Clinical Trials Register

Summary
EudraCT Number:	2022-003532-73
Sponsor's Protocol Code Number:	ADVANCE-AD04-001
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2023-02-15
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

Bulgarian Drug Agency

A.2

EudraCT number

2022-003532-73

A.3

Full title of the trial

A Phase 2b, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Assess the Safety and Efficacy of AD04 in Patients with Early Alzheimer’s Disease - ADVANCE

Фаза 2б, многоцентрово, рандомизирано, плацебо-контролирано, двойно-сляпо изпитване за оценка на безопасността и ефикасността на AD04 при пациенти с ранен стадий на болестта на Алцхаймер - ADVANCE

A.3.1

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

A Phase 2b, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Assess the Safety and Efficacy of AD04 in Patients with Early Alzheimer’s Disease - ADVANCE

A.4.1

Sponsor's protocol code number

ADVANCE-AD04-001

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	ADvantage Therapeutics GmbH
B.1.3.4	Country	Austria
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	ADvantage Therapeutics GmbH
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ADvantage Therapeutics GmbH
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Karl-Farkas-Gasse 22
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1030
B.5.3.4	Country	Austria
B.5.4	Telephone number	004369911098989

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	AD04
D.3.2	Product code	AD04
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aluminium hydroxide
D.3.9.3	Other descriptive name	Aluminium hydroxide
D.3.9.4	EV Substance Code	SUB33625
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

early Alzheimer’s disease

E.1.1.1

Medical condition in easily understood language

early Alzheimer’s disease

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	HLT
E.1.2	Classification code	10001897
E.1.2	Term	Alzheimer's disease (incl subtypes)
E.1.2	System Organ Class	10029205 - Nervous system disorders

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	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of AD04 in slowing progression of the disease in patients with early Alzheimer’s disease (AD) based on the evaluation of the time savings in cognitive and functional and global domains over 6 months

E.2.2

Secondary objectives of the trial

- To investigate safety and tolerability of AD04 in early AD patients over 12 months
- To assess the effect of AD04 in global clinical activity and quality of life over 12 months
- To obtain surrogate biomarkers of AD (wet and structural), immunity, and lipid metabolism over 12 months

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Aged 50-85 years old
2. Has a diagnosis of probable AD based on the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria, integrating both clinical and neuropathological criteria
3. Has a Mini-Mental State Examination (MMSE) score between 22 and 30.
Note: Regarding inclusion criterion #2, it is obvious that patients with an MMSE score ≥27 may not fulfill all NINCDS/ADRDA criteria, especially those referring to or requiring a state of dementia. In such cases, inclusion criteria #4 and #5 ensure the specificity of the diagnosis (prodromal stage of AD/AD-type mild cognitive impairment [MCI]).
4. Has brain MRI showing medial temporal lobe atrophy as assessed by the Scheltens’ scale (score ≥2 at least at one site) or has AD-type CSF signature at a 7:3 ratio of Scheltens to CSF signature. This criterion was chosen with the goal of having a patient cohort which reflects as closely as possible that of the AFF006 study; specific cut-offs for CSF AD biomarkers will be defined based on the methodology of the selected central laboratory. For more details refer to Section 7.1.11.
5. Has a Free and Cued Selective Reminding Test (FCSRT) total recall ≤40 or free recall ≤17, indicating hippocampal damage, episodic memory impairment, and amnestic syndrome.
6. Must have results of a physical examination, including visual and auditory acuity within the acceptable range for the age group to allow neuropsychological testing.
7.Has Hachinski Ischemia Scale score ≤4 to distinguish AD from vascular dementia.
8.Written informed consent of study-related procedures and of genetic investigations signed and dated by the patient and the caregiver.
9.Availability of a partner/caregiver knowing the patient and being able to accompany the patient at the visits. He/ she will be in frequent contact with the participant (defined as at least 10 hours per week), will accompany the participant to the planned study visits and/or be available by telephone at designated times.
10. Women of childbearing potential and men with female partners of childbearing potential must use 2 effective methods of birth control during the course of the trial and for at least 90 days after the last dose in a manner such that risk of failure is minimized. Male participants should refrain from donating sperm during the intervention period and for at least 90 days after the last dose of study intervention.

E.4

Principal exclusion criteria

1. Known or suspected allergy, or history of anaphylaxis, to vaccines or their excipients, if considered relevant by the Investigator
2. Any medical or neurological condition (other than AD) that might cause the participant’s cognitive impairment, including e.g.:
- A significant number of >4 microhemorrhages, a single prior hemorrhage > 1 cm3, >2 lacunar infarcts, a single prior infarct > 1 cm3, radiological finding supporting the NINDS-AIREN criteria as operationalized in Stroke. 2003 Aug;34(8):1907-12, meningioma with a perpendicular diameter of >1cm or significant mass effect on the brain parenchyma, evidence of a cerebral contusion, encephalomalacia, aneurysms, brain neoplasms such as gliomas or subdural hematoma/effusion with a diameter of >1cm, diffuse white matter disease (Fazekas score – deep white matter score >3) or significant mass effect on the brain parenchyma assessed by MRI at screening.
-History of chronic alcohol or drug abuse/ dependence within the past 5 years.
-Patient with past or present suicidal ideation and intent as assessed by the Columbia Suicidality Severity Rating Scale (C-SSRS), or who, in the clinical judgment of the investigator, presents a serious risk of suicide.
-Presence of autoimmune disease, autoinflammatory syndrome, or immunological deficiency syndrome (including human immunodeficiency virus (HIV) infection).
-Relevant cardiovascular, hepatic, gastroenterological, respiratory, endocrinological, hematologic disease, or any other condition that, in the Investigator's opinion, could interfere with the analyses of safety and efficacy in this study, unless patient has been on stable doses of medication for any of these concurrent illnesses for at least 3 months prior to study entry.
-History within the last 2 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment; or has a life expectancy of <2 years.
3. Presence of end stage kidney failure (on dialysis) (which may affect renal clearance of aluminium).
4. Patient has hemochromatosis.
5. If on conventional AD therapies such as donepezil or memantine, anticholinergics in general (including neuroleptics with anticholinergic properties, certain bladder relaxants, anticholinergic drugs for use in lung diseases), or lipid-modifying therapies, doses must be stable for at least 3 months prior to the screening visit and during the entire trial period.
6. Current or anticipated use of immunosuppressive drugs such as, but not limited to, azathioprine, cyclosporine, methotrexate, tacrolimus, or mycophenylate within 2 months or any myelosuppressive or cytotoxic chemotherapies within the 12 months prior to the screening visit. Use of systemic corticosteroids equivalent to ≥20mg/week prednisone within the past 4 weeks before screening and during the course of the study (intranasal or inhaled steroids for allergies/asthma is allowed).
7. Current or anticipated use of allergy immunotherapies.
8. Patient has received or plans to receive any aluminium-adjuvanted vaccines within 14 days prior to any dose of study drug
9. Pregnancy (for patients of childbearing potential, see additional considerations in Section 5.3) .
10. Contraindication for MRI imaging, including but not limited to pacemakers; cochlear implants, cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; other magnetic, electronic, or mechanical implants; claustrophobia; inability to lie motionless for 30 minutes; or any other clinical history or examination finding that, in the judgement of the Investigator, would pose a potential hazard in combination with MRI.
11. Contraindication for CSF collection, including certain conditions and / or medications such as high doses of blood thinning agents.
12. Patient has received any vaccine targeting Aβ or tau for the treatment of AD. For all other experimental AD drugs, including passive immunotherapies, participation in the active treatment phase of any AD clinical trial within 3 months (or 5 half-lives, whichever is longer), prior to Visit 1.
13. Participation in the active treatment phase of any non-AD clinical trial within 30 days prior to Visit 1.
14. Employee at the study site, spouse/partner or relative of any study staff (e.g., investigator, sub-investigators, or study nurse) or relationship to the Sponsor.

E.5 End points

E.5.1

Primary end point(s)

Composite score assessing cognition [adapted AD Assessment Scale cognitive (aADAS-cog)] and daily function [adapted AD Cooperative Study Activities of Daily Living (aADCS-ADL)] and CDR-sb over 6 months measured in overall time saved with treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

E.5.2

Secondary end point(s)

Safety Endpoints
- Incidence of treatment-emergent adverse events (TEAEs)
Key Secondary Efficacy Endpoint
- Change from baseline in Clinical Dementia Rating - sum of boxes (CDR-sb)
Other Secondary Efficacy Endpoints
- Global statistical test (GST) combining cognition [ADAS-cog] and daily function [ADCS-ADL]
- Change from baseline in hippocampal volume (total, right, and left), measured by volumetric Magnetic Resonance Imaging (MRI)
-Change from baseline in cognition score (ADAS-cog and aADAS-cog)
- Change from baseline in function score (ADCS-ADL and aADCS-ADL)
- Neuropsychiatric inventory (NPI)
-Clinician’s Global Impressions of Change (CGIC)
Assessment of Quality of Life in patients with AD and their caregivers
(QOL-AD)

Exploratory endpoints
The following biomarkers will be measured to support treatment effect and dosing regimen:
-Concentrations of aluminium in the blood, cerebrospinal fluid (CSF), and urine for pharmacokinetic profiling of AD04 (AUC and cumulative maximum concentration adjusted for pre-dose baseline values)
-Levels of circulating biomarkers of immune response, lipid metabolism, neuroinflammation, and brain atrophy (temporal dynamics and time dependencies)
- PK/PD relationships (e.g., based on aluminium and IgG antibody measurements)

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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)

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

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

Yes

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

122

F.4.2.2

In the whole clinical trial

122

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)

None

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

2023-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-05-11

P. End of Trial
P.	End of Trial Status	Ongoing

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