Clinical Trials Register

Summary
EudraCT Number:	2019-003302-27
Sponsor's Protocol Code Number:	ANAVEX2-73-AD-004
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-05-20
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2019-003302-27

A.3

Full title of the trial

A Phase 2b/3, Double-Blind, Randomised, Placebo-Controlled 48-week Safety and Efficacy trial of ANAVEX2-73 for the Treatment of Early Alzheimer’s Disease (AD)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A Phase 2b/3, Double-Blind, Randomised, Placebo-Controlled 48- week Safety and Efficacy trial of ANAVEX2-73 for the Treatment of Early Alzheimer’s Disease (AD)

A.3.2

Name or abbreviated title of the trial where available

In the treatment of early AD: A Phase 2b/3 study to evaluate the safety and efficacy of Anavex2-73

A.4.1

Sponsor's protocol code number

ANAVEX2-73-AD-004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03790709

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ANAVEX Life Sciences Corp.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ANAVEX Life Sciences Corp.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Orphan Reach Limited
B.5.2	Functional name of contact point	Jinisha Shukla
B.5.3	Address:
B.5.3.1	Street Address	The Old School/Newport Road/Woughton Park
B.5.3.2	Town/ city	Milton Keynes
B.5.3.3	Post code	MK6 3AP
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+441908251480
B.5.5	Fax number	+441908251499
B.5.6	E-mail	jshukla@emmes.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Anavex2-73
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Blarcamesine
D.3.9.1	CAS number	195615-84-0
D.3.9.2	Current sponsor code	ANAVEX2-73
D.3.9.4	EV Substance Code	SUB197746
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	to 10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Anavex2-73
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Blarcamesine
D.3.9.1	CAS number	195615-84-0
D.3.9.2	Current sponsor code	ANAVEX2-73
D.3.9.4	EV Substance Code	SUB197746
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	to 20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

cognition and function in Patiens with Alzheimer's Disease (AD)

E.1.1.1

Medical condition in easily understood language

cognition and function in Patiens with Alzheimer's Disease (AD)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10001896
E.1.2	Term	Alzheimer's disease
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Reduction in cognitive decline assessed from baseline over 48 weeks with
ANAVEX2-73 compared to placebo using the Alzheimer Disease Assessment Scale-
Cognition (ADAS-Cog) scale.
2. Reduction in decline of the ability to perform daily activities assessed from baseline
over 48 weeks with ANAVEX2-73 compared to placebo using the Activities of Daily
Living Scale (ADCS-ADL) scale.

E.2.2

Secondary objectives of the trial

Secondary Objectives:
1. Reduction in cognitive decline assessed from baseline over 48 weeks with
ANAVEX2-73 compared with placebo using the Clinical Dementia Rating Scale
Sum of Boxes (CDR-SB).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria:
1. Patients aged 60 to 85 years, inclusive, with a 2011 NIA-AA criteria for 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. Additional criteria can be either:
a. Historical records of amyloid CSF assessment compatible with AD that meets at least one of the following criteria:
i. Cut off values of <1054 pg/mL for Aβ42, >213 pg/mL for tTau, >21.3 pg/mL for pTau181, and <0.064 for Aβ42/Aβ40 ratio, according to the automated Elecsys® CSF biomarkers assays (Roche Diagnostics) or comparable commercially used CSF assays OR
ii. CSF pTau181 is > 27 pg/ml (irrespective of the Aβ42/Aβ40 ratio) OR
b. Historical records of PET scan within 36 months of screening (amyloid scan or FDG-PET) OR
c. Historical CT or MRI scan within 18 months of screening (Australia/UK only), which are consistent with a diagnosis of AD according to NIA-AA 2011 criteria OR
d. CSF profile compatible with AD that meets at least one of the following criteria:
i. Cut off values of <1054 pg/mL for Aβ42, >213 pg/mL for tTau, >21.3 pg/mL for pTau181, and <0.064 for Aβ42/Aβ40 ratio, according to the automated Elecsys® CSF biomarkers assays (Roche Diagnostics) or comparable commercially used CSF assays; OR
ii. CSF pTau181 is >27 pg/ml (irrespective of the Aβ42/Aβ40 ratio).
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 and/or another medication for AD (e.g., memantine), or over-the-counter (OTC) supplements/nutraceuticals used to treat AD, dose(s) must be stable for at least 90 days prior to screening.
8. If taking psychoactive or anti-seizure medications, dose must be stable for at least 90 days prior to screening.

E.4

Principal exclusion criteria

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 safe 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.
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 within 60 days 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. Treatment with strong inhibitors or inducers of CYP3A4 or CYP2C19 must be stable (drug, dose) for 90 days prior to screening. Although these medications are not excluded, caution is advised when enrolling participants on potent CYP3A4 or CYP2C19 inducers or inhibitors (see Section 4.11 - Prior and Concomitant Therapy).

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoints
• Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
• Activities of Daily Living Scale (ADCS-ADL)

E.5.1.1

Timepoint(s) of evaluation of this end point

from basline to week 48

E.5.2

Secondary end point(s)

Secondary Endpoints
• Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Safety Endpoint
• Incidence of Adverse Events (AEs) and serious AEs over the 48-week
treatment duration

E.5.2.1

Timepoint(s) of evaluation of this end point

from basline to week 48

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Canada

Netherlands

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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

LPO_February 2022

After End of Trial (EOT): Voluntary Open Label Period: a voluntary option will be offered for all completing patients in the AD-004 study to continue on study product.

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

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

382

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The participant must be able to provide informed consent at the start of the study. If during the study, the patient loses capacity due to their AD, the person responsible will be asked if they wish to provide consent on behalf of the participant.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

350

F.4.2.2

In the whole clinical trial

509

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Voluntary Open Label Period: a voluntary option will be offered for all completing patients in
the AD-004 study to continue on study product.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-08-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-10-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-28

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