2-Hydroxybenzylamine (2-HOBA) Phase 1b/2a Proof-of Concept, Dose-Finding, Biomarker Study in Early Alzheimer's Patients
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Safety/Tolerability (adverse events)
研究概览
简要总结
Investigators propose a phase 1b/2a, randomized, double-blind, placebo-controlled, parallel group dose finding and biomarker study to evaluate the safety, tolerability, and biomarker activity of 2-HOBA in 48 MCI/AD participants. Participants will be randomized 1:1:1:1 to receive 250 mg BID, 250 and 500 mg 2-HOBA acetate TID or placebo for 12 weeks. Blood and cerebral spinal fluid (CSF) will be collected to measure markers of protein modification by dicarbonyls (IsoLGs- & MDA), pTau-181, YKL-40, and NF-L.
详细描述
This is a phase 1b/2a, randomized, double-blind, placebo-controlled, parallel group dose finding and biomarker study to evaluate the safety, tolerability, and biomarker activity of 2-HOBA in 48 MCI/AD participants. Participants will be randomized 1:1:1:1 to receive 250 mg BID, 250 and 500 mg 2-HOBA acetate TID or placebo for 12 weeks. Blood and CSF will be collected to measure markers of protein modification by dicarbonyls (IsoLGs- & MDA), pTau-181, YKL-40, and NF-L. Investigators anticipate screening 120 subjects to randomize up to 60 subjects with the goal of 48 patients completing the study (allowing for up to 25% dropout) for the 12-week study.
The primary aims of this project are to 1) Provide proof-of-concept that 2-HOBA protects proteins from covalent modification by inhibiting lysine-reacting dicarbonyls in the human brain. Investigators hypothesize that 12 weeks of 2-HOBA treatment will significantly reduce CSF levels of the dilysyl-MDA and IsoLG adduct of CSF proteins in a dose-responsive relationship. 2) Evaluate whether 2-HOBA is safe for extended use in patients with early AD. Investigators hypothesize that 2-HOBA will be safe and well tolerated through 12 weeks of use. Tolerability will be assessed by monitoring symptoms, adverse events, vital signs, ECG, and safety labs during the study.
The secondary aims are to evaluate the effect of 2-HOBA treatment on AD biomarkers, brain inflammation, disease severity, and cognitive performance.
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)
盲法说明
Treatment will be supplied in capsules of the same size and color.
入排标准
- 年龄范围
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •MCI due to AD:
- •Male or female, aged 55-85 years (both inclusive) at the time of signing informed consent.
- •Participant must have a subjective memory concern as reported by participant, study partner, or clinician.
- •Mini-Mental State Exam31 score between 24 and 30, inclusive
- •Clinical Dementia Rating (CDR)32 Global = 0.
- •Memory Box score must be at least 0.5
- •Male or female, aged 55-85 years (both inclusive) at the time of signing informed consent.
- •MCI or Mild dementia of the Alzheimer's type according to the NIA-AA 2018 criteria.
- •CDR global score of 0.5 and CDR domain score of 0.5 or more in at least one of the three instrumental activities of daily living categories (personal care, home & hobbies, community affairs) Or CDR global score of 1.0
- •Additional Inclusion Criteria for Both Diagnoses:
- •Age 55-85 (inclusive)
- •Abnormal memory function documented by scoring within the education adjusted ranges on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler
- •Memory Scale - Revised:
- •Less than or equal to 11 for 16 or more years of education
- •Less than or equal to 9 for 8 - 15 years of education
- •Less than or equal to 6 for 0 - 7 years of education
- •Amyloid positivity established using the C2N Precivity2 Plasma test (Aβ42/40 plus p tau217/np-tau
- •(This test uses a statistical algorithm to integrate a patient's Aβ42/40 Ratio and p-Tau217 Ratio to calculate the Amyloid Probability Score 2 (APS2) and determines whether a patient is positive or negative for brain amyloid deposition based on a binary cutoff value).
- •Stable permitted medications for 4 weeks or longer as specified in Section 4.6.3, including:
- •a. Memantine and cholinesterase inhibitors are allowable if stable for 12 weeks prior to screen.
- •Geriatric Depression Scale33 score of less than or equal to
- •Study Partner is available who has frequent contact with the participant (e.g., an average of 10 hours per week or more) and can accompany the participant to most visits to answer questions about the participant.
- •Adequate visual and auditory acuity to allow neuropsychological testing.
- •Good general health with no additional diseases/disorders expected to interfere with the study.
- •For women: participant is not pregnant, lactating, or of childbearing potential (i.e., women must be two years post-menopausal or surgically sterile).
- •For men: male participants with female partners of childbearing potential must use an effective method of contraception from dosing on Day 1 until 1 month after the lastadministration of study medication and agreed not to donate sperm until 1 month after the last administration of study medication.
- •Completed six grades of education or has a good work history.
- •Must speak English fluently.
- •Provide written informed consent. Participants must have the capacity to consent.
排除标准
- •Any other significant neurologic disease including Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic deficits or known structural brain abnormalities.
- •Major depression, bipolar disorder as described in DSM-V within the past 1 year or psychotic features, agitation, or behavioral problems within 3 months, which could lead to difficulty complying with the protocol.
- •History of schizophrenia (DSM V criteria).
- •History of alcohol or substance abuse or dependence within the past 2 years (DSM V criteria).
- •Clinically significant or unstable medical condition, including uncontrolled hypertension, uncontrolled diabetes, or significant cardiac, pulmonary, renal (defined by eGFR score <60 mL/min/1.73 m²), hepatic impairment, endocrine, or other systemic disease that, in the opinion of the Investigator, may put the participant at risk because of participation in the study, influence the results, or affect the participant's ability to participate in the study.
- •Participants with moderate or severe hepatic impairment, defined as Child-Pugh Class B or C, are excluded.
- •Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of non-melanoma skin cancers, resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen post-treatment.
- •Clinically significant abnormalities in B12 or TFTs that might interfere with the study.
- •8. Clinically significant abnormalities in screening laboratories or ECG.
- •Residence in a skilled nursing facility.
- •Use of any excluded medication as described in Section 4.6.2, including:
- •Use centrally acting anti-cholinergic drugs.
- •Use of any investigational drugs within 4 weeks or 5 half-lives, whichever is longer, prior to screening.
- •A current blood clotting or bleeding disorder, or significantly abnormal PT or PTT at screening.
- •Contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or cardiac pacemaker.
- •Participants whom the Site PI deems to be otherwise ineligible.
- •Current use of monoamine oxidase inhibitors (MAOIs) or use within 14 days (or 5 half-lives, whichever is longer) prior to screening, This includes non-selective MAOIs (phenelzine, tranylcypromine, isocarboxazid), MAO-B inhibitors (selegiline, rasagiline, safinamide), reversible MAO-A inhibitors (moclobemide), and other agents with MAOI A inhibitory activity (linezolid, methylene blue at doses >1 mg/kg). This exclusion is required because 2-HOBA has demonstrated MAO-A inhibitory activity in vitro.
研究组 & 干预措施
Placebo
Placebo treatment TID for 12 weeks.
干预措施: Placebo (Other)
250 mg 2-HOBA acetate BID
250 mg of 2-hydroxybenzylamine (2-HOBA) acetate BID for 12 weeks.
干预措施: 2-hydroxybenzylamine acetate (Drug)
250 mg 2-HOBA acetate TID
250 mg of 2-hydroxybenzylamine (2-HOBA) acetate TID for 12 weeks.
干预措施: 2-hydroxybenzylamine acetate (Drug)
500 mg 2-HOBA acetate
500 mg of 2-hydroxybenzylamine (2-HOBA) acetate TID for 12 weeks.
干预措施: 2-hydroxybenzylamine acetate (Drug)
结局指标
主要结局
Safety/Tolerability (adverse events)
时间窗: Baseline to week 12
Rates of adverse events will be compared between active and placebo arms and presented as summary statistics.
Change in dicarbonyl protein adducts
时间窗: Baseline to week 12
Change in CSF levels of the dilysyl-malondialdehyde crosslink and the lysyl-levuglandin adduct of CSF proteins in a dose-responsive relationship
次要结局
- Compliance(Baseline to week 12)
- Measurement of biomarker, p-Tau181(Baseline to week 12)
- Measurement biomarker, human cartilage glycoprotein 39 (YKL-4)(Baseline to week 12)
- Measurment of biomarker, neurofilaments light chain protein (NF-L)(Baseline to week 12)
- Measurement of biomarker, F2-Isoprostanes(Baseline to week 12)
- Measurement of biomarker, 8-hydroxy-2'-deoxyguanosine(Baseline to week 12)