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

Study Overview
=================
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.

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)

Conditions
-----------------
Mild Cognitive Impairment Due to Alzheimer's Disease, Alzheimer's Disease, Early Onset

Intervention / Treatment
-----------------
* Drug: PRI-002
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed and dated written informed consent obtained from the subject and study companion in accordance with applicable regulations Male or female, aged 55 to 80 years, inclusive 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) 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) Diagnosed with MCI due to AD or mild dementia due to AD, according to the NIA-AA criteria11 MMSE score of 22 to 30 points on a scale, inclusive, the highest score achievable is 30 Repeatable battery for the assessment of neuropsychological status - delayed memory index (RBANS-DMI) score ≤85 units on a scale CDR global score of 0.5 or 1 with a memory score ≥0.5 units on a scale Confirmation of AD diagnosis, by CSF biomarker profile reflecting AD, according to NIA-AA11, or existing positive amyloid positron emission tomography (PET) evidence Fluency in local language and evidence of adequate intellectual functioning in the opinion of the investigator 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: Unable to give informed consent in accordance with applicable regulations Diagnosed with moderate or severe dementia due to AD according to National Institute on Aging - Alzheimer's Association (NIA-AA) History or evidence of any other central nervous system (CNS) disorder(s) that could be interpreted as a cause of cognitive impairment or dementia History of known or suspected seizures, loss of consciousness, or significant head trauma within 2 years before Screening History of known or suspected stroke or transient ischaemic attack (TIA) within 2 years before Screening Evidence of other clinically significant lesions on brain MRI (Fazekas score 312) History or presence of clinically evident cerebrovascular disease (diagnosis of possible, probable, or definite vascular dementia) Other significant pathological findings on brain MRI (for example more than 10 microhaemorrhages or a single macrohaemorrhage >10 mm at the greatest diameter) Unstable medical, neurological, or psychiatric condition, or presence of major depressive episode at Screening Life-time history of schizophrenia or history of uncontrolled bipolar disorder within 5 years before Screening 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). 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. 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. Known to be human immunodeficiency virus (HIV) positive Known to be hepatitis C or chronic hepatitis B positive 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 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) Use of anti-Aβ monoclonal antibody therapy at Baseline Treatment with one of the following substances: Typical antipsychotic or neuroleptic medication within 90 days before Screening (except for ≤1 mg risperidon, and ≤300 mg quetiapin). Chronic use of opiates or opioids (including long-acting opioid medication) within 90 days before Screening Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 30 days before Screening Chronic use of benzodiazepines, barbiturates, or hypnotics within 90 days before Screening Contraindication to MRI. Patients with MRI compatible pacemakers may be allowed to enter the study. Prior or current participation in a clinical trial testing active immunisation against Aβ or tau. 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.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PRI-002, PRImus-AD, Clinical Dementia Rating Sum of Boxes (CDR-SB), Prodromal Alzheimer's disease, Mild Alzheimer's disease dementia