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

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)

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.

Study Overview

• Status: Recruiting
• Conditions: Mild Cognitive Impairment Due to Alzheimer's Disease; Alzheimer's Disease, Early Onset
• Intervention / Treatment: Drug: Placebo; Drug: PRI-002

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 Type: Interventional
• Enrollment (Estimated): 270
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alexander Brener, Dr.; Phone Number: 004915150329843; Email: info@prinnovation.org
• Study Contact Backup: Name: Kathrin Thiem, Dr.; Phone Number: 004915150329843; Email: info@prinnovation.org

Study Locations

• Czechia
  • Brno, Czechia, 62800
    • Recruiting
    • Neuro Health Centrum ltd.
  • Hradec Králové, Czechia, 50341
    • Not yet recruiting
    • NeuropsychiatrieHK, s.r.o.
  • Plzen, Czechia, 30100
    • Not yet recruiting
    • A-Shine, s.r.o.
  • Prague, Czechia, 10000
    • Not yet recruiting
    • CLINTRIAL, s.r.o.
  • Prague, Czechia, 14800
    • Not yet recruiting
    • Forbeli s.r.o.
  • Prague, Czechia, 16000
    • Not yet recruiting
    • Neuropsychiatrie s.r.o.
  • Prague, Czechia, 18600
    • Not yet recruiting
    • INEP medical s.r.o.
• France
  • Auvergne Rhône-Alpes
    • Lyon, Auvergne Rhône-Alpes, France, 69002
      • Not yet recruiting
      • Hospices Civils de Lyon
  • Ile De France
    • Paris, Ile De France, France, 75013
      • Not yet recruiting
      • University Hospital - Pitié-Salpêtrière Hospital/ Charles Foix
  • Nouvelle Aquitaine
    • Bordeaux, Nouvelle Aquitaine, France, 30000
      • Not yet recruiting
      • CHU Bordeaux CMRR - IMNc
  • Occitanie
    • Toulouse, Occitanie, France, 31059
      • Not yet recruiting
      • CHU de Toulouse - Hôpital La Grave
  • Provence-Alpes-Côte d'Azur
    • Nice, Provence-Alpes-Côte d'Azur, France, 06100
      • Not yet recruiting
      • Centre Mémoire Institut Claude Pompidou
• Germany
  • Berlin, Germany, 13125
    • Not yet recruiting
    • Charité - Universitätsmedizin
  • Kiel, Germany, 24105
    • Not yet recruiting
    • Universitätsklinikum Schlesweig-Holstein - Klinik für Neurologie
  • Magdeburg, Germany, 39120
    • Not yet recruiting
    • Universitätsklinikum Magdeburg
  • Mannheim, Germany, 68165
    • Not yet recruiting
    • ISPG - Institut für Studien zur Psychischen Gesundheit
  • München, Germany, 81675
    • Recruiting
    • Technische Universität München
  • Münster, Germany, 48149
    • Not yet recruiting
    • Universitätsklinikum Münster - Klinik für Allgemeine Neurologie
  • Rostock, Germany, 18147
    • Not yet recruiting
    • University Medical Center Rostock
  • Ulm, Germany, 89081
    • Not yet recruiting
    • Universitatsklinikum Ulm
• Italy
  • Bologna, Italy, 40139
    • Not yet recruiting
    • Ospedale Bellaria - IRCCS Istituto delle Scienze Neurologiche
  • Brescia, Italy, 25123
    • Not yet recruiting
    • ASST Spedali Civili di Brescia
  • Chieti, Italy, 66013
    • Not yet recruiting
    • Clinica Neurologica Dipartimento di Neuroscienze e Imaging (CAST)
  • Milan, Italy, 20132
    • Recruiting
    • IRCCS Ospedale San Raffaele
  • Milan, Italy, 20133
    • Not yet recruiting
    • Fondazione IRCCS.Istituto Neurologico Carlo Besta
  • Modena, Italy, 41124
    • Not yet recruiting
    • Ospedale Civile di Baggiovara - AOU di Modena
  • Perugia, Italy, 06129
    • Not yet recruiting
    • Ospedale Santa Maria della Misericordia
  • Rome, Italy, 00161
    • Not yet recruiting
    • AOU Policlinico Umberto I
  • Rome, Italy, 00168
    • Not yet recruiting
    • Fondazione Policlinico Universitario A. Gemelli IRCCS
• Netherlands
  • Amsterdam, Netherlands, 1081 GN
    • Recruiting
    • Brain Research Center Amsterdam B.V.
  • Den Bosch, Netherlands, 5223 LA
    • Recruiting
    • Brain Research Center Den Bosch B.V.
  • Zwolle, Netherlands, 8025 AZ
    • Recruiting
    • Brain Research Center Zwolle B.V.
• Poland
  • Bialystok, Poland, 15-756
    • Recruiting
    • Revit Sp. z o.o., Podlaskie Centrum Psychogeriatrii
  • Kraków, Poland, 30-505
    • Not yet recruiting
    • Krakowska Akademia Neurologii Sp. z o.o., Centrum Neurologii Klinicznej
  • Szczecin, Poland, 70-111
    • Recruiting
    • Euromedis Sp. z o.o., Centrum Medyczne EUROMEDIS
  • Warsaw, Poland, 01-684
    • Recruiting
    • Neuroprotect Sp. z o.o., Centrum Medyczne NeuroProtect
  • Zabrze, Poland, 41-800
    • Not yet recruiting
    • Wielospecjalistyczne Centrum Medyczne "Ibismed" s.c.
• Spain
  • Barcelona, Spain, 08028
    • Not yet recruiting
    • Fundació ACE - Institut Català de Neurociències Aplicades
  • Sevilla, Spain, 41003
    • Not yet recruiting
    • Hospital Universitario Virgen Macarena,
  • Valencia, Spain, 46017
    • Not yet recruiting
    • Hospital Universitario Doctor Peset
  • Zaragoza, Spain, 50012
    • Not yet recruiting
    • Hospital Viamed Montecanal
  • Murcia
    • El Palmar, Murcia, Spain, 30120
      • Not yet recruiting
      • Hospital Clinico Universitario Virgen de la Arrixaca
  • Vizcaya
    • Algorta, Vizcaya, Spain, 48993
      • Not yet recruiting
      • CAE Oroitu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Daily oral administration of 3 capsules in the morning and evening.	Drug: Placebo; Oral administration
Experimental: PRI-002, dosage arm 1; Daily oral administration of 3 capsules in the morning and evening, lower dose.	Drug: PRI-002; Oral administration; Other Names: Contraloid
Experimental: PRI-002, dosage arm 2; Daily oral administration of 3 capsules in the morning and evening, higher dose.	Drug: PRI-002; Oral administration; Other Names: Contraloid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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.	Baseline to 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).	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)).	Baseline to week 48.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Percentage of subjects with AEs and SAEs from baseline until end of treatment.	Baseline to week 48.
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).	Percentage of subjects with ARIA-E and ARIA-H from baseline until end of treatment.	Baseline to week 48.
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.	Percentage of subjects who stopped treatment due to AEs or SAEs from baseline until end of treatment.	Baseline to week 48.
To evaluate clinical outcome measures in subjects with MCI or mild dementia due to AD based on psychometric testing.	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).	Baseline to week 48.
To evaluate cerebrospinal fluid (CSF) biomarkers changes after mutiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	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].	Baseline to week 48.
To evaluate plasma biomarker changes after multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	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].	Baseline to week 48.
To follow drug levels of PRI-002 during multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.	Anaysis of PRI-002 plasma concentrations [ng/ml] over time.	Baseline to week 48.

Collaborators and Investigators

• Sponsor: PRInnovation GmbH
• Collaborators: Julius Clinical; Federal Agency for Disruptive Innovation - SPRIN-D; Priavoid
• Investigators: Study Chair: Gerhard Tischler, Dr., PRInnovation

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2023
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 26, 2023

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Mild Alzheimer's disease dementia; Prodromal Alzheimer's disease; PRI-002; PRImus-AD; Clinical Dementia Rating Sum of Boxes (CDR-SB)
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Tauopathies; Cognition Disorders; Dementia; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: PRI-002-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No