Clinical Trials Register

Summary
EudraCT Number:	2022-002568-62
Sponsor's Protocol Code Number:	AVB-PGRN-001
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-10-28
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

France - ANSM

A.2

EudraCT number

2022-002568-62

A.3

Full title of the trial

A Phase 1/2 Open-Label, Ascending Dose, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of AVB-101 Administered by Bilateral Intrathalamic Infusion in Subjects With Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)

A.3.1

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

A study to test whether AVB-101 is both safe and efficacious in a sub-population of genetically defined FTD patients that currently have no other treatment options

A.3.2

Name or abbreviated title of the trial where available

Ph1/2 study of AVB-101 in Subjects with Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)

A.4.1

Sponsor's protocol code number

AVB-PGRN-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	AviadoBio Ltd
B.1.3.4	Country	United Kingdom
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	AviadoBio Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Medpace
B.5.2	Functional name of contact point	Clinical Trial Management
B.5.3	Address:
B.5.3.1	Street Address	Via Olona 2
B.5.3.2	Town/ city	Milan
B.5.3.3	Post code	20123
B.5.3.4	Country	Italy
B.5.4	Telephone number	39 0283413400
B.5.6	E-mail	S.Zambruno@Medpace.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/0000068610
D.3 Description of the IMP
D.3.1	Product name	Recombinant AAV-9 vector expressing the human progranulin protein
D.3.2	Product code	AVB-101
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intracerebral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Frontotemporal Dementia With Progranulin Mutations (FTD-GRN)

E.1.1.1

Medical condition in easily understood language

Dementia

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the safety and tolerability of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.

E.2.2

Secondary objectives of the trial

To evaluate the preliminary clinical and biomarker measures of efficacy of a one-time, bilateral, intrathalamic administration of AVB-101 in subjects with FTD-GRN.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, 30 to 75 years of age, inclusive, at Screening;
2. Carriers of a pathogenic granulin (GRN) mutation as confirmed by a sponsor approved genetic test;
3. Frontotemporal dementia (FTD) as evidenced by Clinical Dementia Rating (CDR)+ National Alzheimer's Coordinating Center (NACC) frontotemporal lobar degeneration (FTLD) global score of 0.5, 1.0, or 2.0;
4. Presence of 1 or more of the criteria for diagnosis of possible behavioral variant FTD or Primary Progressive Aphasia;
5. Identified, informed study partner able to support the subject for the duration of the study
6. The subject and/or legally authorized representative is able and willing to give written informed consent prior to study participation. If a subject lacks capacity to consent in the investigator’s opinion, the subject’s assent should be obtained, if required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained. In countries where local laws, regulations, and customs do not permit subjects who lack capacity to consent to participate in this study, they will not be enrolled.

E.4

Principal exclusion criteria

1. Classification of the mutation in the GRN gene as “not pathogenic,” “likely benign variant,” or “benign variant” in the Alzheimer’s Disease and Frontotemporal Dementia Mutation Database;
2. Severe dementia that precludes ability to comply with study procedures and/or poses unacceptable safety risk to the subject (i.e. CDR+ NACC FTLD score of 3.0);
3. Concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis,
hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency;
4. Clinically significant abnormality on magnetic resonance imaging (MRI) at Screening considered to be a contraindication to intrathalamic infusion;
5. Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned surgical trajectory;
6. Previous treatment with any gene or cell therapy;
7. Previous treatment with any investigational medicinal product within 60 days or 5 half-lives (whichever is longer) prior to study drug dosing;
8. Concomitant disease or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct or the subject's ability to comply with study procedures;
9. Contraindications to MRI as per local guidelines;
10. Contraindications to gadolinium-based contrast agents per local guidelines;
11. Contraindications to general anesthesia for a period of up to 10 hours and/or cardiopulmonary disorders that would result in a higher ASA risk classification;
12. Contraindications to lumbar puncture as per local guidelines;

E.5 End points

E.5.1

Primary end point(s)

Over a 26-week initial and 5year total follow up period:
• Number and incidence of AEs, SAEs, and clinically meaningful laboratory test abnormalities;
• Change from baseline in vital signs, ECG parameters, and physical and neurological examinations, and MMSE
• Change from baseline in mini-mental state examination (MMSE);
• Change from baseline in biochemistry and hematology safety laboratory tests;
• Time to achieve clearance of vector genomes in plasma and semen (male only)
• Incidence of treatment emergent suicidal ideation or behavior as measured using the C-SSRS.
• Change from baseline in MRI including oedema, inflammation, pre-symptomatic/symptomatic hemorrhage and other structural changes

E.5.1.1

Timepoint(s) of evaluation of this end point

26 weeks and 5 years

E.5.2

Secondary end point(s)

Over a 26-week initial and 5-year total follow up period:
• Change from baseline in PGRN protein levels in CSF and blood;
Over a 52-week initial and 5-year total follow up period:
• Change from baseline in NfL levels in CSF and blood
Over a 5-year follow up period:
• Change from baseline in CDR+NACC FTLD-SB score;
• Change in CGI C, PGI-C, CaGI-C

E.5.2.1

Timepoint(s) of evaluation of this end point

26 weeks and 5 years

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

Yes

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

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)

Yes

E.7.1.1

First administration to humans

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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

United States

Belgium

France

Italy

Netherlands

Poland

Spain

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

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Participants will not be enrolled if they are unable to consent at initial screening/consent, but patients' disease may progress during the 5 year follow up period of the
study, such that they will lack capacity to consent for themselves.

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

F.4.2.2

In the whole clinical trial

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)

Participants will receive their usual standard of care.

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

2023-03-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-01-12

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

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