Subjects with a clinical diagnosis of Alzheimer's disease who are APOE 4 carriers (APOE4/4, APOE3/4) and at the Early stage of disease, ages 50-80 years
Conditions
Interventions
Product Name: ALZ-801 tablet 265 mg
Product Code: ALZ-801
Pharmaceutical Form: Coated tablet
INN or Proposed INN: no INN proposed
CAS Number: 1034190-08-3
Current Sponsor code: ALZ-801
Other descripti
Sponsors
Alzheon Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Be between ages of 50 and 80 years, inclusive 2. Has a body weight = 50 kg 3. Has a diagnosis of Probable AD Dementia or MCI due to AD in accordance with NIA AA Working Group Criteria 4. Has a biomarker profile reflecting AD, accord. to the NIA-AA Research Framework defined as follows a) Positive amyloid PET scan on file prior to Screening OR b) CSF AD biomarker result using Lumipulse (Fujirebio) assay at Screening with: i. Aß-42/Aß-40 ratio 61 ng/L OR iii. if p-tau181 concentration=50 to 61ng/L, ratio of p-tau/Aß-42 > 0.11 OR c) CSF AD biomarker result on file within 12 months prior to Screening that is positive for Aß-42 (below the cut-off) AND p-tau (above the cut-off) OR a p-tau181/Aß-42 ratio above the cut-off for that assay (amyloid AND p-tau positive) Note1: Subjects without a prior CSF result must provide a new CSF sample at the Scr–Part 2 V Note2: Subjects with a prior positive CSF result (allowing study enrollment) must provide 2 to 3 aliquots of CSF from their prior diagnostic assessment; and the prior CSF result must be recorded 5. Be willing to undergo LP for CSF testing accord. to Schedule of Assessments 6. Has one of the following apolipoprotein E (APOE) genotypes– either APOE4/4 or APOE3/4 Note: For subjects with a prior (historical) APOE genotype blood test, the test result must be provided and recorded in CRF 7. Has an MMSE score at Screening of 22 to 30 inclusive (> 26 for MCI; 22 to 26 for Mild AD) 8. Has a CDR Global Score at Screening of 0.5 (MCI, Mild AD) or 1 (Mild AD) and a CDR Memory Box Score of = 0.5 9. Has a reliable caregiver or study partner who is willing and able to sign an ICF, to accompany the subject to study visits, and adhere to study requirements 10. Be willing to sign an IRB/ IEC approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for study, and that he/she is willing to participate in study. Subjects are free to withdraw consent at any time. If a subject is unable or deemed not competent to sign the consent form the subject’s legally authorized representative may sign consent form with subject’s assent, except where local regulations and IRB/IEC approval does not allow subjects who are unable or deemed not competent to sign consent form, to participate in study Note: Subjects who participate in PK Profile Substudy for extended PK sampling will sign an additional consent form specific for the substudy 11. Can complete the cognitive testing procedures Corrected visual and auditory acuity must be adequate to comply with protocol 12. Lives at home independently, in a senior living facility, or in an assisted living facility 13. Both subject and caregiver/study partner are fluent in, and able, to read the local language in which study assessments are administered at study site 14. Subject and caregiver/study partner agree to be compliant with study procedures and appear to have a high probability of completing the study 15. Caregiver/study partner agrees not to administer any prohibited concomitant medications during the study 16. If female, must have a negative serum pregnancy test and EITHER be of non-childbearing potential, described as • Post-menopausal prior to Scr–Part 2 V, or • Documented surgically sterile (has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy with or without hysterectomy and greater than 6 weeks have passed since the surgery) OR • If sub
Exclusion criteria
Exclusion criteria: 1.Has a brain MRI at screening indicative of significant abnormality, incl. but not limited to, prior hemorrhage (> 1 cm) or large infarct (> 1 cm), > 2 lacunar infarcts outside the brain stem, severe white matter changes (Fazekas grade 3), superficial hemosiderosis > 1 cm, aneurysm, vascular malformation, subdural hematoma, space-occupying lesion (e.g., abscess or brain tumor such as meningioma), or ventricular enlargement consistent with normal pressure hydrocephalus Note: Ventricular enlargement consistent with AD atrophy(hydrocephalus ex-vacuo) is not exclusionary Note: Subjects who have > 10 microbleeds, require approval by Sponsor Med. Monitor 2.Has a diagnosis of neurodegenerative disorder other than AD 3.Has a current diagnosis of MDD accord. to criteria of Diagnostic and Statistical Manual of Mental Disorders-5th Ed. Subjects who do not meet current criteria for MDD and who are on stable doses of antidepressants or mood stabilizers may be included in the study at discretion of Investigator 4.Has a history of suicidal behavior or has ongoing suicidal ideation 5.Has a history of seizures (excl. febrile seizures of childhood, or a single distant seizure > 10 years). Subjects with a history of one seizure, but without evidence of vascular or mixed dementia, or brain tumor on MRI, may be allowed into study at discretion of Med. Monitor 6.Has a medically confirmed history of recent cerebral infarct or recent transient ischemic attack (within 1 year prior to Scr–Part 2V) 7.Has a medically confirmed history of recent myocardial infarction or unstable, untreated coronary artery disease, or angina pectoris (within 1 year prior to Scr–Part 2V) 8.Has a history of cancer, diagnosed and treated within last 3 years prior to Scr–Part 2V, with exception of following: (a) treated basal cell carcinoma of the skin; (b) treated in situ or Stage 1 cancers of skin (squamous cell only), colon, prostate, breast, or colon 9.Has a hemoglobin level 16 g/dL 10. Has a prothrombin time as measured by INR = 1.5 and a platelet count = 50 x 10 9/L 11. Has donated blood within 8 weeks prior to Scr–Part 2V 12. Has clinically relevant abnormalities in serum TSH or calcium. If subject is taking replacement therapy, corresponding Screening test values must be clinically acceptable 13. Has serum vitamin B12 below lower limit of normal 14. Has any clinical chemistry laboratory value greater than or equal to CTCAE; v4.0; Gr2, unless considered not clinically relevant by Investigator and Med. Monitor 15. The subject at Screening has one or more of following a. Alanine aminotransferase (ALT) = 3 x upper limit of normal (ULN), OR b. Aspartate aminotransferase (AST) = 3 x ULN, OR c. Total bilirubin = 1.5 x ULN 16.Has an estimated glomerular filtration rate 8% (NGSP) or 64 mmol/mol (IFCC) at Scr–Part 1V 18.Has a history of alcohol or drug dependence or abuse within 2 years of Scr–Part 2V or tests positive for drugs of abuse at Scr–Part 2V Note: If positive for opiates, the subject must be taking prescription medicines for pain and be on a stable dose of medication for more than 4 weeks prior to Scr–Part 2V Note: If positive for benzodiazepines, the subject must be taking prescription medicines containing benzodiazepines and be on a permitte
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Objectives • To evaluate the effects of oral ALZ-801 in subjects with Early AD who have the APOE4/4 or APOE3/4 genotype, on the following biomarkers of core AD pathology and disease progression, neurodegeneration and neuroinflammation o CSF markers of core AD pathology: p-tau181 and other core AD biomarkers, beta amyloid – Aß-42/40; p-tau217; o CSF markers of neurodegeneration – NfL and t-tau (neuronal injury markers); neurogranin (synaptic toxicity marker) o CSF markers of neuroinflammation –microglia - sTREM2 (microglial marker); and YKL-40 (astrocytic marker) neuroinflammation o Plasma AD markers: p-tau181, p-tau217, Aß-40, Aß-42, NfL, and GFAP • To evaluate the safety and tolerability of chronic treatment with ALZ-801 in subjects with Early AD who are APOE4 carriers ;Secondary Objective: Secondary Objectives • To evaluate the efficacy of ALZ-801 on tests of cognition and function: o Rey Auditory Verbal Learning Test (RAVLT) o Digit Symbol Substitution Test (DSST) o Amsterdam Instrumental Activities of Daily Living (A-IADL) o MMSE o CDR-SB • To evaluate the effect of ALZ-801 on hippocampal volume, cortical thickness and other imaging parameters as measured by MRI • To evaluate the PK of ALZ-801 and its metabolites in AD subjects • To evaluate the extended PK profile over 8 hours in 24 subjects (12 APOE4/4 homozygotes and 12 APOE3/4 heterozygotes) after 65 weeks of treatment [PK Profile Substudy].;Primary end point(s): Primary Outcome • Change from baseline to Week 104 in CSF biomarker of core AD pathology: p-tau181 Safety and Tolerability • Incidence and nature of treatment-emergent adverse events (TEAE), serious TEAE, and TEAE leading to withdrawal. Continuous safety data will be analyzed descriptively with summary statistics; and categorical safety data will be summarized using counts and percentages. • Changes in laboratory parameters, vital signs, and physical exam. • Changes in 12-lead electrocardiogram (ECG) parameters. • MRI as | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Key Secondary Outcomes • Change from baseline to Week 104 in CSF biomarkers of core AD pathologies, neurodegeneration, and neuroinflammation: Aß-40, Aß-42, p-tau217, NfL, t-tau; neurogranin, sTREM2, YKL-40 • Change from baseline to Week 104 in plasma biomarkers: p-tau181, p-tau217, NfL, Aß 40, Aß 42, and GFAP Pharmacokinetics and Pharmacodynamic Correlations • Plasma and CSF levels of ALZ-801, tramiprosate and its metabolite before and after first dose, at steady state, and at later time points in the study. PK non-compartmental analysis will be performed using Phoenix WinNonlin (version 7.0 or later). • Correlation of PK levels to biomarker outcomes. • Correlation of PK levels to efficacy and safety parameters. • Extended PK profile over 8 hours at Week 65 will be evaluated in approximately 24 subjects (approximately 12 APOE4/4 homozygotes and 12 APOE3/4 heterozygotes) who have consented to participate in the PK Profile Substudy.;Timepoint(s) of evaluation of this end point: Additional Biomarker and Exploratory Clinical Efficacy • Change from baseline to Week 52 for CSF biomarkers • Change from baseline to Weeks 6, 13, 26, 52, and 78 for plasma biomarkers • Change from baseline to Weeks 52 and 104 in hippocampal volume, cortical thickness, and other vMRI parameters • Change from baseline to Week 104 in the following scales: o RAVLT o DSST o A-IADL o MMSE o CDR-SB • Change from baseline to Weeks 13, 26, 52, and 78 for RAVLT and DSST • Change from baseline to Weeks 26, 52, and 78 for MMSE • Change from baseline to Week 52 for A-IADL, CDR-SB • Potential additional exploratory analyses of plasma and CSF biomarkers, including CSF Aß oligomer assays may be performed using state of the art methods, if available | — |
Countries
Czech Republic, Netherlands
Contacts
Public ContactAlzheon CT Information Desk
Alzheon, Inc.
Outcome results
None listed