Lithium + Valproic Acid + KarXT for Healthy Subjects

Recruiting at 1 trial location

Overseen By First line of the email MUST contain the NCT# and Site #.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Karuna Therapeutics

Disqualifiers: Cardiovascular, Hepatic, Renal, Pancreatitis, others

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

Compensation: Varies

Number of Visits: Unknown

130 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the interaction of three medications—lithium, valproic acid, and KarXT (a combination of xanomeline and trospium chloride)—within the body. The main focus is to understand how a single dose of each drug is processed when combined with the others. It involves healthy volunteers without significant medical conditions and with a Body Mass Index (BMI) between 18.0 and 32.0. Generally healthy individuals with no major medical issues may find this trial suitable. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the study involves healthy participants, it is likely that you should not be on any regular medications. Please consult with the study team for specific guidance.

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

Research has shown that lithium can be tricky because the helpful dose is close to the dose that can cause problems. Some issues include slurred speech, blurred vision, and an upset stomach. Monitoring for these effects is crucial.

Valproic acid has received FDA approval for treating seizures and some mood disorders. It can cause skin irritation and, in rare cases, liver problems, especially in young children. Most people tolerate it well when used as directed.

Studies have generally found that Xanomeline-trospium chloride is well-tolerated. Common side effects include nausea, an upset stomach, and high blood pressure. These effects were mostly mild and occurred more frequently than in those taking a placebo.

This trial is in the early phase, which often focuses on checking safety in a small group. While early-phase trials mean safety is still being closely monitored, studying these drugs together suggests some existing understanding of their effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Lithium, Valproic Acid, and KarXT (Xanomeline/Trospium Chloride) because it brings together well-known mood stabilizers with a novel mechanism of action. Unlike typical treatments for mood disorders, which primarily focus on serotonin or dopamine pathways, KarXT targets muscarinic receptors in the brain, potentially offering a new way to manage symptoms. This unique approach could lead to better outcomes for patients who haven't responded well to current options like SSRIs or antipsychotics. Additionally, combining these treatments might enhance effectiveness and reduce side effects, which is a significant step forward in mental health care.

What evidence suggests that this trial's treatments could be effective?

Research shows that lithium often helps with mood disorders and can improve thinking and memory. Studies indicate that valproic acid reduces the number and intensity of seizures and helps stabilize mood. Xanomeline combined with trospium chloride has improved symptoms in people with schizophrenia and has a unique safety profile. This trial will explore the potential benefits of these treatments when used together. Participants will be assigned to different treatment parts to assess their combined effects. ^{6 7 8 9 10}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for healthy individuals who can safely take the medications lithium, valproic acid, and KarXT. Specific eligibility criteria are not provided, but typically participants must meet certain health standards to ensure their safety during the study.

Inclusion Criteria

I am healthy, not able to have children, and all my medical tests are normal.

My BMI is between 18.0 and 32.0.

Exclusion Criteria

I have had pancreatitis before.

I have a history of urinary, gastric issues, glaucoma, prostate enlargement, or frequent nighttime urination.

Other protocol-defined Inclusion/Exclusion criteria apply

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Part A

Evaluation of the effects of lithium and valproic acid on the single-dose pharmacokinetics of KarXT

1 week

Part B

Evaluation of the effects of KarXT on the single-dose pharmacokinetics of lithium and valproic acid

1 week

Part C

Continuation of pharmacokinetic evaluations with different dosing sequences

1 week

Part D

Final evaluation phase of pharmacokinetic interactions

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Lithium
• Valproic Acid
• Xanomeline/Trospium Chloride

Trial Overview The study is testing how taking lithium or valproic acid might affect the levels of a drug called KarXT in the body, and also how KarXT affects the levels of lithium and valproic acid when taken by healthy people.

How Is the Trial Designed?

Group I: Part F Experimental Treatment 2 Interventions

Group II: Part E Experimental Treatment 2 Interventions

Group III: Part D Experimental Treatment 2 Interventions

Group IV: Part C Experimental Treatment 2 Interventions

Group V: Part B Experimental Treatment 2 Interventions

Group VI: Part A Experimental Treatment 2 Interventions

Lithium is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Lithium for:

• Bipolar disorder
• Manic episodes
• Major depressive disorder

Approved in United States as Lithium for:

• Bipolar disorder
• Manic episodes

Approved in Canada as Lithium for:

• Bipolar disorder
• Manic episodes
• Major depressive disorder

Approved in Japan as Lithium for:

• Bipolar disorder
• Manic episodes

Who Is Running the Clinical Trial?

Karuna Therapeutics

Lead Sponsor

Trials

17

Recruited

4,100+

Published Research Related to This Trial

In a study involving 12 healthy volunteers, the bioavailability of two extended-release lithium carbonate products (Eskalith CR and Lithobid) was found to be significantly different from an immediate-release product (Lithotab), with Eskalith CR showing a 40% lower peak plasma concentration compared to Lithotab.

The immediate-release product, Lithotab, reached its maximum plasma concentration faster than the extended-release products, indicating that the formulation affects how quickly lithium enters the bloodstream, although the total amount excreted in urine was similar across all products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-dose bioavailability of two extended-release lithium carbonate products. Kirkwood, CK., Wilson, SK., Hayes, PE., et al.[2013]

Lithium valproate exhibits significant anticonvulsant activity similar to sodium valproate, effectively reducing seizures in experimental models.

The addition of lithium ions alters the neurochemical profile of valproate, increasing levels of GABA and glutamate in the brain, which may contribute to its sedative and tranquilizing effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lithium valproate: its neuropharmacological spectrum and effect on transmitter amino acid content of the brain of rats]. Kharlamov, AN., Shumkova, OV., Blinkova, NF., et al.[2013]

A new sustained-release lithium carbonate (LC) tablet formulation containing 15% carbopol was developed, which allows for smoother and extended absorption, similar to the commercial Eskalith CR, while preventing high peak blood levels that can cause side effects.

This formulation can be administered twice daily instead of three to four times, improving patient compliance during maintenance therapy for conditions like bipolar disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Formulation of sustained - release lithium carbonate matrix tablets: influence of hydrophilic materials on the release rate and in vitro-in vivo evaluation. Emami, J., Tavakoli, N., Movahedian, A.[2013]

Lithium carbonate (Li2CO3) is well-established for treating and preventing mania and bipolar disorders, but recent studies suggest it may also be effective for unipolar depression, aggression, schizophrenia, and other non-psychiatric conditions.

The review highlights potential new uses for lithium in treating various conditions such as movement disorders, asthma, and sleep disorders, indicating a need for further double-blind studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical uses of lithium salts. Frost, RE., Messiha, FS.[2019]

The novel lithium complex medication showed a different pattern of brain electrical activity compared to lithium carbonate, indicating it may induce milder activation of the cerebral cortex.

This new formulation, which includes lithium citrate, aluminum oxide, and polymethylsiloxane, is suggested to be more effective and safer than traditional lithium carbonate for treating neurological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Lithium Preparations on Cerebral Electrophysiological Activity in Rats. Konenkov, VI., Rachkovskaya, LN., Letyagin, AY., et al.[2018]

In a study involving 5 normal volunteers, both lithium carbonate ('Priadel') and lithium citrate ('Litarex') showed similar total bioavailability when administered at the same dose (27.2 mmol lithium).

However, lithium citrate resulted in a significantly lower peak serum lithium level compared to lithium carbonate, indicating differences in how the body processes these two formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability of lithium carbonate and lithium citrate: a comparison of two controlled-release preparations. Tyrer, SP., Peat, MA., Minty, PS., et al.[2013]

In a study involving eight healthy volunteers, lithium carbonate showed a mean biological half-life of approximately 16.5 hours, indicating a slow disposition rate which is important for its therapeutic use.

The controlled release formulation of lithium carbonate resulted in a smoother serum concentration profile, with a 22% lower peak concentration and a delayed time to peak, suggesting it may provide a more stable delivery of the drug compared to the immediate release tablet.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption and disposition kinetics of lithium carbonate following administration of conventional and controlled release formulations. Arancibia, A., Corvalan, F., Mella, F., et al.[2013]

In a double-blind study of severely ill hospitalized manic patients, lithium carbonate and haloperidol significantly improved manic symptoms without causing sedation, while chlorpromazine caused sedation but did not effectively address mania.

Lithium carbonate provided a more consistent and comprehensive improvement in manic symptoms, leading to a higher discharge rate of patients compared to those treated with haloperidol or chlorpromazine, highlighting its potential as a more effective treatment for mania.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychoactive drugs in mania. A controlled comparison of lithium carbonate, chlorpromazine, and haloperidol. Shopsin, B., Gershon, S., Thompson, H., et al.[2019]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK519062/

Lithium - StatPearls - NCBI Bookshelf Adult Dosage​​ Lithium typically requires approximately 1 to 3 weeks to manifest its effects, resulting in symptom alleviation and remission. ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0165032724008723

Human brain 7Li-MRI following low-dose lithium dietary ... Studies using doses of lithium carbonate typical of bipolar disorder treatment have not demonstrated efficacy and the intervention was ...

3. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2024.1414424/full

Retrospective analysis of lithium treatment: examination ... This study aims to investigate the relationship between lithium blood levels and demographic characteristics such as age and gender, as well as possible drug ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10227915/

Beyond its Psychiatric Use: The Benefits of Low-dose Lithium ... Currently, literature shows that low-dose lithium (≤0.5 mM) may be beneficial for cardiovascular, musculoskeletal, metabolic, and cognitive function, as well as ...

5. webmd.com webmd.com/vitamins/ai/ingredientmono-1065/lithium

Lithium - Uses, Side Effects, and More Lithium carbonate and lithium citrate are U.S. FDA approved prescription drugs. Lithium prescription drugs can cause muscle weakness, fatigue, weight gain, and ...

6. sigmaaldrich.com sigmaaldrich.com/PH/en/sds/sial/62484?srsltid=AfmBOopfFP3ja6lL7T8jV_8dGpDhSDMy28UVVNSFrxah7k0mfdZubw05

SAFETY DATA SHEET Central nervous system effects that include slurred speech, blurred vision, sensory loss, ataxia, and convulsions may occur. Diarrhea, vomiting ...

7. spectrumchemical.com spectrumchemical.com/MSDS/L1113_AGHS.pdf?srsltid=AfmBOopeRqkoXZ19zXbQJWfRFb3QZW0L49Blai1U2bb0foMxbKyOqrqo

SAFETY DATA SHEET Causes serious eye irritation. Respiratory or skin sensitization. No information available. Germ cell mutagenicity. No information available.

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/017812s028,018421s027lbl.pdf

LITHIUM CARBONATE Tablets USP ... - accessdata.fda.gov The toxic levels for lithium are close to the therapeutic levels. It is therefore important that patients and their families be cautioned to watch for early ...

9. chemicalbook.com chemicalbook.com/msds/lithium-citrate.pdf

LITHIUM CITRATE - Safety Data Sheet Avoid contacting with skin and eye. Use personal protective equipment.Wear chemical impermeable gloves. Ensure adequate ventilation.Remove all ...

10. fishersci.com fishersci.com/store/msds?partNumber=AA47373&productDescription=keyword&vendorId=VN00024248&countryCode=US&language=en

SAFETY DATA SHEET Precautionary Statements. Prevention. Wear protective gloves/protective clothing/eye protection/face protection.