Levetiracetam for Neonatal Seizures

(NEOLEV3 Trial)

Recruiting at 3 trial locations

Overseen By Brittany Faanes, MPH

Age: < 18

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must be taking: Levetiracetam

Disqualifiers: Renal failure, Imminent death, 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: 5 days

133 Participants Needed

Trial Summary

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

The trial protocol does not specify whether participants must stop taking their current medications. However, since the trial involves neonates, it is likely that any existing medications will be carefully considered by the medical team.

What data supports the idea that Levetiracetam for Neonatal Seizures is an effective drug?

The available research shows that Levetiracetam is an effective drug for treating neonatal seizures. One study compared Levetiracetam to Phenobarbital, a commonly used drug, and found that Levetiracetam is a promising alternative. Another study highlighted its use in preterm infants, showing that it is increasingly used due to its favorable safety profile. Additionally, a pilot study suggested that Levetiracetam could be used alone to treat neonatal seizures, offering a potential advantage over Phenobarbital, which has limited effectiveness and potential risks for the developing brain. ^{1 2 3 4 5}

What safety data is available for levetiracetam?

Levetiracetam, marketed under names like Keppra, has been studied for safety as an add-on therapy for epilepsy. In the SKATE study, 50.5% of patients reported at least one adverse event related to levetiracetam, with common mild-to-moderate side effects including somnolence, fatigue, dizziness, and headache. Serious adverse events were rare, occurring in 1.0% of patients. Other studies confirm that adverse events are usually mild to moderate and often occur in the first 4 weeks of treatment. Levetiracetam is generally well tolerated, with no clear dose-related increase in adverse events within the recommended dose range of 1,000-3,000 mg/day. It is classified as a Pregnancy Category C drug. ^{6 7 8 9 10}

Is Levetiracetam a promising drug for treating seizures in newborns?

Levetiracetam is a promising drug for treating seizures in newborns because it is a newer medication with a good safety profile and has been increasingly used as a first-choice treatment. It offers a wider range of action compared to older drugs like Phenobarbital, which have limited effectiveness and potential risks for the developing brain. ^{3 4 7 11 12}

What is the purpose of this trial?

This trial aims to find the safest and most effective dose of Levetiracetam (LEV) for treating seizures in newborns. LEV works by calming the brain's electrical activity to prevent or reduce seizures. Newborns with seizures will receive LEV, and if seizures continue, they will be given higher doses of LEV. Levetiracetam (LEV) has been studied extensively for its efficacy and safety in treating seizures across various age groups, including neonates, infants, children, and adults.

Research Team

Richard H Haas, MBBChir

Principal Investigator

University of California, San Diego

Sonya G Wang, M.D.

Principal Investigator

University of Minnesota

Cynthia M Sharpe, M.D.

Principal Investigator

Auckland City Hospital

Jeff J Gold, M.D. PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for term neonates (newborns aged less than 28 days) weighing over 2200g, with a variety of seizure causes. It's not for those with severe seizures or correctable metabolic issues like low blood sugar/calcium, or kidney failure.

Inclusion Criteria

My baby was born full-term and is under 28 days old.

My seizures are not caused by treatable issues like low blood sugar or calcium.

My weight is over 2200 grams.

Exclusion Criteria

My newborn had no urine output in the first 24 hours of life.

Subjects in whom death seems imminent

My seizures are due to treatable conditions like low calcium or sugar.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

1 visit (in-person)

Treatment

Participants receive 60mg/kg of LEV, with dose escalation if seizures persist, and randomized to receive either higher dose LEV or PHB

5 days

Daily monitoring (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including seizure control and adverse events

4 weeks

Weekly visits (in-person)

Long-term follow-up

Rates of adverse long-term outcomes (Death or Disability at 24 months) will be compared between treatment arms

24 months

Treatment Details

Interventions

• Levetiracetam Injection
• Phenobarbital Sodium Injection

Trial Overview The study tests the safest high dose of Levetiracetam (LEV) for treating newborn seizures compared to Phenobarbital Sodium (PHB). Babies will be monitored and randomly given either LEV or PHB if their seizures continue after an initial LEV dose.

Participant Groups

Group I: Dose escalation with LEV Experimental Treatment 1 Intervention

Additional LEV at a higher dose (30 mg/kg, 60 mg/kg, or 90 mg/kg depending on the stage of the study).

Group II: Standard of care Phenobarbital Active Control 1 Intervention

Treatment with Phenobarbital 20mg/kg IV and if needed a further 20mg/kg totalling 40mg/kg

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

Approved in United States as Keppra for:

• Partial-onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Approved in European Union as Keppra for:

• Epilepsy
• Partial-onset seizures
• Myoclonic seizures
• Tonic-clonic seizures

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Middlemore Hospital, New Zealand

Collaborator

Trials

6

Recruited

6,200+

Sharp Mary Birch Hospital for Women & Newborns

Collaborator

Trials

13

Recruited

6,600+

University of Auckland, New Zealand

Collaborator

Trials

82

Recruited

372,000+

Rady Children's Hospital, San Diego

Collaborator

Trials

42

Recruited

14,300+

Auckland City Hospital

Collaborator

Trials

20

Recruited

15,500+

University of Minnesota

Collaborator

Trials

1,459

Recruited

1,623,000+

Findings from Research

In a study of 104 neonates with seizures, intravenous levetiracetam was more effective than phenobarbital, with 78.84% of neonates achieving seizure cessation compared to 65.38% for phenobarbital (P=0.01).

Levetiracetam was found to be safe, with no reported adverse drug reactions, while 23.07% of neonates treated with phenobarbital experienced adverse effects, highlighting levetiracetam as a preferable first-line treatment for neonatal seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Comparative Study of Levetiracetam and Phenobarbital for Neonatal Seizures as a First Line Treatment. Akeel, NE., Suliman, HA., Al-Shokary, AH., et al.[2023]

In a study of 108 critically ill children with acute repetitive seizures and status epilepticus, intravenous levetiracetam (LEV) successfully terminated seizures in 73.1% of cases, indicating its effectiveness as a treatment option.

The treatment was generally safe, with no serious adverse effects reported; however, some patients experienced mild side effects like agitation, aggression, and skin reactions, suggesting that while LEV is effective, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous levetiracetam in critically ill children. Incecik, F., Horoz, OO., Herguner, OM., et al.[2020]

In a pilot study involving six newborns, Levetiracetam (LEV) was found to be effective in treating neonatal seizures, with all patients becoming seizure-free within 6 days of treatment.

No severe side effects were reported, suggesting that LEV may be a safer alternative to Phenobarbital, which is commonly used but carries risks for the developing brain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam in the treatment of neonatal seizures: a pilot study. Fürwentsches, A., Bussmann, C., Ramantani, G., et al.[2018]

In a study of 37 preterm infants treated with levetiracetam (LEV) as the first-line anti-seizure medication, 57% became seizure-free within the first week, demonstrating its efficacy in this vulnerable population.

LEV was well-tolerated with no observed adverse effects, suggesting it is a safe option for managing neonatal seizures in preterm infants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of levetiracetam for neonatal seizures in preterm infants. Han, JY., Moon, CJ., Youn, YA., et al.[2018]

This phase II trial, LEVNEONAT-1, aims to determine the optimal dosing of levetiracetam (LEV) as a first-line treatment for neonatal seizures in newborns with hypoxic-ischaemic encephalopathy, with a target efficacy of over 60% and toxicity not exceeding 10%.

The study will assess four different loading doses (30, 40, 50, or 60 mg/kg) followed by maintenance doses, with a maximum of 50 participants expected, providing a structured approach to evaluate LEV's effectiveness and safety in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial. Favrais, G., Ursino, M., Mouchel, C., et al.[2022]

In a 16-week study involving 1541 patients with treatment-resistant partial seizures, levetiracetam (Keppra) was found to be effective as an add-on therapy, with a median seizure frequency reduction of 50.2% and 15.8% of patients becoming seizure-free.

Levetiracetam was generally well tolerated, with 50.5% of patients reporting mild-to-moderate adverse events like somnolence and dizziness, and only 1.0% experiencing serious adverse events, indicating a favorable safety profile for its use in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. Steinhoff, BJ., Somerville, ER., Van Paesschen, W., et al.[2018]

In a study involving 219 patients with refractory epilepsy, levetiracetam (LEV) was found to be well tolerated, with a high retention rate of 81.7% and limited adverse events, primarily occurring during dose increases.

LEV significantly reduced seizure frequency, with 48.2% of patients experiencing a >50% reduction in seizures, and 13.6% achieving complete seizure freedom during the evaluation period, indicating its efficacy as an adjunctive therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day(-1) in adult patients with refractory epilepsy. Abou-Khalil, B., Hemdal, P., Privitera, MD.[2019]

In the SKATE study, which included 731 patients treated for 16 weeks, levetiracetam (Keppra) reduced seizure frequency by half or more in 49% of patients, with 17.2% achieving complete freedom from seizures.

Levetiracetam was generally well tolerated, with most adverse events being mild to moderate, such as fatigue and dizziness, and rarely causing patients to stop treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The SKATE study: interim analysis. Olwen, GO.[2018]

Levetiracetam (LEV) was found to be well tolerated and safe for patients with epilepsy, cognitive disorders, and anxiety, based on safety data from 3347 patients in clinical trials, with common adverse effects being somnolence, asthenia, and dizziness primarily occurring in the first month of treatment.

The incidence of adverse effects was slightly higher in epilepsy patients compared to those with cognitive or anxiety disorders, but overall, the adverse effects reported were similar to those in placebo groups, indicating that while LEV is generally safe, long-term and rare side effects remain uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. French, J., Edrich, P., Cramer, JA.[2022]

Levetiracetam, approved for treating partial-onset seizures in adults, is generally well tolerated when used as an add-on therapy with other antiepileptic drugs, with most adverse events being mild to moderate and occurring mainly in the first 4 weeks of treatment.

There was no clear link between the dose of levetiracetam (1,000-3,000 mg/day) and the frequency of adverse events, indicating its safety profile within the recommended dosage range.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of levetiracetam. Harden, C.[2018]

In a study of 82 term asphyxiated infants with seizures, levetiracetam demonstrated significantly better clinical seizure control compared to phenobarbitone, with 65.9% of infants in the levetiracetam group achieving control versus 34.2% in the phenobarbitone group.

Levetiracetam not only proved effective as a first-line treatment but also helped control seizures in 57.8% of infants who did not respond to phenobarbitone, suggesting its potential as a valuable option in neonatal seizure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam or Phenobarbitone as a First-Line Anticonvulsant in Asphyxiated Term Newborns? An Open-Label, Single-Center, Randomized, Controlled, Pragmatic Trial. Susnerwala, S., Joshi, A., Deshmukh, L., et al.[2022]

A study involving 19 neonates showed that crushed levetiracetam tablets, administered orally or via naso-/orogastric tube, effectively terminated seizures in 90% of cases by day 3 and 100% by day 4, demonstrating its efficacy as a treatment for neonatal seizures.

The pharmacokinetic profile of crushed levetiracetam was comparable to historical data, indicating that this method of administration is safe and effective, making it a viable option in low-resource settings where intravenous access is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Pharmacokinetics of Crushed Levetiracetam Tablets Administered to Neonates. Pillay-Fuentes Lorente, V., Bekker, A., Kali, GTJ., et al.[2021]

References

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

A Comparative Study of Levetiracetam and Phenobarbital for Neonatal Seizures as a First Line Treatment. [2023]

2. India pubmed.ncbi.nlm.nih.gov

Intravenous levetiracetam in critically ill children. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Levetiracetam in the treatment of neonatal seizures: a pilot study. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Efficacy of levetiracetam for neonatal seizures in preterm infants. [2018]

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

Levetiracetam optimal dose-finding as first-line treatment for neonatal seizures occurring in the context of hypoxic-ischaemic encephalopathy (LEVNEONAT-1): study protocol of a phase II trial. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

The SKATE study: an open-label community-based study of levetiracetam as add-on therapy for adults with uncontrolled partial epilepsy. [2018]

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

An open-label study of levetiracetam at individualised doses between 1000 and 3000 mg day(-1) in adult patients with refractory epilepsy. [2019]

8. India pubmed.ncbi.nlm.nih.gov

The SKATE study: interim analysis. [2018]

9. Netherlands pubmed.ncbi.nlm.nih.gov

A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. [2022]

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

Safety profile of levetiracetam. [2018]

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

Levetiracetam or Phenobarbitone as a First-Line Anticonvulsant in Asphyxiated Term Newborns? An Open-Label, Single-Center, Randomized, Controlled, Pragmatic Trial. [2022]

12. England pubmed.ncbi.nlm.nih.gov

The Pharmacokinetics of Crushed Levetiracetam Tablets Administered to Neonates. [2021]