Study to Assess Safety and Efficacy of PRI-002 in Patients With MCI to Mild Dementia Due to Alzheimer's Disease (AD)

Phase 2

Active, not recruiting

• Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease; Alzheimer's Disease, Early Onset
• Interventions: Drug: PRI-002; Drug: Placebo

• Registration Number: NCT06182085
• Lead Sponsor: PRInnovation GmbH

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.

Study Timeline

• Study First Submitted: 2023-11-29
• Study Start: 2023-12-01
• Study First Submitted QC: 2023-12-13
• Study First Posted: 2023-12-26
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-25
• Last Update Posted: 2025-02-26
• Primary Completion: 2026-04-30
• Study Completion: 2026-04-30

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 270

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PRI-002, dosage arm 1	PRI-002	Daily oral administration of 3 capsules in the morning and evening, lower dose.
Placebo	Placebo	Daily oral administration of 3 capsules in the morning and evening.
PRI-002, dosage arm 2	PRI-002	Daily oral administration of 3 capsules in the morning and evening, higher dose.

Primary Outcome Measures

Name	Time	Method
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).	Baseline to week 48.	Number of subjects in all treatment arms with at least 1 drug-related adverse event (AE) or drug-related serious adverse event (SAE) between baseline and Week 48.
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).	Baseline to week 48.	Change of individual cognitive capablities of subjects in all treatment arms from baseline to week 48 as measured by Clinical Dementia Rating-Sum of Boxes (CDR-SB, minimum value = 0, maximum value = 18, higher values correlate with a worse outcome)).

Secondary Outcome Measures

Name	Time	Method
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).	Baseline to week 48.	Percentage of subjects with ARIA-E and ARIA-H from baseline until end of treatment.
To evaluate cerebrospinal fluid (CSF) biomarkers changes after mutiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	Baseline to week 48.	Change of cerebrospinal fluid (CSF) biomarker concentrations: ratio Aβ 1-42 \[pg/ml\] /1-40 \[pg/ml\], p-tau \[pg/ml\], t-tau \[pg/ml\], Aβ oligomers \[fM\], tau oligomers \[fM\].
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.	Baseline to week 48.	Percentage of subjects with AEs and SAEs from baseline until end of treatment.
To evaluate clinical outcome measures in subjects with MCI or mild dementia due to AD based on psychometric testing.	Baseline to week 48.	Change in cognitive performance measured by Alzheimer's disease cooperative study - activities of daily living (ADCS-ADL, minimum value = 0, maximum value = 78, higher values correlate with a better outcome), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog 13, minimum value = 0, maximum value = 85, higher values correlate with a worse outcome), and mini mental state examination (MMSE, minimum value = 0, maximum value = 30, higher values correlate with a better outcome).
To follow drug levels of PRI-002 during multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	Baseline to week 48.	Anaysis of PRI-002 plasma concentrations \[ng/ml\] over time.
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.	Baseline to week 48.	Percentage of subjects who stopped treatment due to AEs or SAEs from baseline until end of treatment.
To evaluate plasma biomarker changes after multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	Baseline to week 48.	Change of plasma biomarker concentrations: ratio Aβ 1-42 \[pg/ml\] /1-40 \[pg/ml\], p-tau \[pg/ml\] , t-tau \[pg/ml\], neurofilament light chain (NfL) \[pg/ml\], glial fibrillary acidic protein (GFAP) \[pg/ml\], Aβ oligomers \[fM\], and tau oligomers \[fM\].

Trial Locations

Locations (40)

Neuro Health Centrum ltd.; 🇨🇿 Brno, Czechia

NeuropsychiatrieHK, s.r.o.; 🇨🇿 Hradec Králové, Czechia

A-Shine, s.r.o.; 🇨🇿 Plzen, Czechia

CLINTRIAL, s.r.o.; 🇨🇿 Prague, Czechia

FORBELI s.r.o.; 🇨🇿 Prague, Czechia

Neuropsychiatrie s.r.o.; 🇨🇿 Prague, Czechia

INEP Medical s.r.o.; 🇨🇿 Prague, Czechia

Uniklinik RWTH Aachen; 🇩🇪 Aachen, Germany

Charité - Universitätsmedizin; 🇩🇪 Berlin, Germany

Universitätsklinikum Düsseldorf; 🇩🇪 Düsseldorf, Germany

Universitätsklinikum Magdeburg; 🇩🇪 Magdeburg, Germany

ISPG - Institut für Studien zur Psychischen Gesundheit; 🇩🇪 Mannheim, Germany

Technische Universität München; 🇩🇪 München, Germany

Universitätsklinikum Münster - Klinik für Allgemeine Neurologie; 🇩🇪 Münster, Germany

University Medical Center Rostock; 🇩🇪 Rostock, Germany

Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

Ospedale Bellaria - IRCCS Istituto delle Scienze Neurologiche; 🇮🇹 Bologna, Italy

ASST Spedali Civili di Brescia; 🇮🇹 Brescia, Italy

Clinica Neurologica Dipartimento di Neuroscienze e Imaging (CAST); 🇮🇹 Chieti, Italy

IRCCS Ospedale San Raffaele; 🇮🇹 Milan, Italy

Fondazione IRCCS.Istituto Neurologico Carlo Besta; 🇮🇹 Milan, Italy

Ospedale Civile di Baggiovara - AOU di Modena; 🇮🇹 Modena, Italy

Ospedale Santa Maria della Misericordia; 🇮🇹 Perugia, Italy

AOU Policlinico Umberto I; 🇮🇹 Rome, Italy

Fondazione Policlinico Universitario A. Gemelli IRCCS; 🇮🇹 Rome, Italy

Brain Research Center Amsterdam B.V.; 🇳🇱 Amsterdam, Netherlands

Brain Research Center Den Bosch B.V.; 🇳🇱 Den Bosch, Netherlands

Brain Research Center Zwolle B.V.; 🇳🇱 Zwolle, Netherlands

Revit Sp. z o.o., Podlaskie Centrum Psychogeriatrii; 🇵🇱 Bialystok, Poland

Krakowska Akademia Neurologii Sp. z o.o., Centrum Neurologii Klinicznej; 🇵🇱 Kraków, Poland

NeuroCor, ul. Medweciego 7/U12; 🇵🇱 Kraków, Poland

Euromedis Sp. z o.o., Centrum Medyczne EUROMEDIS; 🇵🇱 Szczecin, Poland

Neuroprotect Sp. z o.o., Centrum Medyczne NeuroProtect; 🇵🇱 Warsaw, Poland

Wielospecjalistyczne Centrum Medyczne "Ibismed" s.c.; 🇵🇱 Zabrze, Poland

Hospital Clínico Universitario Virgen de la Arrixaca; 🇪🇸 El Palmar, Murcia, Spain

Cae Oroitu; 🇪🇸 Algorta, Vizcaya, Spain

Fundació ACE - Institut Català de Neurociències Aplicades; 🇪🇸 Barcelona, Spain

Hospital Universitario Virgen Macarena,; 🇪🇸 Sevilla, Spain

Hospital Universitario Doctor Peset; 🇪🇸 Valencia, Spain

Hospital Viamed Montecanal; 🇪🇸 Zaragoza, Spain