Inhaled Nitric Oxide for Traumatic Brain Injury

Overseen By Ramon Diaz-Arrastia

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Pennsylvania

Must not be taking: Nitric oxide donors

Disqualifiers: Severe cardiac dysfunction, Large focal injury, Disabling psychiatric disorders, Intracranial vessel disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: 1

Duration: 4 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test whether inhaled nitric oxide (iNO) can improve blood flow in the brain after a traumatic brain injury (TBI), potentially preventing further damage. Participants will receive either iNO or standard respiratory support to determine if iNO affects recovery outcomes over six months. The trial seeks individuals who have experienced a TBI with specific brain imaging results but do not have severe heart or lung issues, large brain injuries, or certain other medical conditions. As a Phase 2 trial, this research focuses on assessing iNO's effectiveness in an initial, smaller group, offering participants a chance to contribute to important medical advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it mentions possible drug interactions with nitric oxide donors like prilocaine, sodium nitroprusside, and nitroglycerin. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that inhaled nitric oxide is likely to be safe for humans?

Research has shown that inhaled nitric oxide (iNO) is generally safe for people. Hospitals already use it to improve blood flow in the lungs for both newborns and adults with breathing problems. Studies have found that iNO can reduce brain swelling and damage after a traumatic brain injury (TBI). In some cases, it also lowered the pressure inside the skull, which is beneficial after a brain injury. Another study found that iNO did not negatively affect lung function or increase pressure inside the skull after TBI. This suggests that iNO is well-tolerated in people with these injuries. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for TBI?

Unlike the standard of care for traumatic brain injury, which typically involves treatments like medication, surgery, or rehabilitation focused on relieving pressure and preventing further damage, inhaled nitric oxide (iNO) offers a novel approach. iNO works by improving blood flow and oxygen delivery to the brain through vasodilation, potentially reducing brain damage more effectively. Researchers are excited about this treatment because it targets the injury at a vascular level and can be administered non-invasively through inhalation, offering a promising new avenue for quicker and potentially more effective support in brain injury recovery.

What evidence suggests that inhaled nitric oxide might be an effective treatment for traumatic brain injury?

Research has shown that inhaled nitric oxide (iNO), which participants in this trial may receive, can aid individuals with traumatic brain injury by enhancing blood flow in the brain. Studies have found that iNO reduces brain damage and swelling and helps protect the brain's barrier from breaking down. In animal studies, iNO improved short-term memory and reduced inflammation after brain injuries. Another study found that iNO lowered pressure inside the skull. These findings suggest that inhaled nitric oxide could be a promising treatment for traumatic brain injury. ^{1 2 5 6 7}

Who Is on the Research Team?

Samuel Shin

Principal Investigator

Assistant Professor

Are You a Good Fit for This Trial?

Adults aged 18-75 with moderate traumatic brain injury (TBI), evidenced by specific criteria such as post-traumatic amnesia, loss of consciousness for a certain time, and particular radiologic findings. Patients both on breathing support and not are included. Excluded are those with severe heart issues, known large vessel brain disease, lung conditions like ARDS or pulmonary hypertension, serious kidney disease, immediate need for brain surgery, or pre-existing major psychiatric/neurological disorders.

Inclusion Criteria

I experienced memory loss for a day after an injury.

Loss of consciousness for 30 minutes to 24 hours

Radiologic findings indicative of primarily diffuse TBI

Exclusion Criteria

I do not have severe heart problems.

I currently have a respiratory infection.

I have a large brain bleed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Within 24 hours

Treatment

Participants receive inhaled nitric oxide (iNO) treatment and standard respiratory therapy in alternating 4-hour sessions over 4 days

4 days

Daily monitoring sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of blood-based biomarkers and functional status

6 months

1 visit (in-person) at 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Inhaled Nitric Oxide

Trial Overview The trial is testing inhaled nitric oxide (iNO), a gas that widens blood vessels to improve blood flow in the brain after TBI. Participants will be randomly assigned to receive iNO soon after their injury. The study will monitor changes in blood flow using optic neuromonitoring and measure recovery outcomes up to six months later.

How Is the Trial Designed?

Group I: Group iNO Experimental Treatment 1 Intervention

Subjects will receive iNO for 4 hours, followed by standard respiratory support (SRS) for 4 hours. This pattern will be reversed the next day (SRS then iNO). on the following day, the pattern will be reversed back to iNO for 4 hours and SRS for 4 hrs.

Group II: Group SRS Placebo Group 1 Intervention

Subjects will receive standard respiratory support (SRS) for 8 hours.

Inhaled Nitric Oxide is already approved in United States, European Union for the following indications:

Approved in United States as INOmax for:

• Hypoxic respiratory failure
• Pulmonary hypertension

Approved in United States as Genosyl for:

• Hypoxic respiratory failure
• Pulmonary hypertension

Approved in European Union as INOmax for:

• Persistent pulmonary hypertension of the newborn
• Acute hypoxic respiratory failure

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

Inhaled nitric oxide (iNO) significantly improved oxygen levels in patients with severe hypoxemia, with arterial oxygen partial pressure (PaO2) increasing from 60.7 to 72.3 mm Hg after treatment (P=.008).

The use of iNO allowed for safe transport of patients to a tertiary care center, with 60.2% of those treated surviving to discharge, compared to a 50% survival rate in patients transported without iNO.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide to improve oxygenation for safe critical care transport of adults with severe hypoxemia. Teman, NR., Thomas, J., Bryner, BS., et al.[2020]

Inhaled nitric oxide (iNO) therapy significantly increases the risk of renal dysfunction in patients with acute respiratory distress syndrome (ARDS), with an adjusted hazard ratio of 1.59 after accounting for confounding factors.

Older patients (aged 65 and above) are particularly vulnerable to kidney injury associated with iNO therapy, highlighting the need for careful monitoring in this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. Ruan, SY., Wu, HY., Lin, HH., et al.[2022]

The implementation of clinical guidelines for inhaled nitric oxide (iNO) therapy in a pediatric intensive care unit led to a significant reduction in the duration of iNO treatment, from a median of 162 hours to 76 hours, without compromising patient care.

Following the guidelines, there was a notable cost savings of $4,600 per patient, demonstrating that standardized protocols can enhance efficiency and reduce unnecessary expenses in iNO therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Quality Improvement Initiative to Standardize Use of Inhaled Nitric Oxide in the PICU. Karsies, TJ., Evans, L., Frost, R., et al.[2022]

Inhaled nitric oxide (iNO) can be safely managed by trained nurses during the transport of critically ill patients, as demonstrated by a study involving patients transported from March 2020 to August 2022.

Out of the patients studied, only 16.7% experienced hypotension, which was manageable and resolved with medication adjustments, while no serious adverse events like worsening hypoxemia or cardiac arrest were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Nurse-Managed Inhaled Nitric Oxide During Critical Care Interfacility Transport. Troncoso, R., Garfinkel, EM., Kaul, K., et al.[2023]

In a study of 860 premature infants under 32 weeks, low-dose inhaled nitric oxide (iNO) did not significantly improve intact survival at 28 days compared to placebo, with survival rates of 61.4% for iNO and 61.1% for controls.

The use of iNO was found to be safe, showing no significant differences in major complications like intraventricular hemorrhage, necrotizing enterocolitis, or patent ductus arteriosus compared to controls, suggesting it does not increase the risk of these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and efficacy of nitric oxide therapy in premature infants. Hascoet, JM., Fresson, J., Claris, O., et al.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05616910

Study Details | NCT05616910 | Inhaled Nitric Oxide for ... The objective of this study is to show that inhaled nitric oxide can increase blood flow in the brain after traumatic brain injury, attenuating brain injury and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3564204/

Inhaled nitric oxide reduces secondary brain damage after ... Long-term application (24 hours NO inhalation) resulted in reduced lesion volume, reduced brain edema formation and less blood–brain barrier disruption.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006899313007506

Inhaled nitric oxide improves short term memory and ... Research Report. Inhaled nitric oxide improves short term memory and reduces the inflammatory reaction in a mouse model of mild traumatic brain injury.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5363657/

Nitric oxide inhalation reduces brain damage, prevents ... Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms.

5. withpower.com withpower.com/trial/phase-2-traumatic-brain-injury-tbi-7-2023-f8560

Inhaled Nitric Oxide for Traumatic Brain Injury Inhaled nitric oxide has been reported to help decrease intracranial pressure (pressure inside the skull) in patients with traumatic brain injury and acute ...

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022480424000155

Just Say NO: Inhaled Nitric Oxide Effect on Respiratory ... iNO had no significant effect on clinically relevant pulmonary parameters or ICPs following TBI in both human patients and a porcine model.

7. aetna.com aetna.com/cpb/medical/data/500_599/0518.html

Nitric Oxide, Inhalational (INO) - Medical Clinical Policy ... The authors concluded that early use of low-dose INO in very premature babies did not improve survival without BPD or brain injury, suggesting that such a ...