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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 304
- 试验地点
- 74
- 主要终点
- 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).
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
- •For male subjects who are sexually active with women of child-bearing potential: agreeing to use acceptable contraception (using a condom or having demonstrated successful vasectomy) and not donate sperm from Screening until 12 weeks after the last dose of study treatment.
- •Body mass index (BMI) between 18.5 and 30.0 kg/m2, inclusive.
- •Diagnosed with MCI due to AD or mild dementia due to AD, according to the NIA-AA criteria.
- •MMSE score of 22 to 30, inclusive.
- •Repeatable battery for the assessment of neuropsychological status - delayed memory index (RBANS-DMI) score ≤
- •CDR global score of 0.5 or 1 with a memory score ≥0.
- •Confirmation of AD diagnosis, by
- •CSF biomarker profile reflecting AD, according to NIA-AA, 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.
排除标准
- •Unable to give informed consent in accordance with applicable regulations.
- •Diagnosed with moderate or severe dementia due to AD according to 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 3).
- •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 <50000 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.
研究组 & 干预措施
PRI-002, dosage arm 2
Daily oral administration of 3 capsules in the morning and evening, higher dose.
干预措施: PRI-002 (Drug)
Placebo
Daily oral administration of 3 capsules in the morning and evening.
干预措施: Placebo (Drug)
PRI-002, dosage arm 1
Daily oral administration of 3 capsules in the morning and evening, lower dose.
干预措施: PRI-002 (Drug)
结局指标
主要结局
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).
时间窗: 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).
时间窗: 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)).
To evaluate the safety and tolerability of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on incidence of drug-related adverse events (AEs).
时间窗: Baseline to week 48.
Percentage of subjects with at least 1 drug- related 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).
时间窗: Baseline to week 48.
Change from Baseline to Week 48 in global outcome as measured by CDR-SB.
次要结局
- To evaluate clinical outcome measures of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.(Through study completion up to 48 weeks.)
- To evaluate safety and tolerability of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD, based on AEs, amyloid related imaging abnormalities oedema (ARIA-E) and haemosiderin (ARIA-H), and treatment discontinuations due to AEs.(Through study completion up to 96 weeks.)
- To evaluate clinical outcome measures of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.(Baseline to study completion.)
- To evaluate clinical outcome measures and biomarkers of multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.(Baseline to study completion.)
- To evaluate the correlation between PRI-002 exposure and efficacy and the correlation between PRI-002 exposure and safety in subjects with MCI or mild dementia due to AD.(Through study completion up to 96 weeks.)
- To follow drug levels of PRI-002 during multiple doses of PRI-002 in subjects with MCI or mild dementia due to AD.(Through study completion up to 96 weeks.)