Senicapoc in Alzheimer's Disease

Official title

Proof of Mechanism Study of Senicapoc in Mild or Prodromal Alzheimer's Disease

Overview

Development of novel disease-modifying therapies for Alzheimer's disease (AD) remains of paramount importance. This study will be a Phase II randomized clinical trial testing Senicapoc in patients with mild or prodromal AD. This will be a small Proof of Mechanism study to prove biological activity and target engagement in humans with early AD. The investigators will study up to 55 patients over 52 weeks, with primary outcomes being Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) scores and blood and cerebrospinal fluid (CSF) markers of neuroinflammation. This pilot study will provide an estimate of treatment effect size on cognitive trajectory, daily function, and brain atrophy.

Detailed description

The investigators will study up to 55 patients (8:3 active treatment with 10 mg/day maintenance dose: placebo) over 52 weeks in either the Sacramento or East Bay locations the University of California Davis Alzheimer's Disease Research Center (ADRC), with cognitive outcomes, blood, and CSF markers of neuroinflammation. This pilot study will provide an estimate of treatment effect size on cognitive trajectory, daily function, and brain atrophy. The trial will last 1 year (52 weeks on 10 mg/day of active drug or placebo) with primary efficacy measures at baseline, week 26, and week 52. Additional safety monitoring visits will occur at weeks 4, 12, and 36 including physical exams, measurement of blood pressure, vital signs, safety labs, electrocardiogram recordings, collection of Adverse Events and Concomitant Medications. The study will culminate with a visit at 78 weeks (26 weeks after last dose, allowing full wash-out from the central nervous system (CNS)) to test if the previously treated and untreated groups show any differences, as would be expected if Senicapoc treatment for 1 year was disease-modifying. All participants will be required to participate in either the CSF Sub-study or the Amyloid Positron Emission Tomography (PET) Sub-study. All participants will be required to participate in the Cognitive Event Related Potential (ERP) Sub-study.

Interventions

• Drug Senicapoc
  10 mg oral tablet
• Other Placebo Tablet
  Placebo Oral Tablet

Primary outcome measures

• Change from Baseline in the Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog 13) score [Time frame: Baseline, Week 26, Week 52]
• Change from Baseline to Week 52 in levels of Cerebrospinal fluid (CSF) biomarkers: IL-1β, IL-6, TNF-α, MCP-1, and IL-10 [Time frame: Baseline, Week 52]
• Change from Baseline to Week 52 in levels of serum biomarkers: IL-6, TNF-α, MCP-1, and IL-10 and high sensitivity C-Reactive protein [Time frame: Baseline, Week 52]

Secondary outcome measures (12)

• Change from Screening in the Clinical Dementia Rating (CDR) sum of boxes score [Time frame: Screening, Week 26, Week 52]
• Change from Baseline in the Everyday Cognition (ECog) score [Time frame: Baseline, Week 26, Week 52]
• Change from Screening in Montreal Cognitive Assessment (MoCA) score [Time frame: Screening, Week 26, Week 52]
• Change from Baseline to Week 52 in Spanish English Neuropsychological Assessment Scales (SENAS) memory score [Time frame: Baseline, Week 52]
• Change from Baseline to Week 52 in Spanish English Neuropsychological Assessment Scales (SENAS) executive composite score [Time frame: Baseline, Week 52]
• Change from Baseline in Bushcke Cued Selective Reminding Task (CSRT) score [Time frame: Baseline, Week 26, Week 52]
• Change from Baseline in Trails B score [Time frame: Baseline, Week 26, Week 52]
• Change from Baseline in Verbal fluency (semantic) score [Time frame: Baseline, Week 26, Week 52]
• Change from Baseline in Verbal fluency (letter) score [Time frame: Baseline, Week 26, Week 52]
• Change from Baseline to Week 52 in Brain MRI measures of total grey matter. [Time frame: Baseline, Week 52]
• Change from Baseline to Week 52 in Brain MRI measures of total brain volume. [Time frame: Baseline, Week 52]
• Change from Baseline to Week 52 in Brain MRI measures of white matter hyperintensities. [Time frame: Baseline, Week 52]

Eligibility criteria

Inclusion criteria

• Age 55-85
• Fluent in either English or Spanish
• Willing to be randomized to active drug (10 mg Senicapoc) vs. placebo (3:1 ratio)
• Clinical Dementia Rating (CDR) global score of 1 or 0.5
• Education adjusted scores between 12-28 on the Montreal Cognitive Assessment (MoCA) at the Screening visit.
• A consensus clinical diagnosis of either amnestic Mild Cognitive Impairment (MCI) or mild AD dementia. Diagnoses are made by a comprehensive case conference review for all participants in the ADRC longitudinal cohort and all CADC referrals, resulting in a consensus diagnosis made according to current research criteria. For patients referred from other clinics, the case will be reviewed by a study physician and neuropsychologist and only patients who satisfy criteria for probable AD (McKhann et al 1984) or amnestic MCI (Petersen et al 2004) will be eligible for enrollment.
• Vision (with or without correction) of at least 20/50 for distant vision
• All participants will need a study partner informant who has at least 6 hours of contact per week with the participant. The study partners are used to help answer questions on the subject's behalf, since many of them will be impaired and may need assistance with providing accurate information. The study partners are not asked to provide any opinions or judgements about the subjects.
• For Females of childbearing potential: Must agree to practice a highly effective method of contraception throughout the study until completion of the Week 78 follow up visit. Highly effective methods of contraception are those that alone or in combination result in a failure rate of less than 1% per year when used correctly and consistently.

Exclusion criteria

• Unstable medical illnesses including hepatic insufficiency (elevated ALT, AST, or GGT; or low albumin attributable to liver disease), renal insufficiency (CK-EPI stage 4 or higher, or estimated GFR <30)
• Unstable ischemic cardiovascular disease, respiratory failure, moderate or severe congestive heart failure - New York Heart Association class III or IV, cancer, unstable hematologic disease or a life expectancy of <3 years
• Use of experimental AD treatments
• Unable to undergo MRI scanning (e.g. pacemaker, metallic implants, severe claustrophobia)
• History of chronic psychiatric illness (e.g. schizophrenia), any episode of major depression within last 2 years, or current Geriatric Depression Scale (GDS) > 6, any recent suicide attempts or suicidal ideation. Subjects with a diagnosis of bipolar disorder may be included if they have been clinically stable for a minimum of 3 years prior to the Screening visit. Clinical stability to be determined by the Principal Investigator.
• History of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis), head trauma resulting in any persistent cognitive deficit
• History of alcohol or drug abuse/dependence within the past 5 years
• Known allergy to chemically related compounds (e.g. clotrimazole)
• Lack of good venous access, such that multiple blood draws would be precluded
• Regular use of any of these CNS active medications: benzodiazepines, antipsychotics, narcotics, or anti-epileptic drugs. Exceptions may be allowed by the Principal Investigator for regular use of low doses of CNS active medications. Subjects using any of these treatments will be instructed to hold their dose on the evening prior and the day of the efficacy visits (Baseline, Week 26 and Week 52). Stable doses (> 6 weeks) of cholinesterase inhibitors or memantine will be allowed, as will stable doses of anti-depressants.
• Female subjects who are pregnant or breastfeeding or who plan to become pregnant during participation in this trial
• Inability to swallow oral tablets

Exclusions for Cerebrospinal Fluid (CSF) Sub-study:

• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
• History of bleeding diathesis or coagulopathy,
• On anticoagulant therapy (within 14 days of lumbar puncture (LP), including but not limited to warfarin, heparin, dabigatran, rivaroxaban, and apixaban,
• Requires daily antiplatelet therapy, including but not limited to aspirin (unless < 81mg/day), clopidogrel, dipyridamole, and ticlopiidinegrel. However, the investigators will not exclude those who can safely hold antiplatelet therapy for 7 days prior to LP. Safety will be determined by the participant's Primary Care Provider and study PI.
• For those who take antiplatelet therapy intermittently (e.g. aspirin as needed for pain), the investigators will exclude any doses within 48 hours of the LP or more than two dosses within 7 days of LP.
• platelet count less than the lower limit of normal (platelet counts between 100,000 and 150,000 mm3 are permissible as long as the investigator confirms there is no evidence of current bleeding diathesis or coagulopathy)
• The investigators will require INR/PT and aPTT labs to be done within 14 days of LP and will exclude those with INR > 1.30 or abnormally elevated aPTT.

Exclusions for PET Sub-Study:

• Does not have good venous access, such that multiple blood draws would be precluded
• Prior radiation exposure of > 2 rem total within last 12 months.
• Probable AD dementia patients with a global cortical SUVr < 1.08.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Other

Study locations

United States · 2 centers

• University of California, Davis Alzheimer's Disease Center — Sacramento
• UC Davis Alzheimer's Disease Center East Bay — Walnut Creek

Identifiers

NCT: NCT04804241 · 945869

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗