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

Trial Summary

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.

What data supports the effectiveness of the drug AGB101 for psychosis in Parkinson's Disease?

Levetiracetam, a component of AGB101, has shown some effectiveness in reducing involuntary movements in Parkinson's patients, as seen in studies where it improved the time patients spent without troublesome dyskinesia (involuntary movements). While these studies focused on movement issues, they suggest that levetiracetam can be beneficial in managing symptoms related to Parkinson's Disease. ^{1 2 3 4 5}

Is AGB101 (Levetiracetam) generally safe for humans?

Levetiracetam, also known as AGB101, is generally well tolerated, but it can cause behavioral side effects like agitation, anxiety, and depression in some people. Serious psychiatric effects, such as psychosis and suicidal behavior, are rare. Most side effects are mild and resolve when the medication is stopped. ^{1 2 6 7 8}

How does the drug AGB101 differ from other treatments for psychosis in Parkinson's disease?

AGB101, also known as Levetiracetam or Keppra, is unique because it is primarily used as an anti-seizure medication, which may offer a different mechanism of action compared to typical antipsychotics used for psychosis in Parkinson's disease. Unlike other treatments that often exacerbate motor symptoms, AGB101 might provide a novel approach by potentially avoiding these side effects. ^{9 10 11 12 13}

What is the purpose of this trial?

This clinical trial will test whether AGB101 (low-dose levetiracetam, 220 mg, extended release tablet) can improve symptoms of psychosis in Parkinson's disease. Participants will be asked to complete up to 5 in-person study visits over approximately 20 weeks. Participants will receive both AGB101 and a placebo to take once a day for 6 weeks, with a 4-week washout in between. Participation will also involve physical/neurological exams, questionnaires, paper and pencil tests, providing blood and urine samples, and completing two MRI exams.

Research Team

Arnold Bakker, Ph.D.

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

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]

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]

References

1. Austria pubmed.ncbi.nlm.nih.gov

Levetiracetam for levodopa-induced dyskinesia in Parkinson's disease: a randomized, double-blind, placebo-controlled trial. [2021]

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

Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson's disease. [2018]

3. United Arab Emirates 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. [2020]

4. Denmark pubmed.ncbi.nlm.nih.gov

Treatment of tardive dyskinesia with levetiracetam in a transplant patient. [2018]

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

Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease. [2018]

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

Catatonia induced by levetiracetam. [2018]

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

Levetiracetam Induced Behavioral Abnormalities in a Patient with Seizure Disorder: A Diagnostic Challenge. [2020]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Levetiracetam: a review of its use in epilepsy. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

[Exogenous psychoses in Parkinson syndrome. Frequency and causal conditions]. [2013]

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

Atypical antipsychotics in Parkinson-sensitive populations. [2018]

11. United States 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. [2019]

12. Germany pubmed.ncbi.nlm.nih.gov

Mianserin treatment of patients with psychosis induced by antiparkinsonian drugs. [2019]

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

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