Study Assessing Tolerability and Safety and Exploring the Immunogenicity and Therapeutic Activity of AFFITOPE® PD01A in PD-GBA Patients

A Randomized, Placebo-controlled, Parallel Group, Patient-blind, Single-center Phase I Pilot Study Assessing Tolerability and Safety and Exploring the Immunogenicity and Therapeutic Activity of AFFITOPE® PD01A, a New Vaccine Against Alpha-synuclein, in Patients With PD-GBA

This is a randomized, placebo-controlled, parallel group, patient-blind, single-center phase I clinical trial of repeated once every 4 weeks administration by subcutaneous injection of AFFITOPE® PD01A, adsorbed to aluminium oxide in 30 patients with PD-GBA over a treatment period of 8 weeks. Patients will be randomized in a 2:1 ratio to two different treatment groups: A) 75 µg AFFITOPE® PD01A, adsorbed to aluminium oxide and B) placebo (= 1 mg aluminium oxide).

Over a study duration of 52 weeks, each patient will receive 3 injections of AFFITOPE® PD01A or placebo during the participation in the clinical trial. Patients will either receive 75 µg AFFITOPE® PD01A adsorbed to 1 mg aluminium oxide or placebo (=1mg aluminium oxide). The treatment group consists of 20 PDGBA patients, the placebo group of 10 PDGBA patients. Male and female patients aged 40 to 80 years can participate in the trial.

AFF010 is part of the project MULTISYN funded by the European Commission (FP7-HEALTH-2013-INNOVATION-1 project; N° HEALTH-F4-2013-602646).

Study Overview

• Status: Withdrawn
• Conditions: Parkinson's Disease
• Intervention / Treatment: Biological: Adjuvant without active component; Biological: AFFITOPE® PD01A + Adjuvant

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • University Hospital Tübingen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of Parkinson's disease and confirmed carrier status for a heterozygous GBA mutation (PDGBA)
• Individuals who present in Hoehn&Yahr Stages I/II/III and fulfill the United Kingdom Parkinson's Disease Society Brain Bank Criteria
• Confirmed carrier status for a heterozygous GBA mutation (PDGBA)-The result of the MRI scan of the patient's brain has to be consistent with the diagnosis of PD
• Written informed consent signed and dated by the patient and, preferentially, the caregiver (caregiver is not mandatory)
• Age between 40 and 80
• In the investigator's opinion, does not have visual or auditory impairments that would reduce the patients' ability to complete study questionnaires or be unable to receive instructions for these
• Female patients of childbearing potential are eligible if they use a medically accepted contraceptive method
• A potential participant treated with conventional PD therapies must be on stable doses for at least 3 months prior to Visit 1 and during the entire trial period
• Accepted PD medications include the following: levodopa (alone or in combination with benserazide, carbidopa), catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone), amantadine, non-ergot dopamine agonists (pramipexol, ropinirol, rotigotine), monoamine oxidase-B (MAO-B) inhibitors (rasagiline, selegiline) and anticholinergic medication
• A potential participant should be on stable doses of all medications he/she is taking because of consisting illnesses according to medical history (except PD therapies, these will be recorded separately) for at least 30 days prior to Visit 1 if considered relevant by the investigator
• Able to communicate well with the investigator, to understand and comply with the requirements of the study

Exclusion Criteria:

• Pregnant women
• Sexually active women of childbearing potential who are not using a medically accepted birth control method
• Participation in another clinical trial within 3 months before Visit 1
• History of questionable compliance to visit schedule; patients not expected to complete the clinical trial
• Presence or history of allergy to components of the vaccine if considered relevant by the investigator
• Contraindication for MRI imaging such as metallic implants (e.g. endoprosthesis, stents, cardiac pacemakers) which are not MR compatible at 3.0 Tesla with the given MR protocol, other foreign metal bodies (e.g. bullets, metal splinters, e.g.) or claustrophobia
• Missing agreement to be informed about incident findings and consultation of a neuroradiologist
• Contraindication for PET, that is, pregnancy and breast feeding.
• Ongoing participation in other interventional studies or clinical trials using radiotracers
• Dementia according to Diagnostic and Statistical Manual (DSM) IV criteria
• History and/or presence of autoimmune disease, if considered relevant by the investigator
• Recent (≤3 years since last specific treatment) history of cancer (Exceptions: non-melanoma skin cancer, intraepithelial cervical neoplasia)
• Active infectious disease (e.g., Hepatitis B, C)
• Presence and/or history of Immunodeficiency (e.g., HIV)
• Significant systemic illness (e.g., chronic renal failure, chronic liver disease, poorly controlled diabetes, poorly controlled congestive heart failure, other deficiencies), if considered relevant by the investigator
• History of significant psychiatric illness such as schizophrenia, bipolar affective disorder or psychotic depression
• Parkinson-like disease secondary to drug therapy side effects (e.g., due to exposure to medications that deplete dopamine [reserpine, tetrabenazine] or block dopamine receptors [neuroleptics, antiemetics])
• Parkinson-plus syndromes (e.g., multiple system atrophy (MSA), progressive supranuclear palsy (PSP)), Dementia with Lewy Bodies (DLB)
• Heredodegenerative disorders other than PDGBA, evidence for other genetic forms of PD (e.g. LRRK2, Parkin gene mutations)
• Alcoholism or substance abuse within the past year (alcohol or drug intoxication)
• Prior and/or current treatment with experimental immunotherapeutics including Intravenous Immunoglobulin (IVIG)

• Prior and/or current treatment with immune modulating drugs:

  1. Interleukins, Interferons, Tumor Necrosis Factor (TNF) and analogues, colony stimulating factor compounds
  2. Ciclosporin, Tacrolimus, Sirolimus and analogues
  3. Cytostatic drugs and certain DMARD for rheumatoid arthritis (and similar autoimmune disorders) (e.g. Cyclophosphamid, Azathioprin, methotrexate, sulfasalazine, leflunomide, sodium aurothiomalate (Gold), cyclosporin) and analogues
  4. Systemic (gluco)corticoid therapy
  5. All antibody therapies (e.g., anti cluster of differentiation 3 (CD3), anti cluster of differentiation 25 (CD25) or also anti-lymphocyte globulins) that might modulate, enhance or weaken an immune response
• Change in dose of standard treatments for PD within 3 months prior to Visit 1
• Change in dose of previous and current medications which the patient is taking because of consisting illnesses according medical history (except PD therapies, these will be recorded separately) within the last 30 days prior to Visit 1, if clinically relevant
• Treatment with deep brain stimulation
• Venous status rendering it impossible to place an i.v. access

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AFFITOPE® PD01A + Adjuvant; 3 injections of 75µg AFFITOPE® PD01A/ adjuvanted, once every 4 weeks	Biological: AFFITOPE® PD01A + Adjuvant; s.c. injection
Placebo Comparator: Adjuvant without active component; 3 injections of Placebo once every 4 weeks	Biological: Adjuvant without active component; s.c. injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who withdraw due to Adverse Events (AEs) and reason for withdrawal		52 weeks
Occurrence of any Serious Adverse Event (SAE) possibly, probably or definitely related to the study vaccine at any time during the study		52 weeks
Occurrence of any Grade 3 or higher AEs possibly, probably or definitely related to the study vaccine within 4 weeks after the vaccinations		12 weeks (week 0 to 12)
Occurrence of solicited local AEs	Injection site pain, erythema (redness), hyperthermia at injection site, itching, edema (swelling), induration [hardening], granuloma within 1 week (Day 1-7) after the vaccinations: Severity and duration	up to 52 weeks
Occurrence of solicited systemic AEs	Headache, myalgia (muscle pain), fever, fatigue, nausea within 1 week (Day 1-7) after the vaccinations: Severity and duration.	up to 52 weeks
Occurrence of unsolicited non-serious AEs within four weeks after the vaccinations	Severity, duration and relationship to vaccination	12 weeks (week 0 to 12)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunological activity of AFFITOPE® vaccine PD01A over time (study period)	Titer of immunoglobulin G (IgG) Abs specific for the immunizing peptide (PD01A), the carrier (KLH) and the target (targeted native α-Synuclein (aSyn) epitope coupled to bovine serum albumin (BSA) (mandatory) or presented in different forms - particularly monomers, pre-fibrils and fibrils (optional)) assessed by Enzyme-Linked Immunosorbent Assay (ELlSA) (or an equivalent method)	52 weeks
Imaging efficacy variables at visit 6 (or EDV) compared to baseline	11C-Pittsburgh Compound B (11C-PIB), 18F-Fluorodeoxyglucose-Positron Emission Tomography (18F-FDG-PET), resting-state functional magnetic resonance imaging (fMRI), diffusion-weighted/tensor magnetic resonance imaging (MRI), Magnetic Resonance-Spectroscopy	52 weeks
Biomarker data at visit 6 (or EDV) compared to baseline	β-Glucocerebrosidase (GCase) enzyme activity	52 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I, II, III and IV at visit 5 and visit 6 (or EDV) compared to baseline	Change in motor/non-motor symptoms over time	52 weeks
Parkinson's Disease Quality of Life-39 (PDQ-39) at visit 5 and visit 6 (or EDV) compared to baseline	Change in non-motor PD symptoms over time	52 weeks
Investigator's global evaluation scale at visit 5 and visit 6 (or EDV)	Change in motor PD symptoms over time. The overall change in the severity of patient's illness, compared to patient's condition at the start of this clinical trial (Visit 1).	52 weeks
Cognitive scales at visit 5 and visit 6 (or EDV) compared to baseline	Change in non-motor PD symptoms over time (MOCA, Trail Making Test (TMF) A and B)	52 weeks
Geriatric Depression Scale at visit 5 and visit 6 (or EDV) compared to baseline	Change in non-motor PD symptoms over time	52 weeks

Collaborators and Investigators

• Sponsor: Affiris AG
• Collaborators: University Hospital Tuebingen
• Investigators: Principal Investigator: Thomas Gasser, Prof. Dr., University Hospital Tübingen, 72076 Tübingen, Germany

Study record dates

Study Major Dates

• Primary Completion (Anticipated): October 1, 2017

Study Registration Dates

• First Submitted: April 26, 2016
• First Submitted That Met QC Criteria: April 28, 2016
• First Posted (Estimate): May 2, 2016

Study Record Updates

• Last Update Posted (Estimate): August 5, 2016
• Last Update Submitted That Met QC Criteria: August 4, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: GBA mutation
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: AFF010; 2016-001462-28 (EudraCT Number)