X/T + X-EC + Lecanemab Phase 2 (NCT07212062) — Alzheimer's Disease

Executive Summary

This Phase 2 clinical trial evaluates the safety and tolerability of combining xanomeline and trospium (X/T) with Lecanemab in participants with Alzheimer's disease who are currently receiving Lecanemab monotherapy. The trial represents a novel combination therapy approach, pairing an existing anti-amyloid antibody with a muscarinic receptor agonist to potentially enhance cognitive benefits through complementary mechanisms.

Executive Summary

This Phase 2 clinical trial evaluates the safety and tolerability of combining xanomeline and trospium (X/T) with Lecanemab in participants with Alzheimer's disease who are currently receiving Lecanemab monotherapy. The trial represents a novel combination therapy approach, pairing an existing anti-amyloid antibody with a muscarinic receptor agonist to potentially enhance cognitive benefits through complementary mechanisms.

Xanomeline is a selective M1/M4 muscarinic acetylcholine receptor agonist that has demonstrated cognitive benefits in previous trials["@karxt_mechanism"]. Trospium chloride is a muscarinic antagonist that does not cross the blood-brain barrier, used to reduce peripheral cholinergic side effects. Lecanemab (BAN2401) is an anti-amyloid-beta protofibril antibody that has shown efficacy in clearing amyloid plaques and slowing cognitive decline in the Clarity AD trial["@lecanemab_clarity"].

Trial Overview

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT07212062 |
| Trial Title | A Phase II, Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Tolerability of X/T+X-EC vs. Placebo in Participants With Alzheimer's Disease Currently Treated With Lecanemab |
| Phase | Phase 2 |
| Status | Not Yet Recruiting |
| Enrollment | 60 participants |
| Sponsor | Neurology Office of South Florida |
| Collaborator | Bristol-Myers Squibb |
| Study Type | Interventional |
| Design | Randomized, Parallel Group, Quadruple-Blind |
| Start Date | December 1, 2025 (Estimated) |
| End Date | April 1, 2028 (Estimated) |

Study Design

This is a quadruple-blind, placebo-controlled, randomized trial evaluating the safety and tolerability of adding Xanomeline/Trospium (X/T) to existing Lecanemab therapy. Participants currently receiving Lecanemab will be randomized to receive either:

• Arm A (Active): Xanomeline and Trospium Chloride Capsules + Lecanemab 10 mg/kg IV every 2 weeks
• Arm B (Placebo): Placebo capsules + Lecanemab 10 mg/kg IV every 2 weeks

Mechanism Rationale

Lecanemab (Anti-Amyloid Therapy)

Lecanemab is a humanized IgG1 monoclonal antibody that selectively binds to amyloid-beta (Aβ) protofibrils, the soluble oligomeric forms of Aβ believed to be more neurotoxic than plaques[@lecanemab_clarity]. By targeting protofibrils, Lecanemab reduces amyloid plaque burden in the brain, which is hypothesized to slow disease progression.

Xanomeline (Muscarinic Agonist)

Xanomeline is a selective M1 and M4 muscarinic acetylcholine receptor agonist. Cholinergic signaling through these receptors is critical for learning, memory, and attention[@muscarinic_adrenergic]. In Alzheimer's disease, cholinergic neurons are lost, leading to cognitive deficits. M1 agonists like xanomeline can:

• Enhance postsynaptic cholinergic signaling
• Improve cognitive function through hippocampal and cortical circuits
• Potentially reduce amyloid processing via M1 receptor activation

Why Combination Therapy?

The rationale for combining Lecanemab with Xanomeline includes:

Eligibility Criteria

Inclusion Requirements

• Age 60–85 years
• Confirmed Alzheimer's disease diagnosis meeting NIA-AA criteria
• Currently receiving Lecanemab treatment (completed ≥14 infusions)
• Mini-Mental State Examination (MMSE) score of 16–24 (mild to moderate dementia)
• Body Mass Index (BMI) 18–35 kg/m²
• Has a reliable caregiver/study partner with ≥10 hours/week contact
• Stable dose of permitted AD medications (if applicable) for ≥12 weeks

Exclusion Criteria

• History of suicidal behavior or active psychiatric disorders
• Significant cardiovascular, pulmonary, renal, or hepatic disease
• History of stroke within 12 months
• Cerebral amyloid angiopathy (CAA)
• Epilepsy or history of seizures
• Central nervous system neoplasm
• Pregnancy or breastfeeding
• Prior exposure to Xanomeline/Trospium (X/T)
• Apolipoprotein E (ApoE) e4 homozygotes (increased risk of ARIA)

Outcomes

Primary Outcome

Safety and Tolerability (through Week 28):

• Incidence of adverse events (AEs)
• Incidence of serious adverse events (SAEs)
• Discontinuation rates due to AEs
• Amyloid-related imaging abnormalities (ARIA) on MRI

Secondary Outcome

Efficacy:

• Quality of Life in Alzheimer's Disease (QoL-AD) score change from Baseline to Week 24

Investigational Products

| Product | Description | Dose |
|---------|-------------|------|
| Xanomeline | Selective M1/M4 muscarinic receptor agonist | Oral capsules, dose escalation protocol |
| Trospium Chloride | Peripheral muscarinic antagonist (reduces peripheral side effects) | Oral capsules |
| Lecanemab | Anti-Aβ protofibril antibody | 10 mg/kg IV every 2 weeks |

Site Information

Principal Investigator: Brian Costell, MD Institution: Neurology Office of South Florida Contact:

• Phone: 561-487-1027
• Email: CostellResearch@fcneurology.net

Clinical Significance

This trial represents an important step in Alzheimer's disease therapeutic development:

If successful, this combination approach could establish a new paradigm for AD treatment, demonstrating that combining disease-modifying and symptomatic therapies can provide enhanced benefits.

Related Pages

• [Lecanemab](/entities/lecanemab)
• [Lecanemab Clarity AD](/clinical-trials/lecanemab-clarity-ad)
• [Combination Therapy for Neurodegeneration](/therapeutics/combination-therapy-neurodegeneration)
• [Muscarinic Receptor Signaling in AD](/mechanisms/gpcr-signaling)
• [Alzheimer's Disease Clinical Trials](/clinical-trials/alzheimers-disease)

Pathway Diagram

The following diagram shows the key molecular relationships involving X/T + X-EC + Lecanemab Phase 2 (NCT07212062) — Alzheimer's Disease discovered through SciDEX knowledge graph analysis: