Scopolamine for Muscarinic Receptor Engagement

(emo_to2 Trial)

Overseen By Mark F Dias, MA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must not be taking: Anticholinergics, Antidepressants, Antipsychotics, others

Disqualifiers: Respiratory, Neurological, Psychiatric, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how scopolamine interacts with M1 Muscarinic Receptors in the brain. Researchers test different doses to assess the drug's connection with these receptors using brain scans. The trial targets healthy individuals without significant health issues who can temporarily stop certain medications. Those who have always been healthy and are not currently on specific medications might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering a unique opportunity to contribute to groundbreaking research.

Will I have to stop taking my current medications?

Yes, you will need to stop taking certain medications. You cannot use prescription medications, drugs with anticholinergic properties, or strong CYP3A4 inhibitors within 14 days of scopolamine dosing. CYP3A4 inducers should not be taken within 21 days of scopolamine administration.

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

Research has shown that scopolamine has been safely used for a long time to treat motion sickness and post-surgery nausea. It reduces symptoms like dizziness and nausea by blocking certain signals in the brain. Most people generally tolerate scopolamine well.

While scopolamine affects different types of signals, studies have mainly focused on its effect on muscarinic receptors, which play roles in various body functions. This can sometimes cause side effects like dry mouth or blurred vision, but these are usually mild and resolve on their own.

Since this study is in its early stages, the main goal is to understand how scopolamine interacts with specific brain signals, with safety being closely monitored. Overall, scopolamine's strong safety record in its approved uses suggests it may be well-tolerated in this study too. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about scopolamine because it works differently from most traditional treatments for conditions involving muscarinic receptors. While current options often focus on managing symptoms over time, scopolamine targets muscarinic receptors directly, potentially offering faster results. This treatment is administered via a quick 15-minute IV infusion, which could make it a more convenient option compared to longer or more frequent dosing schedules typical of standard therapies. Additionally, its ability to engage muscarinic receptors effectively is being evaluated with advanced imaging techniques like PET scans, providing precise insights into its mechanism and effectiveness.

What evidence suggests that scopolamine might be an effective treatment for muscarinic receptor engagement?

Research has shown that scopolamine can quickly and significantly improve symptoms in people with depression, especially those who don't respond well to other treatments. It blocks certain brain parts called M1 muscarinic receptors, which seems to lift mood and alleviate depression symptoms. Known for treating nausea and motion sickness, scopolamine demonstrates versatility. Early findings suggest it might help manage stress-related symptoms by affecting brain chemistry. In this trial, participants will receive either a low or high dose of scopolamine to evaluate its target occupancy at M1 receptors. Overall, scopolamine shows promise in treating depression and other conditions by targeting specific brain areas. ^{1 4 5 6 7}

Who Is on the Research Team?

David Matuskey, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

Healthy adults aged 18-60 who can consent, read, write, and follow study directions. They must be in good health based on medical history, exams, and tests. Excluded are those with hepatitis B/C or HIV; IV drug use history; abnormal lab results or ECG; pregnant/lactating women; recent prescription meds users (with exceptions); scopolamine patch users within 14 days; participants in other trials recently involving drugs or radiotracers; current smokers/nicotine users; substance abuse history within 2 years; positive drug screening.

Inclusion Criteria

My overall health is good based on recent medical exams and tests.

Willing and able to give voluntary, written informed consent

I can read, write, and follow all study instructions.

Exclusion Criteria

Positive drug test at screening

Laboratory tests with clinically significant abnormalities or positive urine toxicology, at screening

Abnormal and clinically significant ECG, as determined by the Investigator or his/her designee, at screening

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Imaging

Participants undergo a baseline PET scan and MRI scan of the brain

1 day

1 visit (in-person)

Treatment and Post-dose Imaging

Participants receive a 15-minute IV infusion of scopolamine followed by a post-dose PET scan

1-2 days

1-2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 48 hours

What Are the Treatments Tested in This Trial?

Interventions

• Scopolamine

Trial Overview The trial is testing how the body's M1 Muscarinic Receptors in the brain respond to different doses of scopolamine given intravenously. It uses a special imaging tracer called [11C]EMO ([11C]LSN3172176) during PET and MRI scans to measure this response in healthy volunteers.

How Is the Trial Designed?

Group I: Scopolamine low dose Experimental Treatment 2 Interventions

The target occupancy (TO) of scopolamine at M1 will be evaluated using the radiotracer \[11C\]EMO and positron emission tomography (PET). TO will be measured following a 15-minute IV infusion of 2.0 μg/kg scopolamine in 0-2 anticipated participants.

Group II: Scopolamine high dose Experimental Treatment 2 Interventions

The target occupancy (TO) of scopolamine at M1 will be evaluated using the radiotracer \[11C\]EMO and positron emission tomography (PET). TO will be measured following a 15-minute IV infusion of 4.0 μg/kg scopolamine in 4-6 anticipated participants.

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

Janssen Scientific Affairs, LLC

Industry Sponsor

Trials

165

Recruited

579,000+

Joaquin Duato

Janssen Scientific Affairs, LLC

Chief Executive Officer since 2022

MBA from ESADE, Master of International Management from Thunderbird School of Global Management

Dr. Jijo James, MD

Janssen Scientific Affairs, LLC

Chief Medical Officer since 2014

MD from St. Johns Medical College, MPH from Columbia University

Published Research Related to This Trial

Scopolamine is an effective treatment for motion sickness and is commonly used for premedication before anesthesia due to its ability to inhibit muscarinic receptors, leading to antiemetic and sedative effects.

The transdermal patch form of scopolamine improves its bioavailability and reduces side effects compared to oral administration, allowing for a steady release of the drug over 72 hours, which helps maintain effective plasma levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics in clinical use of scopolamine. Renner, UD., Oertel, R., Kirch, W.[2022]

Rivastigmine, a cholinesterase inhibitor for Alzheimer's disease, is available in both oral and transdermal patch forms, with the patch showing better tolerability across all stages of the disease compared to the oral form and other cholinesterase inhibitors.

While the transdermal patch formulation is generally safer, there is a risk of overdose if multiple patches are used simultaneously, highlighting the importance of patient and caregiver education on proper usage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine. Khoury, R., Rajamanickam, J., Grossberg, GT.[2020]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/25187432/

M1 and m2 muscarinic receptor subtypes regulate ... Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current ...

2. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK554397/

Scopolamine - StatPearls - NCBI Bookshelf - NIH Scopolamine is a medication used to manage and treat postoperative nausea and vomiting (PONV) and motion sickness. It is in the anticholinergic class of drugs.

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022356524188350

M1 and M2 Muscarinic Receptor Subtypes Regulate ... Scopolamine produces rapid and significant symptom improvement in patients with depression, and most notably in patients who do not respond to current ...

4. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0032082

Scopolamine Administration Modulates Muscarinic, Nicotinic ... Abstract. Studies on the effect of scopolamine on memory are abundant but so far only regulation of the muscarinic receptor (M1) has been reported.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0969996115002302

Rapid antidepressant actions of scopolamine Scopolamine blocks the anhedonia caused by exposure to chronic stress. •. Selective blockade of muscarinic M1 receptors produces antidepressant actions.

6. go.drugbank.com go.drugbank.com/drugs/DB00747

Scopolamine: Uses, Interactions, Mechanism of Action Scopolamine is an anticholinergic belladonna alkaloid that, through competitive inhibition of muscarinic receptors, affects parasympathetic nervous system ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/sites/books/NBK547671/

Antiemetic Antimuscarinics - StatPearls - NCBI Bookshelf - NIH Scopolamine exerts a non-selective influence on all 5 muscarinic receptor subtypes (M1 to M5), raising the theoretical possibility of anticholinergic ...