Um estudo para avaliar os efeitos da vacinação ACI-7104.056 em pacientes com estágios iniciais da doença de Parkinson (VacSYn)

Inclusion criteria for study Part 1 and Part 2:

1. Confirmed diagnosis of clinically established early PD using the modified Movement Disorder Society criteria, after excluding any other known or suspected cause of PD. The presence of motor symptoms should not be of more than 2 years at screening.
2. Monotherapy treatment with L-Dopa at 300 mg per day, with a stable dose prior to baseline for 3 months. The participant has a reasonably low likelihood of requiring dose adjustment within the next 6 to 12 months after enrolment. Any exception to this rule has to be previously agreed with the Sponsor medical monitor.
3. Male or female.
4. Aged ≥40 to ≤75 years.
5. Body weight range of ≥45 kg to ≤110 kg (99 to 242 lbs) and a body mass index of ≥18 to ≤34 kg/m2.
6. Modified Hoehn-Yahr (H&Y) Stage I to II.
7. A centrally read screening brain DaT-SPECT consistent with PD.
8. Participants can understand the informed consent form, are able and willing to provide documented informed consent, and can be expected to comply with the study protocol according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and local regulations.
9. Female participants must be postmenopausal for at least 1 year and/or surgically sterilized, or, if they are female of childbearing potential or not postmenopausal, they must have a negative blood pregnancy test at screening and be willing to use highly effective methods of contraception from the screening visit until the end of the safety follow-up period (approximately 108 weeks). Male participants in the trial with female partners of childbearing potential are required to use barrier methods of contraception (condoms with spermicide) in addition to contraceptive measures used by female partners during the whole study duration. Men must refrain from donating sperm during this same period. The female partners of male participants should use a highly effective method of contraception with a failure rate of less than 1% per year from screening until the end of the safety follow-up period (approximately 108 weeks). The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion criteria for study Part 1 and Part 2:

1. Medical history indicating a Parkinsonian syndrome other than idiopathic PD, including but not limited to, progressive supranuclear palsy, multiple system atrophy, drug induced parkinsonism, essential tremor, vascular parkinsonism, primary dystonia.

2. Known carriers of certain familial PD gene mutations (PRKN, PINK1, DJ1, LRRK2).

3. History of PD-related freezing episodes or falls.

4. History of brain surgery or any neurosurgical procedures.

5. Reside in a nursing home or assisted care facility.

6. A history of cancer within 5 years of baseline with the exception of fully excised non melanoma skin cancers or nonmetastatic prostate cancer that has been stable for at least 6 months, or cervical intraepithelial neoplasia stage I uterine cancer.

7. History of and/or screening brain MRI scan indicative of, clinically significant abnormality including but not limited to prior hemorrhage or infarct >1 cm3 or >3 lacunar infarcts.

8. Diagnosis of a significant central nervous system disease other than PD (including but not limited to Huntington's disease, normal pressure hydrocephalus, cerebrovascular disease including stroke, fronto-temporal dementia, Alzheimer's disease, dementia with Lewy bodies, multiple sclerosis, brain tumor); history of repeated head injury; history of epilepsy or seizure disorder other than febrile seizures as a child.

9. Presence of psychiatric symptoms (eg, confusion, hallucination, delusion, excitation, delirium, abnormal behavior at screening and baseline). Note: mild depression, depressive mood, or mild anxiety arising in the context of PD are not exclusionary.

10. Clinically significant concomitant disease or condition within 6 months prior to screening, or as specified below, that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the study participant:

    1. Autoimmune disease (except well controlled conditions as specified in the study protocol with decision making on a case per case basis).
    2. Any active infectious disease and/or any febrile illness (including noninfectious) within 1 week prior to first dose administration.
    3. Any current psychiatric diagnosis that may interfere with the participant's ability to perform the study.
    4. Female participants who are pregnant or breastfeeding or intending to become pregnant during the study.
    5. Myocardial infarction within 12 months of baseline.
    6. Known history or documentation of uncontrolled hypotension or bradycardia on more than 1 occasion within 3 months prior to baseline and known history or documentation of uncontrolled hypertension on more than 1 occasion within 3 months prior to baseline (up to Principal Investigator's discretion). Resting pulse rate >100 or <45 bpm. A QT interval corrected using Fridericia's formula measurement of 450 ms for males or 470 ms for females at screening or a family history of long QT-syndrome. Intermittent second or third degree atrioventricular (AV) heart block or AV dissociation or any other clinically significant cardiovascular disease.
    7. Clinically significant abnormalities in laboratory test results at the screening visit (specified in more detail in a separate document), positive result for acute or chronic infectious Hepatitis B virus (HBV; [ie, Hepatitis B surface antigen (HBsAg) positive test]), for Hepatitis C virus (HCV), or for Human Immunodeficiency Virus (HIV) 1 or 2. Successfully treated participants with HCV (undetectable HCV RNA) are eligible for enrolment. Participants who are immune due to HBV natural infection or HBV vaccination are eligible.
    8. Use of any of the following: monoamine oxidase (MAO)-B inhibitors, catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone, opicapone, tolcapone), amantadine, adenosine A2a antagonists or anticholinergics, or dopaminergic medication (both ergot and nonergot [pramipexole, ropinirole, rotigotine] dopamine agonists) for more than a total of 90 days or within 90 days of baseline.
    9. Antiepileptic medication (eg, valproate) for nonseizure-related treatment that has not remained stable for at least 60 days prior to baseline.
    10. Antidepressant use that has not remained stable for at least 2 months prior to baseline.
    11. Use of any of the following medications within 90 days prior to baseline: metoclopramide, alpha methyldopa, flunarizine, amoxapine, amphetamine derivatives, reserpine, bupropion, buspirone, cocaine, cannabis, mazindol, methamphetamine, methylphenidate, phentermine, phenylpropanolamine, and modafinil. Exceptional use of norephedrine is allowed (eg, treatment for a cold).
    12. Previous participation in a clinical trial using an active immunotherapy against PD, unless there is firm evidence that the participant received placebo only and the placebo formulation is not expected to induce any specific immune response.
    13. Previous treatment with any investigational and/or marketed passive immunotherapy against PD within 6 months before screening or 5 half-lives, whichever is longer, unless there is firm evidence that the participant received placebo only (in the case of any IMP administered within the frame of a clinical trial participation).
    14. Participation in previous clinical trials for PD and/or for neurological disorders using any small molecule drug with a washout <30 days or <5 half lives of the drug, whichever is longer before screening, unless there is firm evidence that the participant received placebo only.
    15. Concomitant participation in any other clinical trial using experimental or approved medications or therapies (eg, device, stem cell). This does not include noninterventional devices for disease tracking or imaging studies.
    16. Immunomodulating and immunosuppressant drugs including oral corticosteroids within 30 days prior to baseline.
    17. Allergy to any of the components of the study treatment.
    18. Any contraindications to obtaining a brain MRI or DaT-SPECT, getting a lumbar puncture or receiving IM injections.

11. Current, or history of, alcohol or drug (including cannabis) abuse or other dependence (except nicotine dependence) within 12 months before screening.

12. Participants with known hypersensitivity to the study treatment or placebo components.

13. Participants who previously received a vaccination (ie, influenza treatment and COVID 19) within the last 4 weeks prior to randomization or standard-of-care immunizations within the last 2 weeks prior to randomization.

14. Participants being treated with any anticoagulants or antiplatelet drugs, except aspirin at doses of 100 mg daily or lower.

Inclusion criteria for the extension of study Part 1:

1. Participants having completed study Part 1 and having received all 6 administrations of the study treatment as per protocol.
2. Participants can understand the informed consent form, are able and willing to provide documented informed consent, and are expected to comply with the study protocol according to ICH requirements and local regulations.
3. Inclusion criterion 9 from study Part 1 regarding prevention of pregnancy/contraception must continue to apply.

Exclusion criteria for the extension of study Part 1:

Exclusion criteria for the study Part 1 and Part 2 are applicable and should be reassessed for Extension of study Part 1 relative to the rescreening period, with the following exceptions:

1. Exclusion criterion 3: in addition to the history of PD-related freezing episodes or falls, history or presence of severe dyskinesias should be excluded.
2. Exclusion criteria 6, 9, 10e, 10f, 10k, and 10p should be evaluated based on time windows anchored to Visit 16 instead of baseline and Visit 15 instead of screening.
3. Exclusion criterion 10g: the testing for HBV, HCV, and/or HIV can be repeated if considered clinically relevant by the investigator.
4. Exclusion criteria 10h, 10i, and 10j are not applicable for study Part 1 Extension.
5. Exclusion criterion 12 does not refer to treatment with ACI-7104.056 within study Part 1.
6. Exclusion criterion 13 should be evaluated prior to the first booster dose administration in study Part 1 Extension instead of randomization.