A 24-month Phase 1 Pilot Study of AADvac1 in Patients With Non Fluent Primary Progressive Aphasia

Primary Progressive Nonfluent Aphasia Clinical Trial

— AIDA  

Official title:

A 24-month Randomised Parallel Group Single-blinded Multi-centre Phase 1 Pilot Study of AADvac1 in Patients With Non Fluent Primary Progressive Aphasia

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03174886
• Other study ID #: AC-TP-001
• Secondary ID: 2017-000643-41
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: July 31, 2017
• Est. completion date: November 2020

Study information

• Verified date: November 2019
• Source: Axon Neuroscience SE
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a pilot trial evaluating the safety and immunogenicity of AADvac1 in patients with the non-fluent variant of Primary Progressive Aphasia.

50% of participants will receive the 40 µg dosage of AADvac1 and 50% of participants will receive the 160 µg dosage of AADvac1. No placebo is used.

Description:

The non-fluent variant of Primary progressive Aphasia (nfvPPA) is a chronic progressive neurodegenerative disorder of the brain. Over the course of the disease, pathological proteins accumulate in the brain, damaging neurons, thus causing them to lose their connections and die.

No treatments are currently available; symptomatic medications are used off-label in nfvPPA.

AADvac1 is designed to raise antibodies against pathological tau protein (the primary constituent of neurofibrillary pathology, which is the underlying cause of disease in ~80% of nfvPPA cases). These antibodies are expected to prevent tau protein from aggregating, to facilitate the removal of tau protein aggregates and prevent the spreading of pathology, slowing or halting the progress of the disease.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 33
• Est. completion date: November 2020
• Est. primary completion date: November 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Inclusion criteria

1. Patient has a clinical diagnosis of non-fluent/agrammatic variant PPA according to the criteria by Gorno-Tempini et al. (2011) with evidence of left frontal brain hypometabolism. Patients with right-sided hypometabolism are eligible for the study only if they are left-handed.

2. Patient has a FTLD-CDR language domain score of = 2, and other individual FTLD-CDR domain scores = 1.

3. Patient's age is 18 - 85 years inclusive at the time of having provided informed consent.

4. Patient has adequate visual and auditory abilities and premorbid local language skills to allow neuropsychological testing.

5. Sexually active female patients must be using highly effective contraception methods, or be surgically sterile, or be at least 2 years post-menopausal.

6. Sexually active male patients must be using highly effective contraception methods, or be surgically sterile.

7. Patient and caregiver have signed and dated written informed consent.

8. Availability of a partner/caregiver knowing the patient and being able to accompany the patient to the visits.

9. Patient is legally competent.

Exclusion Criteria:

1. The patient's brain MRI is incompatible with a diagnosis of nfvPPA.

2. Patient has a history or evidence of a central nervous system (CNS) disorder other than nfvPPA which may cause symptoms of aphasia or dementia (Alzheimer's disease, Dementia with Lewy Bodies, inflammatory/demyelinating CNS conditions, Creutzfeldt-Jakob disease, Huntington's disease, etc.)

3. Patient has a history or currently suffers from a significant psychiatric illness such as schizophrenia, any type of psychotic disorder or bipolar affective disorder.

4. Patient has a history or evidence of cerebrovascular disease (ischemic or haemorrhagic stroke), or diagnosis of possible, probable or definite vascular dementia.

5. Patient has Wernicke's encephalopathy.

6. Patient has metabolic or toxic encephalopathy or dementia due to a general medical condition.

7. Patient suffers from hypothyroidism, defined as thyroid-stimulating hormone elevation > 5.000 mcIU/mL, and/or fT4 levels < 0.7 ng/dL. Patients with corrected hypothyroidism are eligible for the study provided that treatment has been stable for 12 weeks before study entry.

8. Patient has a known pathogenic mutation in GRN or C9orf72.

9. Presence or history of allergy to components of the vaccine.

10. Presence and/or history of immunodeficiency (e.g., HIV).

11. Patient is currently being treated with immunosuppressive drugs.

12. Patient has a history and/or currently suffers from a clinically significant autoimmune disease, or is expected to receive immunosuppressive or immunomodulatory treatment at the present or in the future.

13. Patient has a recent (= 5 years since last specific treatment) history of cancer (Exceptions: basal cell carcinoma, intraepithelial cervical neoplasia).

14. Patient has an active infectious disease (e.g., Hepatitis B, C).

15. Patient had a myocardial infarction within the last 2 years.

16. Patient has a current clinically important systemic illness that is likely to result in deterioration of the patient's condition or affect the subject's safety during the study:

1. poorly controlled congestive heart failure (New York Heart Association [NYHA] score = 3),

2. poorly controlled diabetes,

3. severe renal insufficiency (Estimated glomerular filtration rate < 30 mL/min),

4. chronic liver disease - ALT (alanine aminotransferase) > 2x upper limit of normal range (ULN), AST (aspartate aminotransferase) > 2x ULN

5. other clinically significant systemic illness, if considered relevant by the investigator.

17. Patient had alcohol or drug dependence within the past year.

18. Patient has a current diagnosis of epilepsy.

19. Pregnant or breastfeeding women.

20. Patient has participated in another interventional clinical trial within 12 weeks before Visit 01.

21. Patient has contraindication for MRI imaging such as metallic endoprosthesis or MRI-incompatible stent implantation.

22. Patient has contraindications for other study procedures, such as CSF sampling.

23. Patient had surgery (under general anaesthesia) within 12 weeks prior to Visit 01 and/or scheduled surgery (under general anaesthesia) during the whole study period.

24. Patient is currently being treated or was treated in the past with any active vaccines for a neurodegenerative disorder.

25. Patients not expected to complete the clinical trial.

26. Patient, in the opinion of the investigator, is unlikely to comply with the clinical study protocol, or is unsuitable for other reasons.

27. Patient is dependent from Sponsor or investigator (e.g. as an employee or as a relative).

Related Conditions & MeSH terms

• Aphasia
• Aphasia, Broca
• Aphasia, Primary Progressive
• Frontotemporal Dementia
• Pick Disease of the Brain
• Primary Progressive Nonfluent Aphasia

Intervention

Drug:
• AADvac1 40 µg
Active immunotherapy against neurofibrillary pathology.
• AADvac1 160 µg
Active immunotherapy against neurofibrillary pathology.

Locations

Country	Name	City	State
Germany	Universitätsmedizin Göttingen, Klinik für Psychiatrie und Psychotherapie	Göttingen
Germany	Klinikum Rechts der Isar der TU München, Klinik und Poliklinik für Psychiatrie und Psychotherapie	München
Germany	Universitätsklinikum Ulm	Ulm

Sponsors (1)

Lead Sponsor	Collaborator
Axon Neuroscience SE

Country where clinical trial is conducted

Germany, 

References & Publications (3)

Kontsekova E, Zilka N, Kovacech B, Novak P, Novak M. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer's disease model. Alzheimers Res Ther. 2014 Aug 1;6(4):44. doi: 10.1186/alzrt278. eCollection 2014. — View Citation

Kontsekova E, Zilka N, Kovacech B, Skrabana R, Novak M. Identification of structural determinants on tau protein essential for its pathological function: novel therapeutic target for tau immunotherapy in Alzheimer's disease. Alzheimers Res Ther. 2014 Aug 1;6(4):45. doi: 10.1186/alzrt277. eCollection 2014. — View Citation

Novak P, Schmidt R, Kontsekova E, Zilka N, Kovacech B, Skrabana R, Vince-Kazmerova Z, Katina S, Fialova L, Prcina M, Parrak V, Dal-Bianco P, Brunner M, Staffen W, Rainer M, Ondrus M, Ropele S, Smisek M, Sivak R, Winblad B, Novak M. Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet Neurol. 2017 Feb;16(2):123-134. doi: 10.1016/S1474-4422(16)30331-3. Epub 2016 Dec 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cerebrospinal fluid (CSF) biomarkers	Temporal change in total CSF neurogranin, phosphorylated neurofilament heavy chain protein, ubiquitin, ß-synuclein, tau protein, phospho-tau pT181, N-terminal tau protein, amyloid ß1-40, amyloid-ß1-42, ubiquitin, a-, ß- and ?-synuclein, Chitinase-3-like protein (YKL-40), Monocyte chemoattractant protein-1 (MCP-1), and other CSF markers	24 months
Other	Serum neurofilament light chain protein (and other blood biomarkers of nfvPPA)	Temporal change in neurofilament light chain protein and other blood biomarkers (exploratory measure; biomarker panel to be finalised based on the state of the art at the time of analysis)	24 months
Other	Magnetic resonance imaging (MRI) volumetry	Temporal change in whole brain volume and set of regions of interest, as measured by MRI	24 months
Other	Frontotemporal lobar degeneration - Clinical Dementia Rating - Sum of Boxes (FTLD-CDR-SB)	Temporal change in FTLD-CDR SB score	24 months
Other	Clinician's Global Impression - Improvement (CGI-I)	Temporal change in CGI-I score	24 months
Other	Instrumental Activities of Daily Living (IADL)	Temporal change in Amsterdam IADL	24 months
Other	Custom Cognitive Battery	Temporal change in the custom Cognitive Battery score	24 months
Other	Addenbrooke's Cognitive Examination	Temporal change in Addenbrooke's Cognitive Examination score	24 months
Other	Unified Parkinson's disease rating scale (UPDRS) part III	Temporal change in UPDRS part III score	24 months
Other	Frontal Systems Behavior Scale (FrSBe)	Temporal change in FrSBe score	24 months
Other	Immune cell (granulocyte, monocyte, and lymphocyte populations)	Temporal change in immunological variables (monocytes, lymphocytes, basophil and neutrophil granulocytes; a range of lymphocyte sub-populations - CD3+, CD3+/CD4+, CD3+/CD4+/CD28+, CD3+/CD4+/CD28+/CD45RA+, CD3+/CD4+/CD28+/CD45RO+, CD3+/CD8+, CD3+/CD8+/CD28+, CD3+/CD8+/CD28+/CD45RA+, CD3+/CD8+/CD28+/CD45RO+) over 24 months	24 months
Other	Correlation of a range of potential immunological predictors with IgG antibody titres against Axon Peptide 108	Correlation of measures of immune response with immunological variables (monocytes, lymphocytes, basophil and neutrophil granulocytes; a range of lymphocyte sub-populations - CD3+, CD3+/CD4+, CD3+/CD4+/CD28+, CD3+/CD4+/CD28+/CD45RA+, CD3+/CD4+/CD28+/CD45RO+, CD3+/CD8+, CD3+/CD8+/CD28+, CD3+/CD8+/CD28+/CD45RA+, CD3+/CD8+/CD28+/CD45RO+) will individually be assessed for correlation with IgG antibody titres. The possibility of multiple independent predictors of the antibody response will be examined using regression trees analysis)	24 months
Primary	Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	The safety assessment is based on the number, type and severity of adverse events (AEs).	25 months
Primary	Immunogenicity (Percentage of patients who develop an IgG immune response, geometric mean titre of titre of antibodies against Axon Peptide 108, IgG to IgM ratio of antibodies against Axon Peptide 108)	AADvac1 depends on raising antibodies that mediate its treatment effects. Immunogenicity assessment includes: Percentage of AADvac1-treated patients who develop an immune response (responder rate), geometric mean titre of antibodies against Axon Peptide 108, IgG to IgM ratio of antibodies against Axon Peptide 108.	24 months