Intramuscular Epinephrine for Out-of-Hospital Cardiac Arrest

(PRIME Trial)

Overseen By Maysaa Assaf

Age: < 18

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Disqualifiers: Traumatic event

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: 6

Duration: Immediate during POHCA event

284 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a pragmatic, two-arm, open-label, prospective stepped-wedge cluster quasi randomized control trial (SW-CRCT) looking to evaluate early intramuscular (IM) epinephrine in the management of pediatric out-of-hospital cardiac arrest (POHCA).

Do I have to stop taking my current medications for the trial?

The trial information does not specify whether participants need to stop taking their current medications.

Is intramuscular epinephrine generally safe for use in humans?

Intramuscular epinephrine is generally considered safe for emergency treatment of severe allergic reactions, but there are potential risks such as rapid increases in blood pressure and pulse rate if accidentally injected into a blood vessel. ^{1 2 3 4 5}

How is intramuscular epinephrine unique for treating out-of-hospital cardiac arrest?

Intramuscular epinephrine is unique because it is a fast-acting drug that can be administered quickly in emergency situations, making it the best available option for out-of-hospital treatment of severe allergic reactions and potentially cardiac arrest, despite the risks of incorrect administration. ^{1 4 6 7 8}

Research Team

Janice Tijssen, MD MSc

Principal Investigator

London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Eligibility Criteria

This trial is for children from birth up to 17 years old who have had a cardiac arrest outside of the hospital and are receiving CPR by trained responders. It's not for those whose cardiac arrest was caused by a clear injury.

Inclusion Criteria

My child, aged 17 or younger, had a cardiac arrest outside of a hospital.

I received CPR from a trained responder for at least 1 minute.

Exclusion Criteria

My child had a cardiac arrest due to a clear injury.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either standard of care epinephrine administration via IV/IO or intramuscular epinephrine via autoinjector/pre-filled syringe during POHCA events

Immediate during POHCA event

Follow-up

Participants are monitored for neurological status, quality of life, and survival outcomes at discharge, 6 months, and 12 months post-POHCA

12 months

Multiple assessments at discharge, 6 months, and 12 months

Long-term follow-up

Participants' survival and quality of life are assessed up to 12 months post-POHCA

12 months

Treatment Details

Interventions

• Epinephrine Injection

Trial Overview The study tests if giving epinephrine as an injection into the muscle early on helps in treating kids with out-of-hospital cardiac arrests. It randomly assigns participants to two groups over time to compare outcomes.

Participant Groups

Group I: Intramuscular Epinephrine Dose Experimental Treatment 1 Intervention

POHCA events will be handled per standard of care, however, first dose epinephrine administration will be via intramuscular (IM) autoinjector and/or pre-filled syringes. Dosing will be dependent on weight as follows: * 3-\<5kg=0.3mg IM epinephrine * 5-\<10kg=0.5mg IM epinephrine * 10-\<20kg=1.0mg IM epinephrine * 20-\<30kg=2.0mg IM epinephrine * 30kg=3.0mg IM epinephrine

Group II: Standard of Care Active Control 1 Intervention

All POHCA events will be handled per standard of care of epinephrine administration via intravenous or intraosseous (IV/IO) based on patient estimated weight.

Epinephrine Injection is already approved in United States, European Union for the following indications:

Approved in United States as Epinephrine for:

• Anaphylaxis
• Cardiac arrest
• Asthma
• Superficial bleeding
• Croup
• Bronchiolitis
• Upper airway obstruction

Approved in European Union as Eurneffy for:

• Emergency treatment of allergic reactions (anaphylaxis) due to insect stings or bites, foods, medicinal products, and other allergens as well as idiopathic or exercise-induced anaphylaxis

Who Is Running the Clinical Trial?

London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

678

Recruited

421,000+

London Health Sciences Centre OR Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

668

Recruited

424,000+

London Health Sciences Centre Research Institute and Lawson Research Institute of St. Joseph's

Lead Sponsor

Trials

686

Recruited

427,000+

Lawson Health Research Institute

Lead Sponsor

Trials

684

Recruited

432,000+

Findings from Research

A clinical trial involving 36 subjects highlighted the cardiovascular risks associated with EpiPen use, including a case of presumed intravascular injection that led to a significant spike in blood pressure and heart rate, demonstrating potential safety concerns.

In contrast, the new intranasal epinephrine spray, ARS-1, showed more stable pharmacokinetics without the same level of cardiovascular response, suggesting it may offer a safer alternative for out-of-hospital treatment of anaphylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid increases in epinephrine concentration following presumed intra-blood vessel administration via epinephrine autoinjector. Ebisawa, M., Kaliner, MA., Lowenthal, R., et al.[2023]

A study involving 71 healthy adults found that the bioavailability of epinephrine from the Auvi-Q autoinjector is similar to that of the EpiPen, indicating that both devices deliver comparable amounts of the medication into the bloodstream.

Both Auvi-Q and EpiPen demonstrated similar safety profiles, with most side effects being mild and resolving on their own; however, Auvi-Q had lower rates of injection-site pain and bleeding compared to EpiPen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of epinephrine from Auvi-Q compared with EpiPen. Edwards, ES., Gunn, R., Simons, ER., et al.[2014]

Intramuscular epinephrine pens, like the Auvi-Q, are effective for managing anaphylaxis and require minimal training for safe use, making them accessible for emergency situations.

Despite a recall due to dosing inaccuracies, some Auvi-Q devices may still be in circulation, highlighting the need for awareness and proper training in their use, especially for administering multiple doses in critical scenarios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Technique for Epinephrine Removal in New Generation Autoinjectors. Robinson, PE., Lareau, SA.[2017]

FMXIN002, a nasal powder spray of epinephrine, demonstrated faster absorption compared to the traditional EpiPen, with a median time to peak concentration of 2.5 minutes versus 9.0 minutes, which could be crucial in emergency situations.

The FMXIN002 nasal spray was well tolerated with only mild, local adverse events reported, making it a safe and user-friendly alternative to intramuscular epinephrine autoinjectors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fast Acting, Dry Powder, Needle-Free, Intranasal Epinephrine Spray: A Promising Future Treatment for Anaphylaxis. Tal, Y., Ribak, Y., Rubin, L., et al.[2023]

Only 18.4% of pharmacists accurately demonstrated all four steps for using epinephrine autoinjectors according to the ASCIA Action Plan, highlighting a need for improved training and education in the community.

Pharmacists who checked for an anaphylaxis action plan, advised calling an ambulance after use, or discussed side effects of epinephrine were significantly more likely to provide accurate demonstrations, suggesting these factors are important for effective patient education.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Demonstration of epinephrine autoinjectors (EpiPen and Anapen) by pharmacists in a randomised, simulated patient assessment: acceptable, but room for improvement. Salter, SM., Loh, R., Sanfilippo, FM., et al.[2022]

Innovative epinephrine delivery methods, such as nasal sprays and sublingual films, show promising pharmacokinetic results comparable to traditional intramuscular injections, potentially improving the emergency treatment of anaphylaxis.

These needle-free alternatives may enhance patient compliance and safety by addressing common barriers associated with epinephrine autoinjectors, such as fear of needles and ease of carriage, making them a viable option for outpatient use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Innovations in the treatment of anaphylaxis: A review of recent data. Lieberman, JA., Oppenheimer, J., Hernandez-Trujillo, VP., et al.[2023]

In a study of 100 mothers with no prior experience using epinephrine autoinjectors, 15% were unable to successfully use the devices after training, highlighting a need for more user-friendly designs and improved training methods.

Mothers found the Anapen(®) significantly easier to use than the EpiPen(®), with 32% successfully performing all procedures for Anapen(®) compared to only 12% for EpiPen(®), suggesting that device choice may impact effective anaphylaxis management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized maternal evaluation of epinephrine autoinjection devices. Brown, J., Tuthill, D., Alfaham, M., et al.[2017]

A study involving 213 pharmacists revealed that while they recognize the triggers and symptoms of anaphylaxis, there are significant gaps in their knowledge regarding its management and current treatment guidelines.

Improving pharmacists' understanding of anaphylaxis is crucial, as they play a key role in patient care for allergic reactions, suggesting a need for enhanced training and awareness programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Level of knowledge among pharmacists regarding anaphylaxis and the use of epinephrine autoinjectors. Worm, M., Molaie, N., Dölle, S.[2019]

References

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

Rapid increases in epinephrine concentration following presumed intra-blood vessel administration via epinephrine autoinjector. [2023]

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

Bioavailability of epinephrine from Auvi-Q compared with EpiPen. [2014]

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

Novel Technique for Epinephrine Removal in New Generation Autoinjectors. [2017]

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

Fast Acting, Dry Powder, Needle-Free, Intranasal Epinephrine Spray: A Promising Future Treatment for Anaphylaxis. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Demonstration of epinephrine autoinjectors (EpiPen and Anapen) by pharmacists in a randomised, simulated patient assessment: acceptable, but room for improvement. [2022]

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

Innovations in the treatment of anaphylaxis: A review of recent data. [2023]

7. England pubmed.ncbi.nlm.nih.gov

A randomized maternal evaluation of epinephrine autoinjection devices. [2017]

8. Germany pubmed.ncbi.nlm.nih.gov

Level of knowledge among pharmacists regarding anaphylaxis and the use of epinephrine autoinjectors. [2019]