Angiotensin (1-7) for Traumatic Brain Injury

(ANGel T Trial)

Overseen By Clinical Research Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Arizona

Disqualifiers: Neurosurgery, Neurodegenerative diseases, Pregnancy, others

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 3 weeks

90 Participants Needed

Trial Summary

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?

Research in mice shows that Angiotensin (1-7) can improve recovery after traumatic brain injury by reducing inflammation, protecting brain cells, and improving cognitive function. This suggests it might help people with similar injuries. ^{1 2 3 4 5}

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. ^{1 2 3 4 6}

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.

Research Team

Bellal Joseph, MD

Principal Investigator

University of Arizona

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 signing up within 2 days after my brain injury.

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)

Trial Overview The 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

Group I: Ang 1-7 200 mcg/kg/day Experimental Treatment 1 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/day Experimental Treatment 1 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: Placebo Placebo Group 1 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)

Who Is Running the Clinical Trial?

University of Arizona

Lead Sponsor

Trials

545

Recruited

161,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

In a study involving 108 male mice with mild traumatic brain injury (mTBI), administration of Angiotensin 1-7 (Ang-1-7) significantly improved cognitive function compared to a control group, suggesting its potential as a therapeutic intervention for TBI.

Ang-1-7 treatment resulted in reduced neuronal damage in cortical and hippocampal areas and altered the expression of key proteins associated with brain injury, indicating its mechanism may involve neuroprotection and modulation of inflammatory responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury. Bruhns, RP., Sulaiman, MI., Gaub, M., et al.[2023]

In a mouse model of traumatic brain injury (TBI), administration of Angiotensin-(1-7) (Ang-(1-7)) significantly improved motor function and cognitive performance, indicating its potential as a therapeutic agent for TBI.

Ang-(1-7) treatment led to reduced brain lesion volumes and decreased inflammation, as evidenced by lower microgliosis and astrogliosis, demonstrating its neuroprotective and anti-inflammatory effects through Mas receptor activation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice. Janatpour, ZC., Korotcov, A., Bosomtwi, A., et al.[2020]

Candesartan, an angiotensin-receptor blocker, has shown significant improvements in neurological function in pre-clinical studies of traumatic brain injury (TBI), with a moderate effect size observed both in the short term (less than 7 days) and long term (7 days or more).

While other RAS-targeting drugs suggest potential benefits, the evidence is limited; thus, further clinical trials of candesartan are recommended to explore its neuroprotective effects in humans after TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis. Baron, DH., Skrobot, OA., Palmer, JC., et al.[2022]

Inhibiting angiotensin II receptor type 1 with candesartan within 4 hours after brain trauma significantly reduced secondary brain damage and improved neurological function in mice, highlighting its potential as a therapeutic target.

Daily treatment with candesartan for 5 days after injury led to sustained reductions in brain damage and inflammation, suggesting that timely and repeated inhibition of this receptor can effectively mitigate the effects of traumatic brain injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma*. Timaru-Kast, R., Wyschkon, S., Luh, C., et al.[2022]

Activation of the angiotensin II receptor type 2 (AT(2)) using the agonist CGP42112A after traumatic brain injury (TBI) in mice led to significant improvements in functional recovery and cognitive performance over 35 days, alongside reduced brain lesion volume.

The treatment also promoted neurogenesis and activated neuroprotective signaling pathways, indicating that AT(2) agonists could be a promising new therapeutic strategy for TBI recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin receptor type 2 activation induces neuroprotection and neurogenesis after traumatic brain injury. Umschweif, G., Liraz-Zaltsman, S., Shabashov, D., et al.[2021]

The brain's local renin-angiotensin system (RAS) plays a significant role in worsening brain damage after traumatic brain injury (TBI), particularly when multiple concussions occur before recovery from an initial injury.

Drugs that inhibit the activation of the type 1 Ang II receptor (AT1R), such as AT1R blockers, renin inhibitors, and ACE inhibitors, may help reduce permanent brain damage caused by TBI, suggesting a potential therapeutic approach for managing TBI-related injuries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of the brain renin-angiotensin system (RAS) in mild traumatic brain injury (TBI). Vadhan, JD., Speth, RC.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Angiotensin-(1-7) improves cognitive function and reduces inflammation in mice following mild traumatic brain injury. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma*. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Angiotensin receptor type 2 activation induces neuroprotection and neurogenesis after traumatic brain injury. [2021]

6. England pubmed.ncbi.nlm.nih.gov

The role of the brain renin-angiotensin system (RAS) in mild traumatic brain injury (TBI). [2022]