A Phase I/II Randomized, Open-Labeled Study to Evaluate Pharmacokinetic and Pharmacodynamic Effects and Safety of ALZT-OP1 in Subjects With Alzheimer's Disease and Normal Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Part A Non-compartmental PK parameters will be calculated and reported for ALZT-OP1a and ALZT-OP1b
研究概览
简要总结
This is a randomized, open-label, cross-over, pharmacokinetic and pharmacodynamic PK/PD study. (Part A)The PK portion of the study is designed to evaluate the pharmacokinetics of ALZT-OP1 (a combination drug therapy) designated as ALZT-OP1a and ALZT-OP1b, in both plasma and CSF, following co-administration of the two active investigational products, in healthy volunteers and Alzheimer subjects aged 55-79 and in good health. (Part B) The PD portion of the study will evaluate the pharmacodynamics of ALZT- OP1, using both plasma and CSF biomarkers, following 60 days of consecutive daily treatment, in AD subjects only.
详细描述
This is a phase I/II randomized, open-label, cross-over, PK/PD study. The PK (Part A) portion of the study is designed to evaluate both single and double doses of ALZT-OP-1a (17.1mg or 34.2 mg) and ALZT-OP1b (10 mg or 20 mg) in both Alzheimer's subjects and healthy volunteers. The PD (Part B) portion of the study is designed to evaluate single doses of ALZT-OP-1a (17.1mg) and ALZT-OP1b (10 mg) in AD subjects treated for 60 days. An Alzheimer's control group will be utilized for comparison to active treatment groups but will not be administered study treatment; however, they will have biomarkers collected.
PK (Part A) n=24, both healthy volunteers and AD subjects
Part A is an open-label study, cross-over, PK study where 24 subjects will be randomly assigned to receive treatment regimen A-B or B-A for two consecutive day of dosing.
Subjects will be admitted to the Phase 1 unit the morning before dosing and will initiate dosing the following morning for 2 consecutive days of dosing (A-B, or B-A).
Day 1 (A-B) will consist of a single inhaled oral dose of ALZT-OP1a via dry powder inhaler + a single oral tablet dose of ALZT-OP1b.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
盲法说明
A Phase I/ II Randomized, Open-Label Study to Evaluate Pharmacokinetic and Pharmacodynamic Effects and Safety of ALZT-OP1 (co-administration of ALZT-OP1a and ALZT-OP1b) in Subjects with Alzheimer's Disease and Normal Healthy Volunteers
入排标准
- 年龄范围
- 55 Years 至 79 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For All Subjects
- •Provide a signed written informed consent;
- •Age 55-79 old (inclusive);
- •ECG without abnormal, clinically significant findings;
- •Body mass index (BMI) ≥ 18 kg/m2 and ≤ 30 kg/m2
- •Negative urine drug screen for selected drugs of abuse at screening;
- •Negative for hepatitis and HIV at screening;
- •Negative for COVID-19 at screening;
- •Good general health, as determined by medical history, physical examination, and clinical laboratory testing;
- •Must provide written informed consent for CSF sampling. For AD Subjects Only
- •In addition to satisfying all of the above inclusion criteria, AD subjects must also meet the following criteria:
- •Diagnosed with mild to moderate Alzheimer's disease;
- •Clinical Dementia Rating (Global) 0.5
- •Mini-mental state examination (MMSE) ≤ 22;
- •Must be fluent in the language of the cognitive testing material being administered;
- •Stability of permitted medications for 4 weeks prior to study start;
- •Visual and auditory acuity adequate for neuropsychological testing.
- •Must provide written informed consent for APOe4 genotype testing; For All Subjects in Part A (PK)
- •Willingness to stay in the unit overnight for the duration of the PK portion of the study.
排除标准
- •For All Subjects
- •Current smokers, or ex-smokers with a remote history (> 100 pack/year);
- •Clinically significant medical conditions;
- •History of abnormal clinically significant ECG abnormalities;
- •Symptomatic viral infection, or suspicion thereof (including rhinitis) in the last 14 days prior to dosing;
- •Signs of active pulmonary infection or other pulmonary inflammatory conditions, even in absence of febrile episodes, in the last 14 days;
- •History or presence of disease in the kidneys and/or heart, lungs, liver, gastrointestinal tract, endocrine organs or other conditions such as metabolic disease known to interfere with the absorption, distribution, metabolism, and excretion of drugs;
- •Malignancy, regardless of location;
- •Autoimmune disorders such as (but not limited to) lupus erythematosus, multiple sclerosis, rheumatoid arthritis, or sarcoidosis;
- •Investigational agents are prohibited one month prior to entry and for the duration of the trial;
- •Currently taking medications known to be CYP2C9 inducers (e.g., carbamazepine and rifampicin;
- •Currently taking cromolyn, or have taken cromolyn products, within the past 30 days;
- •Non-steroidal anti-inflammatory drug (NSAID) use (products containing ibuprofen while on study);
- •Allergy or hypersensitivity to cromolyn (also known as Intal®, Nasalcrom®, Opticrom®, Gastrocrom®, etc.);
- •Allergy or hypersensitivity to ibuprofen (Advil®, Motrin®, Nuprin®, etc.) or aspirin, including Stevens-Johnson syndrome;
- •History of hypersensitivity or allergies to any of the drug compound under investigation (cromolyn sodium, ibuprofen, lactose, or magnesium stearate);
- •Current respiratory disorders and chronic respiratory disease with impaired respiratory effort or difficulty taking inhaled drugs (examples: COPD, emphysema);
- •Abnormal pulmonary function test, defined for this protocol as: FEV1 < 70% of predicted value, indicating moderate or severe respiratory impairment;
- •Any other disease or condition, which, in the opinion of the investigator, would make the subject unsuitable for this study;
- •Female subjects of reproductive potential with a positive pregnancy test (urine or serum) or who are pregnant or lactating.
- •For AD Subjects Only
- •In addition to not meeting any of the above exclusion criteria for Normal Healthy Volunteers, AD subjects must also not meet any of the following criteria:
- •Any significant neurological disease other than suspected incipient AD, such as 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 defaults or known structural brain abnormalities;
- •Major depressive episode, as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) within the past 6 months, which could lead to difficulty complying with the protocol;
- •History of schizophrenia or bipolar disorder (DSM-V criteria);
- •Currently taking medications that could lead to difficulty complying with the protocol; For All Subjects in Part A (PK)
- •Aspirin, or products containing aspirin, while on PK study; For All Subjects in Part B (PD)
- •Chronic daily use of aspirin exceeding standard of care guidelines for low dose aspirin therapy for prevention of stroke and/or other recommended uses, while on PD study.
研究组 & 干预措施
Part A
24 subjects randomized to receive treatment: (A-B) = Single 17.1 mg oral inhaled dose of ALZT-OP1a (cromolyn) via dry powder inhaler and a single oral 10 mg tablet of ALZT-OP1b (ibuprofen) on Day 1. On Day 2, subjects would receive two 17.1 mg doses of ALZT-OP1a via dry powder inhaler and two 10 mg tablets of ALZT-OP1b (ibuprofen), within two minutes of each other.
(B-A) = Two 17.1 mg doses of ALZT-OP1a (cromolyn) and two doses of 10 mg ALZT-OP1b (ibuprofen) on Day 1 and single 17.1 mg dose of ALZT-OP1a cromolyn 17.1 mg and a single 10 mg dose of ALZT-OP1b (ibuprofen) on Day 2.
All subjects will have plasma and CSF collected for PK analysis.
干预措施: ALZT-OP1 (cromolyn and ibuprofen) ALZT-OP1a (cromolyn) and ALZT-OP1b (ibuprofen) (Drug)
Part B
PD - 32 subjects (AD only) will be enrolled in the PD portion of the study. Twenty-four (24) subjects will be assigned to Treatment Group 1 to receive a single (17.1 mg) inhaled dose of ALZT-OP1a (cromolyn) plus a single (10 mg) oral dose of ALZT-OP1b (ibuprofen) daily for 60 days.
All subjects will have plasma and CSF collected for PD biomarker analysis. Eight (8) A subjects will be assigned to Treatment Group 2 (Control Group) and will not be administered study drug.
干预措施: ALZT-OP1 (cromolyn and ibuprofen) ALZT-OP1a (cromolyn) and ALZT-OP1b (ibuprofen) (Drug)
结局指标
主要结局
Part A Non-compartmental PK parameters will be calculated and reported for ALZT-OP1a and ALZT-OP1b
时间窗: • 2 Days
• PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF Cmax
时间窗: 2 Days
Evaluation Cmax (maximum plasma and CSF concentration observed)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF AUC 0-t
时间窗: 2 Days
Evaluation AUC 0-t (area under the curve from 0 to t hours where t is the last measured concentration)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF AUCPLASMA/AUCCSF
时间窗: 2 Days
Evaluation AUCPLASMA/AUCCSF (ratio at 60 min, 120 min, 240 min, 360 min and 480 min)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF t½ (half-life)
时间窗: 2 Days
Evaluation t½ (half-life)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF tmax
时间窗: 2 Days
Evaluation tmax (sampling time at which Cmax occurred)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF Vd/F
时间窗: 2 Days
Evaluation Vd/F (apparent volume of distribution)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF CL/F
时间窗: 2 Days
Evaluation CL/F (apparent total body clearance)
PK profile for ALZT-OP1a and ALZT-OP1b in plasma and CSF AUC 0-∞
时间窗: 2 Days
Evaluation AUC 0-∞ (area under the curve from 0 to infinity)
次要结局
- Biomarker Beta Amyloid (Αβ-42) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Beta Amyloid (Αβ-40) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Beta Amyloid (Αβ-38) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Neurofilament light (Nf-L) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Interferon-γ (IFN-γ) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Total Tau Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker P-Tau (Thr 231) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Glial Fibrillary Acidic Protein (GFAP) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Transforming Growth Factor-β1 (TGF-β1) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Tumor Necrosis Factor-α (TNF-α) Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker CD33 Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)
- Biomarker Neurogranin Sample Analysis plasma and CSF Day 1 to 60 Days(Day 1 to Day 60)