Primary Objectives:* Change from baseline to week 48 in cognition according to the Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo.* Changes from baseline to week 48 in ability to perform daily activities according to the…
ID
Source
Brief title
Condition
- Mental impairment disorders
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints, ADAS-Cog and ADCS-ADL, and their corresponding change
from baseline values will be summarized by visit and treatment group.
Differences between each active treatment group and placebo at week 48 will be
assessed based on the LSMeans from a mixed effects repeated measures ANCOVA
model with fixed effects for treatment group, visit, treatment by visit
interaction, absence/presence of the rs1800866 or rs113895332/rs61143203
variants, and baseline value, and a random effect for subject.
Secondary outcome
Secondary efficacy endpoint:
For the changes in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB
questionnaire) between baseline and week 48 compared to placebo similar
statistical methods from the primary efficacy analysis (ADA-Cog and ADCS-ADL
questionnaires) will be applied.
Sleep Assessment Analyses:
The main input measures from the sleep assessments are average sleep continuity
values from the RSCAQ, the scale scores from the ISI and ESS, and the percent
of subjects per treatment group that endorse two or more symptoms per disorder
cluster at a scale score of > 3. These values will be assessed for group
differences (change from baseline to Week 48) between each active treatment
group and placebo for each endpoint using a model similar to that proposed for
the primary efficacy endpoint. An additional test comparing both active
treatments to placebo will be conducted using the LSMeans from the ANCOVA
model. The analyses will be conducted using the ITT Population.
Other Secondary Efficacy Analyses:
MMSE:
The derived MMSE variable is change from Baseline visit to Week 48. Descriptive
analyses will be performed to describe the cognitive assessments. In addition,
the derived efficacy variables will be tabulated by visit and by treatment.
Change in cognition scores from baseline between two-treatment groups will be
compared to determine whether there is a statistically significant difference.
The other analysis will be a descriptive analysis for responders, if data
permit. Response is defined as a positive change in MMSE score. The analysis
will include the number and % of responders for each dose group.
Other AD Relative Measures* Analyses:
- Zarit Burden Interview (ZBI)
- Quality of Life of Alzheimer*s Disease Patient and Caregiver Report (QoL-AD)
- Neuropsychiatric Inventory Questionnaire (NPI-Q)
- Clinical Global Impression of Severity (CGI-S)
- Clinical Global Impression * Improvement scale (CGI-I)
Two-sample t-tests at * = 0.05 will be used to test if there is a statistical
significance of the change at each visit from baseline between each active
treatment group and placebo and between both active groups and placebo if the
intended metric is symmetrically distributed. Otherwise, the nonparametric
Wilcoxon rank sum test will be used. There will be no correction to be made for
multiple comparisons because of the exploratory nature of the data. Data will
be tabulated by visit and by treatment.
MRI Related Endpoints:
* Based on available data, structural (and optional ASL) MRI scans assessments
characteristic for AD pathophysiology from baseline and compared to placebo at
+48 weeks.
* Change from baseline in whole brain structure and function, including
measures of cortical thickness, and correlational maps and behavioral outcomes
at end of study in ANAVEX 2-73 versus placebo treated subjects.
* Change from baseline in medial temporal cortex structure and function
correlational maps and behavioral outcomes at end of study in ANAVEX 2-73
versus placebo treated subjects.
* Change from baseline in hippocampus structure and function correlational maps
and behavioral outcomes at end of study in ANAVEX 2-73 versus placebo treated
subjects.
* Change from baseline in basal forebrain structure and function correlational
maps and behavioral outcomes at end of study in ANAVEX 2-73 versus placebo
treated subjects.
* Exploration of laterality effects on whole brain volumes and pre-defined
regions of interest volumes at baseline and end of study after treatment with
ANAVEX 2-73 versus placebo.
Two-sample t-tests at * = 0.05 will be used to determine statistical
significance of the structural and optional ASL functional MRI data at week 48
from baseline between each active treatment group and placebo and between both
active groups and placebo. Otherwise, a Wilcoxon rank sum test will be used.
The relationship between ANAVEX2-73 and CSF/serum and MRI parameters related to
AD pathophysiology will also be explored.
Background summary
Cognitive deficits in patients Alzheimer's disease (AD) often involve
dysregulation of neuronal signaling. This neuronal signaling imbalance may be
countered by enhancing neuronal homeostatic mechanisms. Considering the high
unmet medical treatment need for neurodegenerative diseases, novel therapeutic
strategies, such as those targeting neuronal homeostatic mechanisms, could lead
not only to improving acquisition or slowing progression of cognition but also
of other neurologic functions.
ANAVEX2-73 is an investigational oral sigma-1 receptor (*1R) agonist whose
mechanism of action is to activate the *1R, which in turn enhances cellular
homeostasis by targeting mitochondrial dysfunction, including oxidative stress;
protein misfolding; autophagy, neuroinflammation; and other cellular stress
responses, known to be implicated in neurodegenerative disorders. ANAVEX2-73
has been shown pharmacologically to be an effective neuroprotective,
anticonvulsive, and anti-depressant therapeutic agent.
ANAVEX2-73 has shown to significantly improve cognitive functions in various
experimental pre-clinical models.
Because of its targeted upstream mechanism of action, ANAVEX2-73 is assumed to
be potentially disease modifying for Alzheimer's Disease and potentially
possessing a better safety profile than currently approved drugs.
ANAVEX2-73 has been studied in animal models as well as normal volunteers and
patients with mild to moderate AD. In general, ANAVEX2-73 has a favorable
safety profile, with the majority of TEAEs associated with daily oral doses of
50 mg or greater. Furthermore, these studies support ANAVEX2-73*s long-term
efficacy and the possibility of using precision medicine approaches for the
treatment of AD and other neurodegenerative and neurodevelopmental disorders.
Given the current lack of approved treatment options with acceptable side
effect profiles for AD, the development of ANAVEX2-73 could meet this critical
unmet medical need for AD patients.
Study objective
Primary Objectives:
* Change from baseline to week 48 in cognition according to the Alzheimer
Disease Assessment Scale-Cognition (ADAS-Cog) compared to placebo.
* Changes from baseline to week 48 in ability to perform daily activities
according to the Activities of Daily Living Scale (ADCS-ADL) compared to
placebo.
Secondary Objectives:
* Change from baseline to week 48 on Clinical Dementia Rating Scale Sum of
Boxes (CDR-SB) compared to placebo.
* To establish safety and tolerability of ANAVEX2-73 in AD patients.
* To evaluate whether ANAVEX2-73 improves sleep continuity as assessed on a
serial basis (weeks 0, 4, 12, 24, 36, and 48) with a questionnaire that assess
retrospectively reported sleep continuity (RSCAQ) and the Insomnia Severity
Index (ISI).
Further AD-related Objectives
* Changes on the Neuropsychiatric Inventory Questionnaire (NPI-Q) at week 48
compared to placebo.
* Change in dementia symptom severity according to the Mini-Mental-State
Examination (MMSE) at week 48 compared to placebo.
* Changes in Quality of Life of the patient and caregiver according to the
Quality of Life of Alzheimer*s Disease Patient and Caregiver Report (QoL-AD) at
week 48 compared to placebo.
* Changes in the level of burden experienced by caregivers according to the
Zarit Burden Interview (ZBI) at week 48 compared to placebo.
* Clinical Global Impression of Severity (CGI-S) at week 48 compared to placebo.
* The Clinical Global Impression * Improvement scale (CGI-I) at week 48
compared to placebo.
* Structural and optional Arterial Spin Labeling (ASL) MRI scan assessments
characteristic for AD pathophysiology from baseline and compared to placebo at
week 48.
* Blood assessnt from baseline and compared to placebo at week 48: Abeta40,
Abeta42, T-tau, NF-L, YKL-40, BACE1, Glutamate and related metabolites
concentrations,
* Changes in CSF parameters (Abeta40, Abeta42, T-tau, P-tau, NFL, YKL-40,
neurogranin, BACE1 concentration) characteristic for AD pathophysiology from
baseline and compared to placebo at week 48 (except for participants in
Australia and in the UK).
* AD relevant pre-specified genetic variants will be assessed. Statistical
testing of treatment differences within subgroups will be performed.
Further Sleep-related Endpoints
* Longitudinally evaluate changes in sleep disorders symptomatology and daytime
sleepiness as assessed with repeated single point assessments: (1) the Sleep
Disorders Symptom Check List (SDS-CL-25) and the (2) Epworth Sleepiness Scale
(ESS), both evaluated at weeks 0, 4, 12, 24, 36, and 48.
Study design
This is a Phase 2b/3, randomized, placebo-controlled, double-blind, 48-week
study to evaluate the effects of ANAVEX2-73 on cognition and functioning after
48 weeks of daily treatment. Additional outcome measures include refined
measures of sleep and behavioral symptoms typically observed in AD, changes in
daily functioning of participants and changes in caregiver burden, as well as
changes in quality of life measures of both, patients and caregivers during
treatment with ANAVEX2-73. In addition, safety assessments, pharmacokinetic
(PK) assessments and collections of CSF and blood markers of AD pathophysiology
before and after treatment will be performed.
The study design requires about 450 patients with early AD and will follow the
below medication schedule.
* Randomization to three parallel groups (placebo, ANAVEX2-73 30 mg/day, and
ANAVEX2-73 50 mg/day).
* Treatment: 48-week treatment will include:
- A gradual 3-week titration period with incremental increase of 10 mg
per week for the first 3 weeks (Week 1: placebo, or ANAVEX2-73 10 mg/day; Week
2: placebo or ANAVEX2-73 20 mg/day and then Week 3: placebo or ANAVEX2-73 30
mg/day), and a final 20 mg/day increase to ANAVEX2-73 50 mg/day for the 50 mg
group.
- A maintenance period (Week 4 to Week 48): of placebo, or ANAVEX2-73
30mg/day or ANAVEX2-73 50mg/day .
* During the up-titration phase:
- Dose reduction will be allowed for Adverse Events or tolerability
concerns.
- Participants may remain at 10 mg/day for stabilization or for possible
drug-related AEs to resolve but should attempt to re-titrate to their target
dose once their AE has resolved.
- If a patient is not able to tolerate a dose, the study investigator
should contact the safety and medical monitor for resolution.
* During the maintenance phase:
- Subjects should be able to tolerate the lowest maintenance dose (10 mg)
directly or after a dose reduction. If not able to maintain a dose of 10 mg/d
or higher then they will be taken off the study drug and will complete the
Early Terminatin Visit.
- Participants who experience any dose interruption equal > 10
consecutive days must be withdrawn from the study.
Safety and tolerability will be assessed throughout the study, starting from
the first dose of study medication.
Intervention
3 treatment arms will be used in this study. Subjects will be randomly assigned
to a treatment arm with a 1:1:1 ratio:
The study medication and placebo are delivered as capsules and have the same
appearance.
ANAVEX2-73 capsules are available in the dose of 10 mg and 20 mg.
- ANAVEX2-73 arm: 30 mg/day QD;
- ANAVEX2-73 arm: 50 mg/day QD;
- Placebo arm
As of baseline there will be a two week titration period.
The ANAVEX2-73 30 mg arm starts with 10 mg/day for one week then 20 mg/day for
one week to reach the 30 mg/day.
The ANAVEX2-73 50 mg arm starts with 10 mg/day for one week then 20 mg/day for
one week then 30 mg/day for one week to reach the 50 mg/day.
The study medication/ placebo will be taken once daily for a period of 48
weeks.
Study burden and risks
Currently there are no well-developed treatment menthods for people who are
diagnosed with Alzheimer*s Disease. The development of ANAVEX2-73 could meet
the critical unmet medical need for AD patients.
ANAVEX2-73 will be delivered as capsules for oral intake.
Side effects of ANAVEX2-73 are: dizziness, headache, euphoric mood, depression
like syndrome and gastrointestinal disorders like nausea, vomiting, diahrroea
and constipation.
Risk associated to study assessments:
ECG: redness and itching caused by the sticky pads.
Blood draws: discomfort, bruising, minor infection or bleeding.
Lumbar punction: discomfort or pain during the procedure. There could also be
an infection, nerve damage, bleeding into the spinal cord or headache.
MRI scan: claustrophobia
PET scan: radiation exposure which could later to cancer in future.
The following procedures are performded:
- Measurement of vital signs * all visits;
- Physical and neurological examination * screening, baseline and week 48;
- ECG * screening, baseline, week 24 and week 48;
- Lumbar puncture * screening and week 48 (for biomarker assessment and
possibly at screening for AD diagnosis);
- Blood draws:
- clinical chemistry and hematology * screening, baseline, week 24 and
week 48;
- AD biomarkers * screening, baseline and week 48;
- DNA/RNA * baseline and week 48 (RNA sampling only);
- Pharmacokinetics: 1x pre-dose and 1x post-dose * baseline, week 24
and week 48 (only post-dose);
- Standard urine analysis * screening, baseline, week 24 and week 48;
- Urine drug screen * screening and baseline;
- MRI for brain structure and function * baseline and week 48 (optionally
followed by an ASL MRI on both visits);
- Questionnaires * during all visits multiple questionnaires will be completed,
with or without the help of the caregiver.
W 52nd Street, 7th floor 51
New York NY10019
US
W 52nd Street, 7th floor 51
New York NY10019
US
Listed location countries
Age
Inclusion criteria
1. Patients aged 60 to 85 years, inclusive, with a NIA-AA diagnosis of mild
cognitive impairment (MCI) due to AD or early stage mild dementia due to AD. AD
diagnosis must be made by an appropriately qualified board-certified or
equivalent medical specialist.
2. At least one of the following criterion must be utilized to support AD
diagnosis:
a. Historical records of amyloid CSF assessment or
b. Historical records of PET scan (amyloid scan or FDG-PET) or
c. Historical CT or MRI scan within 18 months of screening,
which are consistent with a diagnosis of AD. CSF collection would be required
as part of the screening process unless historical records (CSF or PET) are
available, except for participants in Australia and United Kingdom (UK).
3. Mini Mental State Examination (MMSE) score between 20-28, inclusive at both
the Screening Visit and the Randomization Visit.
4. Free Recall score *17 or Total Recall score <40 on the Free and Cued
Selective Reminding Test (FCSRT).
5. Participants are either outpatients, or residents of an assisted-living
facility. Participant has a designated study partner, who spends at least 10 hr
per week with the participant, in order that assessments (e.g., carer burden
instruments) are completed with true knowledge of the participant.
6. No suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating
Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought(s) with
intent but without specific plan, or active suicidal thought(s) with plan and
intent) OR suicidal behavior in the past 2 years (i.e., actual attempt,
interrupted attempt, aborted attempt, or preparatory acts or behavior).
7. If taking an acetylcholinesterase inhibitor or other AD medication (e.g.
memantine), or OTC supplements/nutraceuticals used to treat AD, dose(s) must be
stable for at least 90 days before screening.
8. If taking a psychoactive or anti-seizure medications, dose must be
stable for at least 90 days prior to screening.
Exclusion criteria
1. Patients who have a progressive medical or neurological condition that in
the opinion of the investigator would interfere with the conduct of the study.
Exception: If diagnosed with seizures, must be on stable anti-seizure
medication for at least 3 months prior to screening.
2. Current clinically significant systemic illness that is likely to result in
deterioration of the patient*s condition or affect the patient*s safety during
the study.
3. History or clinically evident stroke or clinically significant carotid or
vertebrobasilar stenosis or plaque.
4. History of neurologic (e.g., stroke, traumatic brain injury) or psychiatric
condition that the investigator deems may interfere with interpretability of
data.
5. History of untreated thyroid disorder, Type 1 diabetes, and insulin
dependent or uncontrolled Type II diabetes, as determined by the investigator
(e.g., non-insulin-controlled Type II diabetes, whose HbA1c value is higher
than 8.0%).
6. If a participant has a Body Mass Index (BMI) > 35, no co-morbidities,
related to weight that would preclude participation in the study in the opinion
of the investigator.
7. History of clinical hepatic dysfunction.
8. Current symptomatic and unstable/uncontrolled gastrointestinal, hepatic,
renal, respiratory, cardiovascular, metabolic, immunological, hematological or
hormonal disorders.
9. Indication of liver disease, defined by serum levels of ALT (SGPT), AST
(SGOT), or alkaline phosphatase above 3x upper limit of normal (ULN) as
determined during screening.
10. Significant history of drug addiction (with the exception of nicotine
dependence) or abuse (including alcohol, as defined in DSM-5 or in the opinion
of the investigator) within the last two years prior to informed consent, or a
positive urine drug screen for cocaine, opioid, phencyclidine (PCP),
amphetamine or marijuana at screening. Prescription medication yielding a
positive drug screen are acceptable except for tricyclic antidepressants (e.g.,
Amitriptyline, Amoxapine, Desipramine, (Norpramin) Doxepin, Imipramine
(Tofranil), Nortriptyline (Pamelor), Protriptyline (Vivactil), Trimipramine
(Surmontil)).
11. Clinically significant infection within the last 30 days prior screening
(e.g., chronic persistent or acute infection, urinary tract infections (UTI)).
12. Treatment with tricyclic antidepressants 60 days weeks prior to screening.
13. Treatment with immunosuppressive medications (e.g., systemic
corticosteroids), within 90 days prior to screening (topical and nasal
corticosteroids and inhaled corticosteroids for asthma are permitted), or
chemotherapeutic agents for malignancy within the last 3 years.
14. Myocardial infarction within the last year.
15. History of cancer within the last 3 years, with the exception of basal cell
carcinoma and non-metastatic squamous cell carcinoma of the skin and prostate
cancer with currently normal PSA.
16. Other clinically significant abnormality on physical, neurological,
laboratory, or electrocardiogram (ECG) examination (e.g., atrial fibrillation)
that could compromise the study or be detrimental to the participant.
17. Hemoglobin < 11 g/dL.
18. Smoking > 1 pack of cigarettes per day (as assessed for the 30 days prior
to screening).
19. Alcohol use of more than 2 drinks per day.
20. Current use of over-the-counter (OTC) supplements or nutraceuticals unless
they are on stable dose for at least 3 months prior to screening and are
documented in the eCRF.
21. Use of over the counter (OTC) or prescription medication for sleep on 2 or
more occasions per week.
22. Being treated with psychoactive medications on a stable dose for less than
3 months.
23. Any prior exposure to ANAVEX2-73.
24. Individuals enrolled in previous AD clinical trial involving an
investigational drug treatment less than 3 months ago (longer than 3 months ago
allowed).
25. Any known hypersensitivity to any of the excipients contained in the study
drug formulation.
26. Any other criteria (such as a clinically significant screening blood test
result), which in the opinion of the Investigator causes the participant not to
qualify for the study.
27. Evidence of cerebrovascular dementia with a Hachinski score of 4 or more.
28. Use of St. John*s wort within 30 days of screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-003302-27-NL |
| CCMO | NL72333.056.19 |
| Other | NTC03790709 |