Clinical trial NCT06182085: Study to Assess Safety and Efficacy of PRI-002 in Patients With MCI to Mild Dementia Due to Alzheimer's Disease (AD)
Official title: Randomised, Double-blind, Placebo-controlled Study to Assess Safety and Efficacy of PRI-002 in Patients With MCI to Mild Dementia Due to Alzheimer's Disease (AD) (PRImus-AD)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease
Alzheimer's Disease, Early Onset
Keywords: PRI-002
PRImus-AD
Clinical Dementia Rating Sum of Boxes (CDR-SB)
Prodromal Alzheimer's disease
Mild Alzheimer's disease dementia
Lead sponsor: PRInnovation GmbH
Sponsor class: INDUSTRY
Collaborators: name: Priavoid
name: Federal Agency for Disruptive Innovation - SPRIN-D
name: Julius Clinical
First posted: 2023-12-26
Enrollment: 270
Sex: ALL
Minimum age (years): 55
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Alzheimer's disease (AD) is the most common form of dementia. In the brains of people with AD, certain small substances stick together. This leads to changes in thinking and behaviour. The company PRInnovation is developing a new treatment for Alzheimer's disease, called PRI-002. It is thought that PRI-002 can cut the sticked substances back into small pieces. That would reduce the effects of Alzheimer's disease. In the current study the investigators examine whether PRI-002 is safe and effective in participants with mild cognitive impairment (MCI) or mild dementia due to AD.

Detailed description: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The post-mortem pathology of AD is mainly characterised by neurodegeneration as well as extracellular amyloid plaques and intracellular neurofibrillary tangles. Research suggests that the amyloid-β-peptide (Aβ) aggregation plays a major role in the development of AD, while Aβ oligomers are thought to be the most toxic species. Therefore, various strategies to develop AD therapeutics address Aβ and some examples include trying to reduce its formation, inhibit its aggregation to fibrils or enhancing its clearance.

PRI-002 is being investigated as a possible treatment for cognitive impairment due to AD. PRI-002 is an all D-amino acid peptide (all-D-peptide) consisting of a rationally designed primary structure, resulting in efficient removal of Aβ oligomers. PRI-002 specifically aims to eliminate neurotoxic Aβ oligomers by disassembling prion-like behaving Aβ oligomers into non-toxic Aβ monomer units. This therapeutic principle is new and unique and differs from that of other amyloid related drug candidates currently in clinical development, which aim to increase the degradation rate of different Aβ species.

The current trial is a Phase 2 proof-of-concept study to further investigate the safety and efficacy of PRI-002 in patients with mild cognitive impairment (MCI) or mild dementia due to AD.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated written informed consent obtained from the subject and study companion in accordance with applicable regulations
2. Male or female, aged 55 to 80 years, inclusive
3. For female subjects: not being of child-bearing potential. This is defined as either permanently sterilised (via hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as no menses for 12 months without an alternative medical cause)
4. Body mass index (BMI) between 18.5 and 30.0 kg/m2, inclusive, (weight in kilograms and height in meters will be combined to report BMI in kg/m2)
5. Diagnosed with MCI due to AD or mild dementia due to AD, according to the NIA-AA criteria11
6. MMSE score of 22 to 30 points on a scale, inclusive, the highest score achievable is 30
7. Repeatable battery for the assessment of neuropsychological status - delayed memory index (RBANS-DMI) score ≤85 units on a scale
8. CDR global score of 0.5 or 1 with a memory score ≥0.5 units on a scale
9. Confirmation of AD diagnosis, by

   * CSF biomarker profile reflecting AD, according to NIA-AA11, or
   * existing positive amyloid positron emission tomography (PET) evidence
10. Fluency in local language and evidence of adequate intellectual functioning in the opinion of the investigator
11. Having a reliable informant or caregiver who is willing and able to act as the study companion throughout the duration of the subject's participation. The subject and the study companion must have frequent interaction (defined as a minimum of 6 hours/week on average) according to subject's report

Exclusion Criteria:

1. Unable to give informed consent in accordance with applicable regulations
2. Diagnosed with moderate or severe dementia due to AD according to National Institute on Aging - Alzheimer's Association (NIA-AA)
3. History or evidence of any other central nervous system (CNS) disorder(s) that could be interpreted as a cause of cognitive impairment or dementia
4. History of known or suspected seizures, loss of consciousness, or significant head trauma within 2 years before Screening
5. History of known or suspected stroke or transient ischaemic attack (TIA) within 2 years before Screening
6. Evidence of other clinically significant lesions on brain MRI (Fazekas score 312)
7. History or presence of clinically evident cerebrovascular disease (diagnosis of possible, probable, or definite vascular dementia)
8. Other significant pathological findings on brain MRI (for example more than 10 microhaemorrhages or a single macrohaemorrhage \>10 mm at the greatest diameter)
9. Unstable medical, neurological, or psychiatric condition, or presence of major depressive episode at Screening
10. Life-time history of schizophrenia or history of uncontrolled bipolar disorder within 5 years before Screening
11. Having a bleeding disorder that is not under adequate control (defined as a platelet count \<50 000 or international normalised ratio \[INR\] \>1.5). Participants who are on anticoagulant therapy (for example, warfarin), should have their anticoagulant status optimised and be on a stable dose for 30 days before Screening. Anticoagulant therapy (e.g., clopidogrel bisulfate, carbasalate calcium 100 mg/day, or aspirin 325 mg/day or less) is permitted provided this therapy does not represent a contraindication for a lumbar puncture and CSF sampling (if CSF sampling is required in the absence of historical PET evidence).
12. Having significant kidney disease as indicated by either of the following:

    * Creatinine clearance (eGFR) ≤30 mL/min/1.73m2) as estimated using the modification of diet in renal disease (MDRD) method, or
    * Creatinine ≥2 mg/dL.
13. Having impaired hepatic function as indicated by aspartate amino transferase (AST) or alanine amino transferase (ALT) \>3-fold the upper limit of normal (ULN), or total bilirubin \>2-fold ULN, at Screening.
14. Known to be human immunodeficiency virus (HIV) positive
15. Known to be hepatitis C or chronic hepatitis B positive
16. Having any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, MRI, or ECG at Screening or Baseline which in the opinion of the investigator requires further investigation or treatment or which may interfere with study procedures or safety
17. Use of licensed symptomatic AD medication for less than 90 days or at a non-stable dose over the past 90 days at Baseline (for example acetylcholinesterase inhibitors, memantine, ginkgo)
18. Use of anti-Aβ monoclonal antibody therapy at Baseline
19. Treatment with one of the following substances:

    1. Typical antipsychotic or neuroleptic medication within 90 days before Screening (except for

       ≤1 mg risperidon, and ≤300 mg quetiapin).
    2. Chronic use of opiates or opioids (including long-acting opioid medication) within 90 days before Screening
    3. Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 30 days before Screening
    4. Chronic use of benzodiazepines, barbiturates, or hypnotics within 90 days before Screening
20. Contraindication to MRI. Patients with MRI compatible pacemakers may be allowed to enter the study.
21. Prior or current participation in a clinical trial testing active immunisation against Aβ or tau.
22. Participation in a clinical trial and having taken at least 1 dose of the investigational medicinal product (IMP), within 5 times the IMP half-life time before Baseline, unless confirmed as having been on placebo.

Primary outcomes:
measure: To evaluate the safety and tolerability of multiple doses of PRI-002 in subjects with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease (AD), based on incidence of drug-related adverse events (AEs).
timeFrame: Baseline to week 48.
measure: To evaluate the efficacy of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB).
timeFrame: Baseline to week 48.
Secondary outcomes:
measure: To evaluate safety and tolerability of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on AEs recorded in all 3 treatment arms.
timeFrame: Baseline to week 48.
measure: To evaluate safety and tolerability of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on amyloid related imaging abnormalities oedema (ARIA-E) and haemosiderin (ARIA-H).
timeFrame: Baseline to week 48.
measure: To evaluate safety and tolerability of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on treatment discontinuations due to AEs.
timeFrame: Baseline to week 48.
measure: To evaluate clinical outcome measures in subjects with MCI or mild dementia due to AD based on psychometric testing.
timeFrame: Baseline to week 48.
measure: To evaluate cerebrospinal fluid (CSF) biomarkers changes after mutiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.
timeFrame: Baseline to week 48.
measure: To evaluate plasma biomarker changes after multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.
timeFrame: Baseline to week 48.
measure: To follow drug levels of PRI-002 during multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.
timeFrame: Baseline to week 48.
Other outcomes:
Locations:
city: Brno
country: Czechia
facility: Neuro Health Centrum ltd.
city: Hradec Králové
country: Czechia
facility: NeuropsychiatrieHK, s.r.o.
city: Plzen
country: Czechia
facility: A-Shine, s.r.o.
city: Prague
country: Czechia
facility: CLINTRIAL, s.r.o.
city: Prague
country: Czechia
facility: FORBELI s.r.o.
city: Prague
country: Czechia
facility: Neuropsychiatrie s.r.o.
city: Prague
country: Czechia
facility: INEP Medical s.r.o.
city: Aachen
country: Germany
facility: Uniklinik RWTH Aachen
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mannheim
country: Germany
facility: ISPG - Institut für Studien zur Psychischen Gesundheit
city: München
country: Germany
facility: Technische Universität München
city: Münster
country: Germany
facility: Universitätsklinikum Münster - Klinik für Allgemeine Neurologie
city: Rostock
country: Germany
facility: University Medical Center Rostock
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Bologna
country: Italy
facility: Ospedale Bellaria - IRCCS Istituto delle Scienze Neurologiche
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Chieti
country: Italy
facility: Clinica Neurologica Dipartimento di Neuroscienze e Imaging (CAST)
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Milan
country: Italy
facility: Fondazione IRCCS.Istituto Neurologico Carlo Besta
city: Perugia
country: Italy
facility: Ospedale Santa Maria della Misericordia
city: Rome
country: Italy
facility: AOU Policlinico Umberto I
city: Rome
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli IRCCS
city: Amsterdam
country: Netherlands
facility: Brain Research Center Amsterdam B.V.
city: Den Bosch
country: Netherlands
facility: Brain Research Center Den Bosch B.V.
city: Zwolle
country: Netherlands
facility: Brain Research Center Zwolle B.V.
city: Bialystok
country: Poland
facility: Revit Sp. z o.o., Podlaskie Centrum Psychogeriatrii
city: Kraków
country: Poland
facility: Krakowska Akademia Neurologii Sp. z o.o., Centrum Neurologii Klinicznej
city: Kraków
country: Poland
facility: NeuroCor, ul. Medweciego 7/U12
city: Szczecin
country: Poland
facility: Euromedis Sp. z o.o., Centrum Medyczne EUROMEDIS
city: Warsaw
country: Poland
facility: Neuroprotect Sp. z o.o., Centrum Medyczne NeuroProtect
city: Zabrze
country: Poland
facility: Wielospecjalistyczne Centrum Medyczne "Ibismed" s.c.
city: El Palmar
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
state: Murcia
city: Algorta
country: Spain
facility: Cae Oroitu
state: Vizcaya
city: Barcelona
country: Spain
facility: Fundació ACE - Institut Català de Neurociències Aplicades
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena,
city: Valencia
country: Spain
facility: Hospital Universitario Doctor Peset
city: Zaragoza
country: Spain
facility: Hospital Viamed Montecanal
Study officials:
affiliation: PRInnovation
name: Gerhard Tischler, Dr.
role: STUDY_CHAIR
References: