| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 |
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| E.1.1.1 | Medical condition in easily understood language |
| Early stage Alzheimer’s disease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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 – Aβ-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, Aβ-40, Aβ-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 |
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| E.2.2 | Secondary objectives of the trial |
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]. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK Profile Substudy:
A total of 24 subjects (12 APOE4/4 homozygotes and 12 APOE4 heterozygotes) will be consented to participate in a substudy. These subjects will come to the site at Visit 9 (Week 65), and pre-dose and 8 post-dose plasma samples will be obtained for PK profile analyses.
Twenty-four (24) subjects who agree to be part of the PK Profile Substudy will be consented using a separate ICF. The PK substudy will enroll 24 subjects who will undergo extended PK sampling over 8 hours at the Week 65 visit.
Plasma PK samples will be used to evaluate the PK of ALZ-801 and its metabolites in all study subjects, as well as to evaluate the 8-hour PK profile in 24 subjects in the PK substudy. |
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| E.3 | Principal 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. Aβ-42/Aβ-40 ratio < 0.61 AND
ii. p-tau > 61 ng/L OR
iii. if p-tau181 concentration=50 to 61ng/L, ratio of p-tau/Aβ-42 > 0.11 OR
c) CSF AD biomarker result on file within 12 months prior to Screening that is positive for Aβ-42 (below the cut-off) AND p-tau (above the cut-off) OR a p-tau181/Aβ-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 subject is of child-bearing potential, must have a negative urine pregnancy test prior to dosing at baseline, use a highly effective method of contraception for duration of the study and for 8 weeks after the last dose of study medication
Note: Highly effective methods include surgical sterilization, IUD, IUS, hormonal contraception associated with inhibition of ovulation. Total abstinence is also acceptable if it is the preferred and usual lifestyle of a subject
17. Has a Screening brain MRI that is not inconsistent with the diagnosis of AD and determined to be of adequate quality
Note: This MRI will provide baseline data for MRI biomarker and safety assessments
18. If treated with an AChEI, subject must be on stable treatment for at least 12 weeks prior to Scr–Part 2 V and must be able to continue on the same dose/regimen for the duration of the study
Note: Memantine is not allowed and must not be taken within 12 weeks of Scr–Part 2 V
19. With the exception of a diagnosis of AD and the presence of stable medical conditions is, in the opinion of the Investigator, in good general medical health based upon the results of medical history, physical examination, laboratory tests, vital signs and ECG
20. If treated with antidepressants, mood stabilizers or other psychotropic medications, is on a stable dose accord. to Tab2
21. If taking permitted, non-psychotropic medications for the treatment of non-excluded medical conditions, is on a stable dose accord. to Tab2 |
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| E.4 | Principal 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 < 11 g/dL in male subjects, or < 10 g/dL in female subjects, or 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 < 40 ml/min per 1.73 m2 accord. to Modification of Diet in Renal Disease formula
17.Has a glycosylated hemoglobin (HbA1c) > 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 permitted dose accord. to Tab2
19.Has a lifetime history of schizophrenia, schizoaffective disorder or bipolar disorder
20.Has any significant medical condition (e.g. uncontrolled cardiovascular, GI, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, renal or other major disease or malignancy) that is unstable and that would either (a) place the subject at undue risk from administration of study drug or from undergoing study procedures or (b) interfere with interpretation of safety or efficacy evaluations obtained in course of study
21.Has participated in a clinical study of any potential disease-modifying AD treatment, and received active drug within 6 months prior to Scr–Part 2V
22.Has participated in a clinical study and received active treatment with an anti-amyloid or anti-tau vaccine
23.Has received any of treatments listed in Tab2 more recently than the indicated period before Scr–Part 2V
24.Anticipates receiving any of treatment listed in Tab2, during current clinical study (unless meeting criteria for exceptions)
25.Is unable to swallow ALZ-801 tablets or has a known intolerance or hypersensitivity to tramiprosate or any of excipients contained in ALZ 801 tablets
26.Has a history of or currently has, any clinically significant ECG finding or a QT interval corrected by Fridericia’s method (QTcF) of > 450 msec for males and > 470 msec for females
27.Has positive serology for HIV or for hepatitis B or C virus |
|
| E.5 End points |
| E.5.1 | 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 assessments for Amyloid-Related Imaging Abnormalities with edema (ARIA E) or microhemorrhages (ARIA-H).
• Continuous safety data will be analyzed descriptively with summary statistics, and categorical safety data will be summarized using counts and percentages. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| • Change from baseline to Week 52 for CSF biomarkers |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Outcomes
• Change from baseline to Week 104 in CSF biomarkers of core AD pathologies, neurodegeneration, and neuroinflammation: Aβ-40, Aβ-42, p-tau217, NfL, t-tau; neurogranin, sTREM2, YKL-40
• Change from baseline to Week 104 in plasma biomarkers: p-tau181, p-tau217, NfL, Aβ 40, Aβ 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. |
|
| E.5.2.1 | 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 Aβ oligomer assays may be performed using state of the art methods, if available |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 35 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 35 |
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