Levetiracetam for Neonatal Seizures

(NEOLEV3 Trial)

Recruiting at 4 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the safest and most effective dose of Levetiracetam (LEV), an anti-seizure medication, for treating seizures in newborns. Researchers seek to assess whether doses higher than 60 mg/kg improve seizure control. Babies at risk of seizures or suspected of having them may qualify for participation. The study will compare different doses of LEV to the standard treatment, Phenobarbital, to identify the most effective option. This trial is open to newborns, excluding those with certain correctable metabolic issues or severe seizures. As a Phase 2 trial, this research focuses on evaluating the treatment's effectiveness in an initial, smaller group of newborns.

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.

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

Research has shown that levetiracetam (LEV) is safe for newborns, including those born prematurely. Studies have found that newborns with seizures tolerate it well when given as an injection. However, some research suggests that LEV alone might not completely stop seizures, so it may be used alongside other treatments.

In past studies, LEV was compared to other common anti-seizure drugs and demonstrated similar safety levels, meaning it does not cause more side effects than other treatments.

Since this trial is in the early stages, the researchers aim to find the safest dose of LEV for newborns with seizures. More information about the safety and optimal dose will be gathered as the trial progresses. ^{1 2 3 4 5}

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

Researchers are excited about Levetiracetam injections for neonatal seizures because they offer a new approach compared to the standard treatment with Phenobarbital. Unlike Phenobarbital, which is a barbiturate and can have sedative effects, Levetiracetam works by targeting a different neurotransmitter pathway, potentially leading to fewer side effects. Moreover, Levetiracetam can be administered in various escalating doses, which allows for more tailored treatment based on the severity of the seizures. This flexibility and potential for a more favorable side effect profile make Levetiracetam an exciting option for treating neonatal seizures.

What evidence suggests that Levetiracetam might be an effective treatment for neonatal seizures?

Research has shown that Levetiracetam (LEV), which participants in this trial may receive, can help reduce seizures in newborns. One study found that LEV successfully controlled 45% of newborn seizures. Another study discovered that over 70% of newborns needed only one dose of LEV, and nearly 85% remained seizure-free for the next 48 hours. These findings suggest that LEV could be a promising treatment for newborn seizures, even though it is not yet approved for children under two years old. Meanwhile, another group in this trial will receive the standard care treatment with Phenobarbital. ^{6 7 8 9 10}

Who Is on the Research Team?

Sonya G Wang, M.D.

Principal Investigator

University of Minnesota

Richard H Haas, MBBChir

Principal Investigator

University of California, San Diego

Jeff J Gold, M.D. PhD

Principal Investigator

University of California, San Diego

Cynthia M Sharpe, M.D.

Principal Investigator

Auckland City Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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 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]

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, 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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3082578/

Levetiracetam for Treatment of Neonatal Seizures - PMC Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2405650225000371

Efficacy and safety of intravenous Levetiracetam as first ... More than 70 % of neonates required only a single dose, and nearly 85 % remained seizure-free within 48 h. While these findings suggest favorable outcomes with ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01720667

Efficacy of Intravenous Levetiracetam in Neonatal Seizures Levetiracetam (LEV) has great potential as a treatment for neonatal seizures but is not approved for use in children less than 2 years of age. This study aims ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34124790/

Levetiracetam as the first-line treatment for neonatal seizures Results: Fourteen studies assessing 1188 neonates were included ... What this paper adds Levetiracetam is effective in 45% of neonatal seizures.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03107507

Efficacy of Levetiracetam in Control of Neonatal Seizures ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6301299/

Levetiracetam for epilepsy: an evidence map of efficacy, safety ... Our evidence map indicated that LEV had similar efficacy in seizure freedom compared with conventional AEDs and was superior to placebo in ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02550028

Levetiracetam Treatment of Neonatal Seizures This study aims to obtain essential data regarding the efficacy and safety of oral Levetiracetam in neonatal population and simultaneously to use EEG monitoring ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4418685/

Levetiracetam in Neonatal Seizures: A Review - PMC Authors concluded that LEV was safe in neonates, including premature neonates; however, LEV monotherapy may not achieve seizure control because adjunctive ...

9. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2023/022285s034lbl.pdf

Keppra XR - accessdata.fda.gov Risk Summary. Levetiracetam is excreted in human milk. There are no data on the effects of KEPPRA XR on the breastfed infant, or the effects on milk production.

10. isrctn.com isrctn.com/ISRCTN53371491

safety of intravenous levetiracetam for neonates with seizures Study information ; Treatment · Levetiracetam (Keppra®) in neonates: safety of intravenous levetiracetam for neonates with seizures.