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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates whether a new drug, Angiotensin (1-7), is safe and effective for individuals with moderate to severe traumatic brain injury (TBI). Researchers aim to determine if it can enhance cognitive skills and reduce signs of physical brain damage. Participants will receive daily injections for 21 days, provide blood samples, undergo two brain scans, and complete tasks and questionnaires. The trial will compare two different doses of the drug to a placebo to identify the most effective option. It is suitable for individuals with a recent moderate to severe TBI confirmed by a CT scan showing brain injury. As a Phase 1 and Phase 2 trial, it focuses on understanding the treatment's mechanism in people and assessing its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Angiotensin (1-7) is safe when administered as an injection under the skin in humans. Previous studies have not identified any major safety concerns, indicating that the treatment is generally well-tolerated. Participants in those trials did not experience serious side effects, which is encouraging for those considering joining a clinical trial with this drug. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Researchers are excited about Angiotensin (1-7) for traumatic brain injury (TBI) because it offers a fresh approach compared to standard treatments like supportive care and medications that mainly manage symptoms. Angiotensin (1-7) works by targeting the renin-angiotensin system, which is different from the typical focus on reducing intracranial pressure or inflammation in TBI care. This treatment is also administered via a subcutaneous injection, offering a potentially convenient and precise dosage method. By addressing underlying mechanisms rather than just symptoms, Angiotensin (1-7) could lead to more effective recovery outcomes for patients with TBI.

What evidence suggests that Angiotensin (1-7) might be an effective treatment for traumatic brain injury?

This trial will evaluate the effects of Angiotensin (1-7) on brain function after a traumatic brain injury (TBI). Research suggests that Angiotensin (1-7) might improve brain function, as studies with mice have shown promise by aiding recovery and enhancing thinking skills compared to those who didn't receive it. Participants in this trial will receive either Angiotensin (1-7) at doses of 100 mcg/kg/day or 200 mcg/kg/day, or a placebo. Angiotensin (1-7) affects a system in the body involved in brain injuries, potentially reducing brain damage and enhancing mental abilities. While these results are promising in animals, more research is needed to determine its effectiveness in humans. ^{1 2 3 4 6}

Who Is on the Research Team?

Bellal Joseph, MD

Principal Investigator

University of Arizona

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06282965

Safety and Efficacy of Angiotensin (1-7) in Persons With ... 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 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7034274/

a promising target for traumatic brain injury therapeutics Subcutaneous administration of angiotensin-(1-7) improves recovery after traumatic brain injury in mice. J Neurotrauma. 2019 doi: 10.1089 ...

3. frontiersin.org frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2022.903980/full

Angiotensin-(1-7) improves cognitive function and reduces ... Results: Administration of Ang-(1-7) daily for 5 days post-mTBI significantly increased cognitive function as compared to saline control-treated ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S1878747923019980

The Renin Angiotensin System as a Therapeutic Target in ... This comprehensive review will provide an overview of the various components of the RAS, with a focus on their direct relevance to TBI pathology.

5. withpower.com withpower.com/trial/phase-2-brain-injuries-traumatic-2-2024-65772

Angiotensin (1-7) for Traumatic Brain Injury (ANGel T Trial) In a study involving 108 male mice with mild traumatic brain injury (mTBI), administration of Angiotensin 1-7 (Ang-1-7) significantly improved cognitive ...

6. neurotherapeuticsjournal.org neurotherapeuticsjournal.org/article/S1878-7479(23)01998-0/fulltext

The Renin Angiotensin System as a Therapeutic Target in ... These data point to a therapeutic use for the ACE2/Ang-(1–7)/MasR pathway, not only in the acute phase of the response to TBI, but also in the chronic phase to ...