Mangafodipir Imaging for Drug-Resistant Epilepsy

Recruiting at 1 trial location

Overseen By Aaliyah M HamidullahThiam

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)

Must be taking: Anti-seizure drugs

Must not be taking: Calcium-channel blockers

Disqualifiers: HIV, Pregnancy, Claustrophobia, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 2-10 days

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether mangafodipir, a contrast agent, can safely highlight brain areas affected by drug-resistant epilepsy during an MRI scan. The goal is to determine if it can provide clearer images of the brain regions involved in epilepsy, potentially aiding in managing the condition. The trial targets adults aged 18-60 who have had epilepsy for at least a year without relief from standard treatments. Participants will undergo various tests and imaging over several visits to assess their brains' response to the contrast agent. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, ongoing treatment with calcium-channel blockers is an exclusion criterion, so you may need to stop those if you are taking them.

Is there any evidence suggesting that mangafodipir is likely to be safe for humans?

Research has shown that mangafodipir is generally well tolerated. In one study, only 7% of patients reported side effects, which were not serious and did not affect heart rate or other vital signs. Another study found that about 23% of patients experienced side effects, but most were mild to moderate and did not require treatment. These findings suggest that mangafodipir is likely safe for humans, with only a small chance of causing mild side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Mangafodipir is unique because it offers a new approach to tackling drug-resistant epilepsy by using a manganese-based compound for enhanced brain imaging. Unlike standard treatments, which often involve anti-seizure medications like valproate or carbamazepine, Mangafodipir aims to improve the diagnosis and management of epilepsy by providing clearer images of brain activity. This allows doctors to better understand the specific areas of the brain involved in seizures, potentially leading to more targeted and effective treatments. Researchers are excited about this treatment because it could revolutionize how we diagnose and treat epilepsy, especially in patients who don't respond well to current medications.

What evidence suggests that mangafodipir is effective for imaging drug-resistant epilepsy?

Research has shown that mangafodipir can offer valuable insights during MRI scans for epilepsy. In past studies, MRI scans enhanced with mangafodipir provided extra diagnostic information for nearly half of the patients, sometimes helping doctors adjust treatment plans. In this trial, participants will receive mangafodipir as a contrast agent to make areas of the brain affected by epilepsy more visible. Although primarily used for liver imaging, its potential use in epilepsy could enhance understanding of how the disease affects the brain. Early findings suggest it is safe for short-term use, which is promising for potential participants. ^{3 4 5 6 7}

Who Is on the Research Team?

Sara K Inati, M.D.

Principal Investigator

National Institute of Neurological Disorders and Stroke (NINDS)

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with drug-resistant epilepsy, who have had seizures not controlled by medication for at least a year and experience at least one seizure monthly. Participants must be able to consent and should already be enrolled in protocol 18-N-0066. Exclusions include HIV positive individuals, pregnant or breastfeeding women, those with manganese allergies or certain medical conditions like Parkinson's disease.

Inclusion Criteria

Able to give written informed consent directly

Prior or concurrent enrollment in protocol 18-N-0066 required

I have epilepsy that hasn't improved with treatment for over a year, with at least one seizure a month.

Exclusion Criteria

Unwilling to allow sharing of coded data for future studies

I have been diagnosed with Parkinson's Disease or Parkinsonism.

Significant structural brain abnormality on baseline MRI scan

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-3 months

1 visit (in-person)

Treatment

Participants receive mangafodipir through an IV and undergo MRI scans to assess blood-brain barrier disruption

2-10 days

5 MRI scans over a 10-day period, inpatient stay for video-EEG monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including a final MRI scan

At least 2 weeks after treatment

1 visit (in-person) for final MRI

What Are the Treatments Tested in This Trial?

Interventions

• Mangafodipir

Trial Overview The study tests if mangafodipir can safely highlight brain areas affected by epilepsy on MRI scans. Participants will undergo multiple visits over 1-3 months including an inpatient stay of 2-10 days for video EEG monitoring, IV catheter placement, administration of mangafodipir, and several MRI scans before and after the contrast agent is given.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 1 Intervention

Patients will be given the study drug

Who Is Running the Clinical Trial?

National Institute of Neurological Disorders and Stroke (NINDS)

Lead Sponsor

Trials

1,403

Recruited

655,000+

Published Research Related to This Trial

Ultrahigh field imaging significantly enhances the sensitivity and resolution of MR imaging, which is crucial for identifying epileptogenic zones in patients with drug-resistant epilepsy.

Accurate detection of these zones through advanced imaging techniques can lead to better treatment outcomes, such as seizure reduction or freedom, for the over one million people in the U.S. suffering from uncontrolled seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UltraHigh Field MR Imaging in Epilepsy. Verma, G., Delman, BN., Balchandani, P.[2023]

In a study of 119 patients, the contrast agent mangafodipir trisodium (MnDPDP) was found to be well-tolerated, with no severe adverse events reported and only mild reactions in five patients.

MnDPDP significantly improved the detection of focal hepatic lesions in MR imaging compared to non-enhanced MR and contrast-enhanced CT, leading to changes in management for 10.1% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerability and utility of mangafodipir trisodium injection (MnDPDP) at the dose of 5 mumol/kg body weight in detecting focal liver tumors: results of a phase III trial using an infusion technique. Padovani, B., Lecesne, R., Raffaelli, C., et al.[2019]

In a study involving 624 patients, MnDPDP (Teslascan) significantly improved the detection of liver lesions in MR imaging compared to unenhanced images, with 45% of patients showing additional information not found in unenhanced scans.

The safety profile of MnDPDP was favorable, with only 7% of patients reporting adverse events and no clinically significant changes in heart rates or blood pressure, indicating it is a safe option for enhanced MR imaging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MnDPDP for MR imaging of the liver. Results from the European phase III studies. Torres, CG., Lundby, B., Sterud, AT., et al.[2022]

Mangafodipir trisodium (MnDPDP) is shown to be a safer alternative to manganese chloride (MnCl2) for enhancing MRI imaging, without compromising its effectiveness in increasing relaxation rates (R1) at a clinical dose of 5 mumol/kg.

Both MnDPDP and MnCl2 produced a positive dose-response in R1 and tissue manganese concentration in rat and pig organs, but MnDPDP demonstrated added cardiovascular safety, making it a preferable choice for clinical applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NMR relaxation studies with MnDPDP. Southon, TE., Grant, D., Bjørnerud, A., et al.[2022]

Mangafodipir trisodium (MnDPDP) infusion at doses of 5 and 10 mumol/kg provides significant enhancement in MRI imaging of abdominal organs like the liver, pancreas, and kidneys, indicating its efficacy as a contrast agent.

The study found that after infusion, Mn was rapidly cleared from the plasma, with 15-20% excreted in urine and 50-60% in feces, suggesting efficient renal elimination and minimal adverse effects, with only moderate flushing reported in some subjects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MR imaging properties and pharmacokinetics of MnDPDP in healthy volunteers. Wang, C., Gordon, PB., Hustvedt, SO., et al.[2022]

A new MRI contrast agent that can cross the blood-brain barrier significantly improves the visualization of lesions in patients with drug-resistant focal epilepsy, potentially increasing the effectiveness of surgical treatment.

In mouse models, this contrast agent responds to electric-field changes during seizures, enhancing MRI signals and helping to identify seizure foci that are otherwise difficult to detect, which could lead to better diagnosis and management of epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy. Wang, C., Sun, W., Zhang, J., et al.[2021]

A 25-year-old male with drug-resistant epilepsy experienced seizure relapse after surgery, which was traced to a secondary epileptogenic focus in the contralateral insula, highlighting the need for thorough monitoring of distant seizure foci after initial surgery.

The use of volumetric stereotactic radiofrequency ablation (vRFA) proved effective in treating the secondary focus, resulting in the patient being seizure-free for 20 months, demonstrating the potential of this novel technique for larger cortical ablation compared to traditional methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Contralateral insular epileptogenic hub causing seizure relapse after opercular focal cortical dysplasia surgery and response to radiofrequency thermocoagulation: illustrative case. Jayapaul, P., Aslam, S., Rajamma, BM., et al.[2022]

Interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering effectively localizes seizure onset zones (SOZ) and irritative zones (IZ) in pediatric patients with drug-resistant epilepsy (DRE), even when MRI results are negative.

Patients with clustered dipoles showed a higher likelihood of successful surgical outcomes, indicating that the proximity of these dipoles to the resection area is predictive of better results after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Presurgical accuracy of dipole clustering in MRI-negative pediatric patients with epilepsy: Validation against intracranial EEG and resection. Ntolkeras, G., Tamilia, E., AlHilani, M., et al.[2023]

Out of 1200 patients assessed for epilepsy surgery, 190 (16%) had no distinct lesions on MRI, and among those who underwent surgery, 38% became seizure-free, indicating that surgical intervention can be beneficial even for MRI-negative patients.

The study found that improved MRI techniques could help identify subtle lesions, which may lead to better surgical outcomes, as 7 out of 9 MRI-negative patients with detectable lesions became seizure-free compared to only 20% of those without any histopathological findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characteristics and surgical outcomes of patients with refractory magnetic resonance imaging-negative epilepsies. Bien, CG., Szinay, M., Wagner, J., et al.[2009]

In a study of 40 patients suspected of having pancreatic cancer, Mn-DPDP enhanced MRI demonstrated a remarkable sensitivity of 100% for detecting pancreatic lesions, indicating it is highly effective in identifying potential issues.

However, the specificity was only 56%, suggesting that while it is good at finding lesions, it may also produce false positives, and therefore should be used as a complementary imaging method rather than a standalone diagnostic tool.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[MR imaging of pancreatic lesions with Mn-DPDP. A histopathologic correlation]. Dobritz, M., Fellner, FA., Baum, U., et al.[2015]

Citations

1. ninds.nih.gov ninds.nih.gov/health-information/clinical-trials/investigation-blood-brain-barrier-breakdown-using-manganese-magnetic-resonance-imaging-drug

Investigation of Blood-Brain-Barrier Breakdown Using ... Objective: The primary goals of this pilot study is to (1) describe the safety profile of administration of mangafodipir in patients with epilepsy and (2) ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02531880

Study Details | NCT02531880 | Investigation of Blood-Brain ... The primary goals of this pilot study are to (1) describe the safety profile of administration of mangafodipir in patients with epilepsy and (2) investigate the ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/11050638/

results of the U.S. Multicenter phase III clinical trials. ... Mangafodipir-enhanced MRI uniquely provided additional diagnostic information in 48% of the patients, and patient management was consequently altered in 6% of ...

4. clinconnect.io clinconnect.io/trials/NCT02531880?queryID=8815c91fda77d86091fe&apos=23

Investigation of Blood-Brain-Barrier Breakdown Using This clinical trial is studying a potential new way to see how epilepsy affects the brain by using a special contrast agent called mangafodipir during MRI scans ...

5. researchgate.net researchgate.net/publication/227881229_Safety_and_Efficacy_of_Mangafodipir_Trisodium_MnDPDP_Injection_for_Hepatic_MRI_in_Adults_Results_of_the_US_Multicenter_Phase_III_Clinical_Trials_Safety

Safety and Efficacy of Mangafodipir Trisodium (MnDPDP ... The short-term1 safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/10931579/

results of the U.S. multicenter phase III clinical trials (safety) Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most ...

7. withpower.com withpower.com/trial/phase-1-drug-resistant-epilepsy-4-2022-b1418

Mangafodipir Imaging for Drug-Resistant Epilepsy The safety profile of MnDPDP was favorable, with only 7% of patients reporting adverse events and no clinically significant changes in heart rates or blood ...