AGB101 for Psychosis in Parkinson's Disease

(AGB101 PDP Trial)

Overseen By Arnold Bakker, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Johns Hopkins University

Must be taking: Cholinesterase inhibitors, Antidepressants

Must not be taking: Anticonvulsants

Disqualifiers: Severe renal impairment, Schizophrenia, 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 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 16 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a medication called AGB101 (also known as Levetiracetam or Keppra) can reduce psychosis symptoms in people with Parkinson's disease. Participants will receive both the medication and a placebo over two separate 6-week periods, with a break in between. Suitable candidates for this trial should have Parkinson's disease with frequent hallucinations or delusions that have persisted for over a month. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Do I need to stop taking my current medications to join the trial?

You may need to stop certain medications, as patients being treated for specific symptoms must be off those medications for at least 2 weeks before starting the trial. However, you can continue taking medications for Parkinson's disease and other permitted medications if they have been stable for at least 4 weeks before the trial.

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

Research has shown that AGB101, a low-dose version of the drug levetiracetam, is generally safe for people. In earlier studies, participants taking AGB101 did not experience more negative side effects than those taking a placebo, which is a harmless pill. Serious side effects were not commonly reported. Some individuals might experience mild effects like dizziness or tiredness, but these are not serious. Since levetiracetam is already approved for treating other conditions like epilepsy, it has a proven safety record at different doses. Overall, evidence suggests AGB101 is relatively safe, but discussing any concerns with a healthcare provider before joining a trial is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for psychosis in Parkinson's disease?

Unlike the standard antipsychotic medications used for treating psychosis in Parkinson's disease, AGB101 uses a low-dose of levetiracetam, typically known as an anti-seizure medication, to target symptoms. Researchers are excited because AGB101 offers a new approach by potentially reducing psychosis without the side effects commonly associated with traditional antipsychotics, such as worsening motor symptoms. The extended-release formulation allows for a steady release, which could enhance its effectiveness and tolerability. This novel mechanism and delivery method set AGB101 apart from existing treatments, offering hope for improved management of psychosis in Parkinson's disease patients.

What evidence suggests that AGB101 might be an effective treatment for psychosis in Parkinson's disease?

Research has shown that low-dose levetiracetam, the main ingredient in AGB101, may help treat psychosis symptoms in people with Parkinson's disease. In this trial, participants will receive either AGB101 first followed by a placebo, or a placebo first followed by AGB101. Studies have found that low doses can be effective, while higher doses are not as beneficial. AGB101 has also been tested for other conditions, such as mild memory problems, and may help slow cognitive decline. Researchers believe that AGB101 works by calming overactive brain signals, potentially reducing psychosis symptoms. Although more research is needed specifically for psychosis related to Parkinson's, early results are promising. ^{1 2 3 4 5}

Who Is on the Research Team?

Arnold Bakker, Ph.D.

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for people with Parkinson’s disease who are between 40 and 85 years old and experiencing hallucinations (such as seeing things that other people don’t see) at least once a week. Participants cannot join if they have other neurological disorders besides Parkinson’s, or a severe mental illness unrelated to Parkinson’s disease.

Inclusion Criteria

Are you between 40 and 85 years old?

You have been diagnosed with Parkinson's Disease

Are you willing to have an MRI scan done for the study?

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive AGB101 or placebo once daily for 6 weeks, followed by a 4-week washout, then crossover to the other treatment for another 6 weeks

16 weeks

5 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AGB101

Trial Overview AGB101 (a low-dose formulation of an FDA approved anti-seizure medication called levetiracetam) is being tested for its effectiveness in treating hallucinations and memory changes in Parkinson’s disease over approximately 20 weeks. The trial involves taking AGB101 and placebo sequentially with a break between treatments. It includes physical and neurological exams, questionnaires, cognitive tests, blood and urine samples, and two MRI scans.

How Is the Trial Designed?

Group I: placebo first, then AGB101 Experimental Treatment 1 Intervention

Placebo capsule once daily for 6 weeks, washout (4 weeks), then AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 6 weeks.

Group II: AGB101 first, then placebo Experimental Treatment 1 Intervention

AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) once daily for 6 weeks, washout (4 weeks), then placebo capsule once daily for 6 weeks.

AGB101 is already approved in United States, European Union, Canada, China for the following indications:

Approved in United States as Levetiracetam for:

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

Approved in European Union as Levetiracetam for:

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

Approved in Canada as Levetiracetam for:

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

Approved in China as Levetiracetam for:

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

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

AgeneBio

Industry Sponsor

Trials

3

Recruited

250+

Published Research Related to This Trial

In a pilot study involving 14 patients with Parkinson's disease, aripiprazole showed some statistically significant improvements in psychiatric symptoms, as measured by the Brief Psychiatric Rating Scale (BPRS).

However, the treatment was associated with worsened motor symptoms in several patients, leading to a high dropout rate, which suggests that aripiprazole may not be a promising option for managing psychosis in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label flexible-dose pilot study to evaluate the safety and tolerability of aripiprazole in patients with psychosis associated with Parkinson's disease. Friedman, JH., Berman, RM., Goetz, CG., et al.[2019]

Approximately 30% of patients treated with dopaminergic agents for Parkinson's disease experience visual hallucinations, highlighting the need for careful monitoring of neuropsychiatric side effects, especially in elderly patients and those with dementia.

Dopaminergic agents stimulate D2 dopamine receptors, which may contribute to neuropsychiatric effects; managing these effects often involves dosage reduction or the use of antipsychotic medications for severe symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Behavioral complications of drug treatment of Parkinson's disease. Cummings, JL.[2022]

Levetiracetam, an antiepileptic drug, is generally well tolerated but can cause mild behavioral side effects like agitation and anxiety, which usually resolve after stopping the medication.

This report highlights a rare case of catatonia in a 43-year-old woman linked to levetiracetam, marking the first documented instance of this serious psychiatric side effect associated with the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catatonia induced by levetiracetam. Chouinard, MJ., Nguyen, DK., Clément, JF., et al.[2018]

In a study of 152 Parkinson's disease patients, 27.6% experienced exogenous psychotic symptoms while on various antiparkinsonian medications, particularly those receiving levodopa combined with a decarboxylase inhibitor, suggesting a link between longer treatment duration and increased risk of psychosis.

Factors such as older age at treatment initiation, severe neurological symptoms, dementia, and additional physical illnesses were identified as predisposing conditions for developing psychotic symptoms, indicating that levodopa is not the sole cause of these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Exogenous psychoses in Parkinson syndrome. Frequency and causal conditions]. Schneider, E., Fischer, PA., Jacobi, P., et al.[2013]

About 30% of Parkinson's disease patients experience drug-induced hallucinations and psychosis, which can lead to nursing home placement, highlighting the need for effective treatment options.

Recent atypical antipsychotics like clozapine, risperidone, olanzapine, and quetiapine have been evaluated for their effects on motor function in Parkinson's patients, but challenges remain in assessing their safety and efficacy in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atypical antipsychotics in Parkinson-sensitive populations. Friedman, JH., Fernandez, HH.[2018]

In a pilot study involving 32 Parkinson's disease patients with levodopa-induced dyskinesia, levetiracetam (LEV) demonstrated mild antidyskinetic effects, significantly improving dyskinesia scores compared to placebo after 11 weeks of treatment.

LEV was well tolerated at doses up to 2,000 mg/day, with no significant adverse effects on Parkinsonian symptoms or levodopa efficacy, suggesting it could be a safe add-on therapy for managing dyskinesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. Wolz, M., Löhle, M., Strecker, K., et al.[2021]

Levetiracetam is an effective second-generation antiepileptic drug that significantly reduces seizure frequency in both pediatric and adult patients with refractory partial onset seizures, as shown in multiple randomized controlled trials.

It has a unique mechanism of action involving binding to synaptic vesicle protein 2A and inhibiting excessive neuronal activity, while also being well-tolerated with a low incidence of severe side effects compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam: a review of its use in epilepsy. Lyseng-Williamson, KA.[2022]

A systematic review of seven clinical trials involving 150 Parkinson's disease patients found that levetiracetam showed only mild anti-dyskinetic effects and poor tolerability, with some studies reporting no significant benefits.

Current evidence does not support the efficacy of levetiracetam for managing levodopa-induced dyskinesia in Parkinson's disease, highlighting the need for more randomized controlled trials to better assess its potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Levetiracetam for the Management of Levodopa- Induced Dyskinesia in Patients with Parkinson's Disease: A Systematic Review. Ebada, MA., Alkanj, S., Ebada, M., et al.[2020]

A 68-year-old woman with tardive dyskinesia, caused by long-term use of metoclopramide, showed significant improvement in her symptoms after starting treatment with levetiracetam, with her Abnormal Involuntary Movement Scale score dropping from 27 to 8 within a week.

Levetiracetam appears to be an effective treatment option for tardive dyskinesia, allowing the patient to continue using metoclopramide for gastrointestinal issues, but further research with larger studies is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of tardive dyskinesia with levetiracetam in a transplant patient. Zivković, SA., Costa, G., Bond, G., et al.[2018]

In a multicenter trial with 38 Parkinson's disease patients, levetiracetam (LEV) at 1,000 mg/day significantly reduced 'On with LID' time by 75 minutes and increased 'On without LID' time by 55 minutes, indicating its efficacy in managing levodopa-induced dyskinesias (LID).

The study demonstrated that LEV was safe and well-tolerated, with no increase in 'Off' time, suggesting it could be a beneficial treatment option for LID with minimal side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease. Stathis, P., Konitsiotis, S., Tagaris, G., et al.[2018]

In a study of 12 Parkinson's disease patients experiencing drug-induced psychosis, treatment with mianserin (averaging 36.7 mg for 8 weeks) led to complete or marked improvement in psychotic symptoms for 8 patients, indicating its efficacy as a 5-HT2 receptor antagonist.

Mianserin not only alleviated psychotic symptoms but also slightly reduced parkinsonian disability in 8 patients, suggesting that targeting serotonin receptors may benefit both psychosis and parkinsonism in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs. Ikeguchi, K., Kuroda, A.[2019]

In a pilot study involving 9 Parkinson's disease patients, levetiracetam (LEV) significantly increased the percentage of awake time without dyskinesia or with nontroublesome dyskinesia, improving from 43% to 61% at the endpoint (P=0.02).

Despite the positive effects on dyskinesia, the study had a high dropout rate of 56%, primarily due to somnolence, indicating a potential safety concern with LEV use in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease. Zesiewicz, TA., Sullivan, KL., Maldonado, JL., et al.[2018]

Levetiracetam is an effective broad-spectrum antiepileptic drug approved for treating partial and generalized tonic-clonic seizures, but it can cause significant neuropsychiatric side effects in some patients, particularly those with a history of psychiatric disorders.

In a case study, a 28-year-old woman with a history of schizoaffective disorder experienced severe behavioral changes, including aggression and paranoia, after starting Levetiracetam, highlighting the importance of monitoring for psychiatric symptoms, especially in high-risk individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam Induced Behavioral Abnormalities in a Patient with Seizure Disorder: A Diagnostic Challenge. Ogunsakin, O., Tumenta, T., Louis-Jean, S., et al.[2020]

Citations

1. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/38/NCT03486938/Prot_SAP_000.pdf

A multicenter, randomized, double-blind, placebo- ... Consistent with clinical and preclinical data, low-dose administration of levetiracetam was effective, while high dose had no effect (Sanchez et ...

2. trialfinder.panfoundation.org trialfinder.panfoundation.org/en-US/trial/listing/461457

Clinical Trial of AGB101 for Mild Cognitive Impairment The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10664284/

Levetiracetam for the treatment of mild cognitive impairment in ... This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03486938

Study of AGB101 in Mild Cognitive Impairment Due to ... The primary objective of the study is to evaluate the efficacy of AGB101 on slowing cognitive and functional impairment as measured by changes in the Clinical ...

5. go.drugbank.com go.drugbank.com/drugs/DB01202/clinical_trials?conditions=DBCOND0037331&phase=2&purpose=treatment&status=recruiting

Levetiracetam Recruiting Phase 2 Trials for Parkinson's ... Clinical Trial Evaluating the Efficacy and Safety of AGB101 for Treatment of Parkinson's Disease Related Psychosis. Levetiracetam (DB01202) ...