Senicapoc Alzheimer's Disease Trial - NCT04804241

Trial Overview

Senicapoc is a novel intermediate-conductance calcium-activated potassium channel (IKCa3, also known as KCNN4) blocker being evaluated as a potential disease-modifying therapy for Alzheimer's disease. This Phase 2 proof-of-mechanism study is being conducted by the University of California Davis Alzheimer's Disease Research Center to evaluate biological activity and target engagement in patients with mild or prodromal AD.

Trial Details

Trial Overview

Senicapoc is a novel intermediate-conductance calcium-activated potassium channel (IKCa3, also known as KCNN4) blocker being evaluated as a potential disease-modifying therapy for Alzheimer's disease. This Phase 2 proof-of-mechanism study is being conducted by the University of California Davis Alzheimer's Disease Research Center to evaluate biological activity and target engagement in patients with mild or prodromal AD.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT04804241 |
| Phase | Phase 2 |
| Sponsor | University of California, Davis |
| Collaborators | Alzheimer's Drug Discovery Foundation, Alzheimer's Association, Biossil Inc. |
| Status | Recruiting |
| Participants | 55 (estimated) |
| Study Start Date | March 18, 2022 |
| Estimated Completion | June 2026 |
| Duration | 52 weeks treatment + 26-week follow-up |
| Age Range | 55-85 years |
| Diagnosis | Mild or Prodromal Alzheimer's Disease, Amnestic MCI |

Mechanism of Action

IKCa3 (KCNN4) Channel Biology

Senicapoc (also known as TRAM-34) is a potent and selective inhibitor of the intermediate-conductance calcium-activated potassium channel IKCa3 (KCNN4). This channel plays important roles in:

• Microglial activation: IKCa3 is expressed in microglia and contributes to pro-inflammatory signaling. Blocking this channel reduces microglial activation and neuroinflammation
• Neuroinflammation: The channel is involved in the inflammatory response in the CNS. Inhibition may reduce cytokine production and neuroinflammatory cascades implicated in AD pathogenesis
• T-cell function: IKCa3 is important for T-cell activation and proliferation. Modulation may affect immune responses relevant to AD

Why Alzheimer's Disease?

Neuroinflammation is increasingly recognized as a central component of Alzheimer's disease pathogenesis. Microglial activation and elevated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) are found in AD brains and correlate with disease severity. By inhibiting IKCa3, Senicapoc may:

• Reduce microglial activation and inflammatory cytokine production
• Modulate neuroinflammation-driven neurodegeneration
• Provide disease-modifying effects beyond symptomatic relief

Study Design

The trial employs a randomized, double-blind, placebo-controlled, parallel-group design:

• Allocation: Randomized 3:1 (active:placebo) — 8:3 ratio
• Masking: Quadruple-blind (participants, care providers, investigators, outcomes assessors)
• Duration: 52 weeks of treatment, with follow-up at week 78 (26 weeks post-treatment)
• Intervention: 10 mg daily oral Senicapoc vs. placebo

Treatment Regimen

Participants receive either:

• Active: 10 mg daily Senicapoc oral tablet for 52 weeks
• Placebo: Matching placebo tablet for 52 weeks

Eligibility Criteria

Inclusion Criteria

• Age 55-85 years
• Fluent in English or Spanish
• Clinical Dementia Rating (CDR) global score of 0.5 or 1.0
• MoCA score 12-28 (adjusted for education)
• Consensus diagnosis of amnestic MCI or mild AD dementia
• Has a study partner with ≥6 hours/week contact
• For females: willing to use highly effective contraception through week 78

Key Exclusion Criteria

• Unstable medical illnesses (hepatic insufficiency, renal insufficiency stage 4+, NYHA class III/IV heart failure)
• Use of experimental AD treatments
• Unable to undergo MRI
• History of schizophrenia or major depression within 2 years
• History of alcohol/drug abuse within past 5 years
• Regular use of benzodiazepines, antipsychotics, narcotics, or anti-epileptic drugs

Outcomes

Primary Outcomes

Secondary Outcomes

• Change in CDR sum of boxes score
• Change in Everyday Cognition (ECog) score
• Change in MoCA score
• Change in SENAS memory and executive composite scores
• Change in Buschke Cued Selective Reminding Task (CSRT) score
• Change in Trails B score
• Change in verbal fluency (semantic and letter)
• Brain MRI measures: total grey matter, total brain volume, white matter hyperintensities
• Amyloid PET (florbetaben) binding changes
• Cognitive ERP measures: P600 word repetition, alpha suppression, theta-alpha/beta coupling

Sub-Studies

All participants are required to participate in:

• Exclusions: implanted CNS devices, bleeding diathesis, anticoagulant therapy

Trial Sites

| Location | Status |
|----------|--------|
| UC Davis Alzheimer's Disease Center, Sacramento, CA | Recruiting |
| UC Davis Alzheimer's Disease Center East Bay, Walnut Creek, CA | Recruiting |

Contacts

• Principal Investigator: John Olichney, MD (UC Davis)
• Contact: Rita Venua — (916) 734-1708 — rmvenua@ucdavis.edu
• Contact: Selene Leal Carrillo — (925) 357-6914 — slealcarrillo@ucdavis.edu
• Site Contact: Martha Forloines, PhD — 916-734-5223 — mrforloines@ucdavis.edu

Clinical Significance

This proof-of-mechanism study is significant for several reasons:

References

Related Pages

• [Alzheimer's Disease Clinical Trials](/clinical-trials/alzheimers-disease-trials)
• [Phase 2 Clinical Trials](/clinical-trials/phase-2-trials)
• [Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation-alzheimers)
• [Microglia and Alzheimer's Disease](/cell-types/microglia)
• [Potassium Channels in Neurobiology](/mechanisms/ion-channels-neurology)