| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Early stage Alzheimer’s disease |
|
| 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 |
Prim. Obj.
To evaluate the effects of oral ALZ-801 in subjects with Early AD who have the APOE4/4 or APOE3/4 genotype, on the plasma biomarkers of core AD pathology and brain volumes
Primary Plasma Biomarkers Outcome: p-tau181
Key Imaging Outcome: hippocampal volume on vMRI
Saf. Obj.
To evaluate the safety and tolerability of chronic treatment with ALZ-801 in subjects with Early AD who are APOE4 carriers
Expl. Fluid Biomarker Obj.
To evaluate the effects of oral ALZ-801 on other plasma and CSF biomarkers:
Plasma biomarker of astrocytic activation: GFAP
Plasma biomarker of neurodegeneration: NfL
CSF biomarkers of core AD pathology: p-tau181, p-tau217, Aβ40 and Aβ42
CSF biomarker of synaptic toxicity: neurogranin
CSF biomarkers of neurodegeneration: total tau (t-tau) and NfL
CSF neuroinflammation markers: TREM2 (microglia) and YKL-40 (astrocytes)
Clin. Obj.
To evaluate the efficacy of ALZ-801 on tests of cognition and function: RAVLT, DSST, A-IADL, MMSE and CDR-SB |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Obj
•To evaluate the effects of oral ALZ-801 on other plasma biomarkers of core AD pathology and brain volumes
Secondary Plasma Biomarker Out.: Aβ40, Aβ42, and p-tau217
Secondary Imaging Biomarker Out.: cortical thickness and ventricular volume
Pharmacokinetic Obj
•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 after 65 weeks of treatment
Add. Exploratory Obj
•To evaluate the effect of ALZ-801 on other AD biomarkers as assays become available (Aβ oligomers, other p-tau isoforms, or other emerging AD biomarkers)
•To evaluate the effect of ALZ-801 on other MRI imaging measures
LTE
Objectives of LTE periods of the study are to evaluate long-term safety and efficacy of ALZ-801 over a total of 156 and 208 weeks or 3 and 4 years of treatment. This includes evaluation of safety parameters, fluid biomarkers, vMRI and clinical outcomes over an additional 104 weeks of treatment in LTE periods |
|
| 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 APOE3/4 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.
LTE
PK Profile Substudy: Approximately 12 subjects (6 APOE4/4 homozygotes and 6 APOE4 heterozygotes) will be consented to participate in a PK substudy in the LTE Year 1 at Week 156 (Visit 5E), and plasma samples will be obtained for PK analysis at a pre-dose timepoint and after 30 min, and 1, 2, 4 and 6 hours post-dose.
For LTE Year 2, an optional PK Profile Substudy will occur at Visit 5E (Week 156). |
|
| 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 acc. with NIA-AA WGC
4. Has a biomarker profile reflecting AD, acc. to the NIA-AA Research Framework defined as follows
a) Positive amyloid PET scan on file prior to Scr OR
b) CSF AD biomarker result using Lumipulse assay at Scr with:
i. Aβ42/Aβ40 ratio < 0.61 AND
ii. p-tau > 61 ng/L OR
iii. if p-tau181 concentration=50 to 61 ng/L, ratio of p-tau/Aβ42 > 0.11 OR
c) CSF AD biomarker result on file within 12 months prior to Screening that is positive for Aβ42 (below the cut-off) AND p-tau (above the cut-off) OR a p-tau181/Aβ42 ratio above the cut-off for that assay (amyloid AND p-tau positive)
5. Be willing to undergo LP for CSF testing acc. to Schedule of Assess.
6. Has one of the following apolipoprotein E (APOE) genotypes– either APOE4/4 or APOE3/4
7. Has an MMSE score at Screening of 22 to 30 inclusive
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 study and 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 do not allow subjects who are unable or deemed not competent to sign consent form, to participate in study
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 either
• Post-menopausal prior to Scr–P2V 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
17. Has a Screening brain MRI that is not inconsistent with the diagnosis of AD and determined to be of adequate quality
18. If treated with an AChEI, subject must be on stable treatment for at least 12 weeks prior to Scr–P2V and must be able to continue on the same dose/regimen for the duration of study
Note: Memantine is not allowed and must not be taken within 12 weeks of Scr–P2V
19. With the exception of a diagnosis of AD and the presence of stable medical conditions is, in the opinion of 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 acc. to Tab2
21. If taking permitted, non-psychotropic medications for treatment of non-excluded medical conditions, is on a stable dose acc. to Tab2
LTE Year1 (W104-160)
1.Complete the last visit (Week 104) of the core study
LTE Year2 (W156-212)
1.Complete the last visit (Week 156) of the LTE Year 1
LTE (same for Year 1 and 2)
2.Be willing sign an IRB/IEC-approved ICF indicating that he/she understands the purpose of the study and the procedures that are required for the study and that he/she is willing to participate in the 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 the consent form with the subject’s assent, except where local regulations and IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign the consent form, to participate in the study
3.Agree (subject and caregiver/study partner) to be compliant with study procedures and, in the opinion of Investigator, have a high probability of completing the study
4.Have stable medical conditions in the opinion of Investigator |
|
| 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
2.Has a diagnosis of neurodegenerative disorder other than AD
3.Has a current diagnosis of MDD accord. to criteria of DSMMD-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 Inv
4.Has a history of suicidal behavior or has ongoing suicidal ideation
5.Has a history of seizures. 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 MM
6.Has a medically confirmed history of recent cerebral infarct or recent transient ischemic attack
7.Has a medically confirmed history of recent myocardial infarction or unstable, untreated coronary artery disease, or angina pectoris
8.Has a history of cancer, diagnosed and treated within last 3 years prior to Scr–P2V, with exception of following: (a) treated basal cell carcinoma of the skin, or (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–P2V
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 Inv and MM
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 (TBL) ≥ 1.5 x ULN
16.Has an estimated glomerular filtration rate < 40 ml/min per 1.73 m2 accord. to Modif. of Diet in Renal Disease formula
17.Has a glycosylated hemoglobin (HbA1c) > 8% (NGSP) or 64 mmol/mol (IFCC) at Scr–P1V
18.Has a history of alcohol or drug dependence or abuse within 2 years of Scr–P2V or tests positive for drugs of abuse at Scr–P2V
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–P2V
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 T2 more recently than the indicated period before Scr–P2V
24.Anticipates receiving any of treatment listed in T2, during current clinical study
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
LTE Year1
1.Withdrew from core study before completing W104 visit
2.Were noncompliant (<70%) with the study medication or in Investigator’s or Sponsor’s opinion, with study procedures in core study
3.Had a clinically significant medical, surgical, laboratory, or other abnormality at the W104 visit of core study that would compromise their participation in the LTE or compromise their safety in opinion of Inv
LTE Year2
1.Withdrew from LTE Year 1 before completing W156 visit
2.Were noncompliant (<70%) with study medication or, in Investigator's or Sponsor's opinion, with study procedures in LTE Year 1
3.Had a clinically significant medical, surgical, laboratory, or other abnormality at Week156 visit of LTE Year 1 that would compromise their participation in the continued LTE or compromise their safety in opinion of Inv |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoints - Core Study
Primary and Key Secondary Outcome
• Primary Plasma Biomarker Outcome: change from baseline to Week 104 in plasma biomarker of core AD pathology: p-tau181
• Key Imaging Outcome: change from baseline to Week 104 in hippocampal volume on vMRI
Safety Outcomes
• Incidence and nature of TEAE, serious TEAE, and TEAE leading to withdrawal
• Changes in laboratory parameters, vital signs, and physical examination
• Changes in 12-lead electrocardiogram (ECG) parameters
• MRI assessments for Amyloid-Related Imaging Abnormalities with edema (ARIA-E) or microhemorrhages (ARIA-H)
Long-Term Extension (Years 1 and 2)
Primary and Key Secondary Outcomes
• Primary Plasma Biomarker Outcome: change from baseline to Week 156 and to Week 208 in plasma biomarkers: p-tau181
Key Imaging Outcome: change from baseline to Week 156 and to Week 208 in hippocampal volume on vMRI
Safety Outcomes
•Safety and tolerability over 52 weeks and then 104 weeks of the LTE - assessments as listed in Study Protocol Section 2.2.2 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Core Study
Primary and Key Secondary Outcome
• Primary Plasma Biomarker Outcome: change from baseline to Week 104 in plasma biomarker of core AD pathology: p-tau181
• Key Imaging Outcome: change from baseline to Week 104 in hippocampal volume on vMRI
Long-Term Extension (Years 1 and 2)
Primary and Key Secondary Outcomes
• Primary Plasma Biomarker Outcome: change from baseline to Week 156 and to Week 208 in plasma biomarkers: p-tau181
• Key Imaging Outcome: change from baseline to Week 156 and to Week 208 in hippocampal volume on vMRI
Safety Outcomes
•Safety and tolerability over 52 weeks and then 104 weeks of the LTE-assessments as listed in protocol section 2.2.2 |
|
| E.5.2 | Secondary end point(s) |
Core study
Secondary Fluid Biomarker Outcome
• Change from baseline to Week 104 in plasma biomarkers of other core AD pathologies: Aβ40, Aβ42, and p-tau217
Secondary Imaging Biomarker Outcome
• Change from baseline to Week 104 in cortical thickness and ventricular volume
Exploratory Fluid Biomarker Outcomes
• Change from baseline to Week 104 in biomarker of plasma GFAP
• Change from baseline to Week 104 in plasma NfL
• Change from baseline to Week 104 in CSF p-tau181, p-tau217, Aβ40, and Aβ42
• Change from baseline to Week 104 in CSF neurogranin
• Change from baseline to Week 104 in CSF t-tau and NfL
• Change from baseline to Week 104 in CSF TREM2 and YKL-40
Clinical Outcomes
• Change from baseline to Week 104 in RAVLT, DSST, A-IADL MMSE, CDR-SB
Pharmacokinetic and Pharmacodynamic Outcomes
• 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 on 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.
Additional Fluid and Imaging Biomarker Outcomes
• Change from baseline to Weeks 6, 13, 26, 52, and 78 for plasma biomarkers
• Change from baseline to Week 52 in hippocampal volume, cortical thickness, and ventricular volume
• Change from baseline to Week 52 and 104 in other exploratory MRI imaging outcomes (to be described in the SAP)
• Change from baseline to Week 52 for CSF biomarkers
• 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
Additional Clinical Outcomes
• Change from baseline to Weeks 13, 26, 52, and 78 for RAVLT and DSST
• Change from baseline to Weeks 13, 26, 39, 52, 65, 78, and 91 for MMSE
• Change from baseline to Week 52 for A-IADL and CDR-SB
Long-Term extension (Years 1 and 2)
Secondary Fluid Biomarker Outcome
•Change from baseline to Week 156 and to Week 208 in plasma biomarkers: p-tau217, Aβ40, and Aβ42
Secondary Imaging Biomarker Outcome
•Change from baseline to Week 156 and to Week 208 in hippocampal volume, cortical thickness and ventricular volume on vMRI
Exploratory Fluid Biomarkers Outcomes
•Change from baseline to Week 156 and to Week 208 in plasma GFAP
•Change from baseline to Week 156 and to Week 208 in plasma NfL
•Change from baseline to Week 156 in CSF p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Week 156 in CSF neurogranin
•Change from baseline to Week 156 in CSF t-tau and NfL
•Change from baseline to Week 156 in CSF sTREM2 and YKL-40
Clinical Outcomes
•Change from baseline to Weeks 130, 156, and 208 in the clinical outcomes: RAVLT, DSST, MMSE, A-IADL, and CDR-SB
Pharmacokinetic Outcomes
•PK assessments for ALZ-801 and its metabolites as in Study Protocol Section 2.2.7
Additional Fluid and Imaging Biomarker Outcomes
•Change from baseline to Weeks 130 and 208 in plasma biomarkers: GFP, NfL, p-tau181, p-tau217, Aβ40, and Aβ42
•Change from baseline to Weeks 130 and 208 in hippocampal volume, cortical thickness, and ventricular volume
•Change from baseline to Weeks 130,156 and 208 in other exploratory MRI imaging outcomes (as described in the SAP)
•Change from LTE baseline (Week 104) to Weeks 130, 156 and 208 in MRI diffusion tensor imaging (DTI) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Core Study
Second. Fluid Biomarker O.
from BSL to W104
Second. Imaging Biomarker O.
from BSL to W104
Exploratory Fluid Biomarker O.
from BSL to W104
Clin. O.
from BSL to W104
Additional Fluid and Imaging Biomarker O.
from BSL to W6, 13, 26, 52, 78
from BSL to W52
from BSL to W52, 104
from BSL to W52
Add. Clinical O.
from BSL to W13, 26, 52, 78 for RAVLT, DSST
from BSL to W13, 26, 39, 52, 65, 78, 91 for MMSE
from BSL to W52 for A-IADL, CDR-SB
LTE
Second. Fluid Biomarker, Second. Imaging Biomarker O.
from BSL to W156, 208
Exploratory Fluid Biomarkers O.
BSL to W156, 208-GFAP, NfL
BSL to W156
Clin. O.
from BSL to W130, 156, 208
Add. Fluid and Imaging Biomarker O.
from BSL to W130, 208
from BSL to W130, 208
from BSL to W130, 156, 208
from LTE BSL to W130, 156, 208 |
|
| 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 | 3 |
| 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
|
|
| 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 | 59 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 59 |
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