin (1-7) or placebo for 21 days, provide blood samples, undergo MRI scans, and complete tasks and questionnaires.
3 weeks
Daily visits for injections, 2 MRI visits
Follow-up
Participants are monitored for safety and effectiveness after treatment, including assessments of cognitive function and biomarkers.
90 days
Treatment Details
Interventions
- Angiotensin (1-7) (Peptide)
Trial OverviewThe trial tests Angiotensin (1-7)'s safety and effectiveness in improving mental function and reducing physical signs of TBI damage. It involves daily injections for 21 days, blood samples, two MRI scans, tasks, and questionnaires to assess brain function.
Participant Groups
3Treatment groups
Experimental Treatment
Placebo Group
Group I: Ang 1-7 200 mcg/kg/dayExperimental Treatment1 Intervention
Angiotensin I/II (1-7) acetate will be delivered as a subcutaneous injection at a dose of 200 micrograms per kilogram per day for 21 days.
Group II: Ang 1-7 100 mcg/kg/dayExperimental Treatment1 Intervention
Angiotensin I/II (1-7) acetate will be delivered as a subcutaneous injection at a dose of 100 micrograms per kilogram per day for 21 days.
Group III: PlaceboPlacebo Group1 Intervention
Sterile saline (NaCl) will be delivered as a subcutaneous injection for 21 days.
Angiotensin (1-7) is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as TXA127 for:
- Rare neuromuscular and connective tissue diseases
- Pulmonary arterial hypertension
- Myelodysplastic Syndrome (MDS)
- Duchenne muscular dystrophy (DMD)
- Limb-girdle muscular dystrophy (LGMD)
- Congenital muscular dystrophy MDC1A
- Marfan syndrome
- Dystrophic Epidermolysis Bullosa (DEB)
🇪🇺 Approved in European Union as TXA127 for:
- Duchenne muscular dystrophy (DMD)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of ArizonaTucson, AZ
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Who Is Running the Clinical Trial?
University of ArizonaLead Sponsor
United States Department of DefenseCollaborator
References
Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury. [2023]Traumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI. This study examined the therapeutic effect of Ang-(1-7) on secondary injury observed in a murine model of mild TBI (mTBI) in a closed skull, single injury model.
Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice. [2020]Angiotensin II (Ang II)-mediated activation of its type I receptor (AT1R) in the central nervous system promotes glial proliferation, local inflammation, and a decrease of cerebral blood flow. Angiotensin-(1-7) (Ang-(1-7))-an Ang II derivative peptide-signals through the Mas receptor (MasR) in opposition to Ang II/AT1R, promoting anti-inflammatory, vasodilatory, and neuroprotective effects. As our laboratory has previously demonstrated beneficial effects of AT1R inhibition following controlled cortical impact (CCI) in mice, we asked whether activation of Ang-(1-7)/MasR signaling would also be beneficial in this model. Adult male C57BL/6 mice were injured by CCI. Ang-(1-7) or vehicle was administered subcutaneously (S.Q.) at 1 mg/kg/day at 1 or 6 h post-injury, until animals were sacrificed at 3 or 29 days post-injury (dpi). Ang-(1-7) attenuated motor deficits at 3 dpi and improved performance in the Morris Water Maze at 28 dpi. Brain histology or magnetic resonance imaging (MRI) indicated that Ang-(1-7)-treated mice had smaller lesion volumes at 3, 10, 24, and 29 dpi. Pre-treatment with A779, a MasR antagonist, prevented Ang-(1-7) from reducing lesion volume at 3 dpi, suggesting that the benefits of Ang-(1-7) were MasR-dependent. Immunohistochemistry revealed that Ang-(1-7) reduced microgliosis at 3 and 29 dpi, and astrogliosis at 29 dpi. Ang-(1-7) decreased neuronal and capillary loss at 29 dpi. In summary, S.Q. administration of Ang-(1-7) after injury had anti-inflammatory, neuroprotective, and cerebrovascular-protective actions leading to improved functional and pathological recovery in a mouse model of traumatic brain injury (TBI). These data show for the first time that Ang-(1-7) has potential therapeutic use for TBI.
Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis. [2022]Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the United Kingdom and worldwide; however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the renin-angiotensin system (RAS) as a treatment pathway for TBI in adults. Relevant electronic databases were searched on December 18, 2019, and updated May 16, 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened. Eighteen pre-clinical randomized controlled trials (RCTs) (n = 2269) and two clinical cohort studies (n = 771) were included. Meta-analyses of six pre-clinical RCTs (n = 99) indicated that candesartan improved neurological function over the short term (< 7 days: standardized mean difference [SMD] 0.61, 95% confidence interval [CI] 0.19-1.03, I2 = 0%) and over the long term (≥ 7 days: SMD 1.06, 95% CI 0.38; 1.73, I2 = 0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited because there were few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in pre-clinical studies with moderate quality of evidence (Grading of Recommendations Assessment, Development and Evaluation [GRADE]). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, because there is strong and consistent evidence of neuroprotection shown by these pre-clinical studies.
Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma*. [2022]To investigate the regulation of the cerebral renin-angiotensin system and the effect of angiotensin II receptor type 1 inhibition on secondary brain damage, cerebral inflammation, and neurologic outcome after head trauma.
Angiotensin receptor type 2 activation induces neuroprotection and neurogenesis after traumatic brain injury. [2021]Angiotensin II receptor type 2 (AT(2)) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT(2) was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT(2) activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT(2) agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT(2) antagonist PD123319. Our results suggest that AT(2) activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.
The role of the brain renin-angiotensin system (RAS) in mild traumatic brain injury (TBI). [2022]There is considerable interest in traumatic brain injury (TBI) induced by repeated concussions suffered by athletes in sports, military personnel from combat-and non-combat related activities, and civilian populations who suffer head injuries from accidents and domestic violence. Although the renin-angiotensin system (RAS) is primarily a systemic cardiovascular regulatory system that, when dysregulated, causes hypertension and cardiovascular pathology, the brain contains a local RAS that plays a critical role in the pathophysiology of several neurodegenerative diseases. This local RAS includes receptors for angiotensin (Ang) II within the brain parenchyma, as well as on circumventricular organs outside the blood-brain-barrier. The brain RAS acts primarily via the type 1 Ang II receptor (AT1R), exacerbating insults and pathology. With TBI, the brain RAS may contribute to permanent brain damage, especially when a second TBI occurs before the brain recovers from an initial injury. Agents are needed that minimize the extent of injury from an acute TBI, reducing TBI-mediated permanent brain damage. This review discusses how activation of the brain RAS following TBI contributes to this damage, and how drugs that counteract activation of the AT1R including AT1R blockers (ARBs), renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, and agonists at type 2 Ang II receptors (AT2) and at Ang (1-7) receptors (Mas) can potentially ameliorate TBI-induced brain damage.