Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT04671589 |
| Other study ID # |
N2014 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
June 2021 |
| Est. completion date |
December 2022 |
Study information
| Verified date |
December 2020 |
| Source |
Mabaret Al-Asafara Hospitals |
| Contact |
Nancy M Ahmed, MSc |
| Phone |
01005607730 |
| Email |
dr.nancymohamed[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Acute Valproic acid (VPA) toxicity is an emergency condition which may commonly present with
central nervous system (CNS) depression(5). In mild poisoning, associated with VPA ingestions
of 200 mg/kg, sedation and lethargy commonly occur(6); while in severe VPA poisoning
associated with ingestions of 400 mg/kg or more, life threatening events are likely to occur
as respiratory depression, metabolic acidosis, encephalopathy, hemodynamic instability, and
cerebral edema which may progress to coma and even death -if not treated promptly. Supportive
care along with early gastric decontamination using activated charcoal (AC) (which may only
be given if patient presented early after ingestion), in addition to intravenous (IV)
administration of Levocarnitine (L-Carnitine) and ensuring adequate airway protection are the
cornerstone of treatment, but there remains no drug listed as a specific antidote for acute
VPA intoxication. Carbapenem antibiotics augment the clearance of VPA through suppressing its
enterohepatic recirculation, as they inhibit the acylpeptide hydrolase enzyme responsible for
the reabsorption of the hydrolyzed valproate back to VPA active molecule. Taking advantage of
this well-established drug-drug interaction between VPA and carbapenems resulting in
significant drop of VPA serum concentration during concomitant use, we propose that
administration of meropenem (member of carbapenems group) will prove effectiveness in
managing VPA toxicity by achieving lower plasma levels of VPA and/or enhanced alertness;
compared with standard care.
Description:
JUSTIFICATION AND SIGNIFICANCE:
Valproic acid (VPA) -a branched chain carboxylic acid- introduced by the Food and Drug
Administration in 1978 for the treatment of seizure disorders(1). In the following years, VPA
gained further approved indications to treat bipolar and behavioral disorders(2), migraine
prophylaxis(3) as well as other psychiatric indications(4).The growing use of VPA and its
availability resulted in increased prevalence of VPA overdoses(5,6). The rising incidence of
acute VPA toxicity is either resulting from suicidal attempts, accidental ingestions, or
following VPA dose increments to achieve the desired therapeutic effect(7). Acute VPA
toxicity is an emergency condition which may commonly present with central nervous system
(CNS) depression(5). In mild poisoning, associated with VPA ingestions of 200 mg/kg, sedation
and lethargy commonly occur(6); while in severe VPA poisoning associated with ingestions of
400 mg/kg or more, life threatening events are likely to occur as respiratory depression,
metabolic acidosis, encephalopathy, hemodynamic instability, and cerebral edema which may
progress to coma and even death -if not treated promptly(5,8). Serum VPA concentration is the
most functional tool in diagnosing and determining the severity of toxicity. Supportive care
along with early gastric decontamination using activated charcoal (AC) (which may only be
given if patient presented early after ingestion), in addition to intravenous (IV)
administration of Levocarnitine (L-Carnitine) and ensuring adequate airway protection are the
cornerstone of treatment, but there remains no drug listed as a specific antidote for acute
VPA intoxication(5,9).
Carbapenems are a group of β-lactam antibiotics with a growing need to use in the empiric and
definitive treatment, due to the emerging resistance to antibiotics(10). A multitude of case
reports(11-13), retrospective observational studies(14-19) and reviews(20-22) demonstrated
that combined use of VPA and carbapenem antibiotics -mainly meropenem (16)(23)- is associated
with a potential drug interaction that can significantly decrease VPA serum
concentration(24). One retrospective trial included 36 patients concluded that VPA mean ± SEM
serum concentration dropped from 50.8 ± 4.5 µg/mL to 9.9 ± 2.1 µg/mL(P < .001) following
meropenem administration with a mean decrease of 82.1% ± 2.7%(18), while a recent prospective
observational trial determined that the mean drop in serum VPA level was 80% ranging
from(49%-99%)(23). However, despite VPA toxicity with fatal events being reported for over 20
years, only a few case reports documented successful intentional use of meropenem as an
antidote for VPA poisoning(25-27). To date, no randomized-controlled trials were conducted.
Specific aims: Determine if meropenem is effective in treating acute VPA toxicity, manifested
by achieving reduced VPA plasma levels and/or enhanced mentation.
Hypothesis: Administration of meropenem combined with standard care is effective in managing
VPA intoxication, affirmed by providing lower serum VPA concentrations and/or better level of
consciousness; in contrast to standard care alone.
Background: VPA is an antiepileptic drug that has psychiatric indications as well(28). VPA
acute intoxication is a critical condition listed among fatal pharmaceutical exposures, with
CNS toxicity being the most common manifestation and may progress to respiratory depression
and/or coma(5). In 2018, the American Association of Poison Control Centers (AAPCC) Toxic
Exposure Surveillance System (TESS) database reported 7699 VPA exposures, of which: 2079 were
treated in health care facilities, 87 resulted in major toxicity, and 19 resulted in
deaths(29). These data denote that VPA poisoning is becoming an area of growing concern among
toxicologists.
Supportive care and ensuring adequate airway protection are the cornerstone of treatment;
yet, no drug specified as an antidote for managing VPA intoxication(5). Carbapenem
antibiotics augment the clearance of VPA through suppressing its enterohepatic recirculation,
as they inhibit the acylpeptide hydrolase enzyme responsible for the reabsorption of the
hydrolyzed valproate back to VPA active molecule(21). Taking advantage of this
well-established drug-drug interaction between VPA and carbapenems resulting in significant
drop of VPA serum concentration during concomitant use(15,17,23), we propose that
administration of meropenem (member of carbapenems group) will prove effectiveness in
managing VPA toxicity by achieving lower plasma levels of VPA and/or enhanced alertness;
compared with standard care.
Research design and methodology:
Operational definitions of research variables:
VPA toxicity: Ingestion of VPA, at doses higher than 60 mg/kg/day, with a serum VPA
concentration above the therapeutic threshold of 100 µg/mL and/or altered sensorium.
Standard care: Encompasses supportive care: administration of IV fluids, endotracheal
intubation for securing airway in patients with altered sensorium, benzodiazepines should be
administered only if seizures occur and L-carnitine 100 mg/kg IV in cases of hyperammonemia.
Primary outcome: Evaluate serum VPA concentrations among the two study groups. Secondary
outcome: Assess patients level of consciousness according to the Glasgow Coma Scale (GCS)
among the placebo and treatment groups.
Study Design and Location: This is a multicentered, randomized (1:1), double blinded, placebo
controlled study where eligible patients will be randomly assigned into two groups using
simple random sample technique, each patient will either receive: IV meropenem 1gram every 8
hours together with standard care; or placebo along with standard care. Computer generated
random number tables, will be used to allocate patients to either treatment or placebo
groups. We will make the participant and the assessing physician unaware of the treatment.
The study will be conducted in three poison control centers (PCC) in Egypt: (1) poison
control center of Ain Shams university hospitals; (2) poison control center of Alexandria
university hospitals; (3) poison control center of Tanta university hospitals. We will obtain
their institutional review board and/or ethics committee approval to conduct the study
protocol prior to study initiation.
Interventions and Monitoring: Serial VPA serum concentrations to be assessed every two to
four hours until a steady significant declined level is noted, while neurological status
assessment of patients will be performed according to the GCS three times daily.
Sample Size & Power: Based on VPA toxicity levels, mean VPA serum level of 378.3 mg/mL ±
310.2 mg/mL were reported(7), following meropenem administration, the mean drop in serum VPA
level was 80%(18,23). Owing to this data, we estimated that a minimum of 48 patients will be
needed to confirm this effect (α= 5% and power of 90 %).
Study duration: Reviewing annual reports of PCCs in Egypt, a single PCC received 44 cases of
VPA toxicity throughout the year 2011(30). Hence, an estimated one-year duration will be
sufficient to conduct our study over three PCCs in Egypt.
Proposed statistical analysis: Data will be presented as mean ± standard deviation or median
with interquartile range. Differences between the two groups will be tested using independent
sample t-test or Mann-Whitney U-test. Univariate analysis for comparing different demographic
data between meropenem group and placebo group using Chi square test and t-test as
applicable, Linear regression will be used to adjust for confounders. The analysis will be
carried out according to the intention to treat principle.
Differences will only be considered significant at P <0.05 and statistical analysis will be
performed using the Stata statistical software, version 16.0.
Study Limitations: 1) VPA overdoses may occur among patients with history of epilepsy.
Meropenem is a drug that possess seizure potential, but mainly seizures were reported in
patients with history of epilepsy and patients with declined renal function. Meanwhile,
overall seizure rate being 0.7% among immunocompetent patients (24). Meropenem dosage
reduction is recommended in patients with advanced age and/or patients with renal impairment.
Compliance to the recommended dosage regimens in addition to bedside digital
electroencephalogram (EEG) tracings will be urged in epileptic patients.
2) The results of this study would only apply to patients with the study inclusion criteria,
further studies should be conducted to cover the excluded criteria population.
Anticipated results: Meropenem with standard care will exhibit effectiveness in VPA toxicity
treatment, by achieving lower mean serum concentrations of VPA and/or higher median GCS
denoting improved sensorium; when compared with standard care alone.
