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.
| 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 |
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
The therapeutic hypothesis is that IKCa3 blockade will reduce neuroinflammation, a key driver of Alzheimer's disease progression, potentially slowing cognitive decline.
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
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
Participants receive either:
- Active: 10 mg daily Senicapoc oral tablet for 52 weeks
- Placebo: Matching placebo tablet for 52 weeks
- 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
- 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
- Change in ADAS-Cog 13 score from baseline to weeks 26 and 52
- CSF biomarker changes: IL-1β, IL-6, TNF-α, MCP-1, IL-10 at baseline and week 52
- Serum biomarker changes: IL-6, TNF-α, MCP-1, IL-10, hs-CRP at baseline and week 52
- 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
All participants are required to participate in:
- CSF Sub-study: Lumbar puncture for biomarker analysis
- Exclusions: implanted CNS devices, bleeding diathesis, anticoagulant therapy
- Amyloid PET Sub-study: Florbetaben PET imaging
- ERP Sub-study: Cognitive event-related potential measurements
| Location |
Status |
| UC Davis Alzheimer's Disease Center, Sacramento, CA |
Recruiting |
| UC Davis Alzheimer's Disease Center East Bay, Walnut Creek, CA |
Recruiting |
This proof-of-mechanism study is significant for several reasons:
- Novel mechanism: IKCa3 blockade represents a different approach from amyloid-targeting therapies
- Target engagement: The study includes CSF and serum biomarker measurements to verify biological activity
- Disease modification potential: The 78-week total duration (including 26-week post-treatment follow-up) allows assessment of whether effects persist after treatment cessation
- Early-stage focus: By targeting mild/prodromal AD, the study addresses a stage where disease-modifying interventions may have the greatest impact
- NCT04804241 - Senicapoc in Alzheimer's Disease
- UC Davis Alzheimer's Disease Research Center
- Study Information - UC Davis