Tri-therapy (SPINALON)-Elicited Spinal Locomotor Network Activation: Phase I-IIa Clinical Trial in Patients With Chronic Spinal Cord Injury
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Heart rate
研究概览
简要总结
As a first-in-class (Central Pattern Generator or CPG activator) approach, this tritherapy candidate called SPINALON has been identified and is currently under development for its capacity to temporarily induce episodes of involuntary locomotor movements. The primary objective of this Phase I/IIa study is to assess safety and tolerability of a single escalating dose of SPINALON (levodopa + carbidopa + buspirone) in chronic spinal cord-injured patients. As a secondary objective, preliminary evidence of efficacy will also be sought.
详细描述
Spinal cord injury (SCI) is generally considered as an irreversible condition for which no curative treatment has yet been found. A recent study sponsored by the Christopher & Dana Reeve Foundation revealed an incidence ranging between 40 and 60 cases per million population and a prevalence estimated to be several times greater (new data: 1,275,000 cases) than previously reported(previous data: 200,000 cases).
SPINALON (levodopa + carbidopa + buspirone) was discovered by Dr. Guertin and colleagues as a drug treatment candidate that can acutely elicit temporarily (lasting approximately 30-60 minutes) episodes of CPG activity and corresponding powerful weight-bearing hindlimb stepping in completely SCI subjects (preclinical efficacy data obtained from mice and turtles completely spinal cord transected thoracically).
As such, SPINALON is currently being developed to become a chronic treatment (physical activity-based approach driven pharmacologically) against the multiple health problems or so-called 'secondary complications' associated specifically with the lack of physical activity (sarcopenia, osteoporosis, cardiovascular problems, dyslipidemia, obesity, type II diabetes, anemia, immune system deficiency, deep vein cloth, depression, etc.).
This study is a randomized, placebo-controlled, double-blind, single dose escalation study with fifty-one (51) patients who will receive either placebo capsules(starch) or capsules with buspirone only, levodopa/carbidopa only or buspirone/levodopa/carbidopa (SPINALON).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Clinical diagnosis of complete or motor-complete SCI (ASIA-A, ASIA-B)
- •Chronically injured (at least 3 months post-injury)
- •Paraplegic (within T1-T12) or tetraplegic (within C3-C8)
- •In relatively good health condition (no significant bed sore, urinary tract infection)
- •18-65 years of age
- •Men and women
- •Quebec Province residents only
排除标准
- •With unclear diagnosis
- •Displayed a form of involuntary rhythmic leg muscle activity (restless leg syndrome, spontaneous activity in supine position, etc.) in the last 3 months prior to this study.
- •Acute or subacute stage (within 1 day and 3 months post-injury)
- •Non-traumatic (e.g., multiple sclerosis, syringomyelia, spinal tumor,etc.)
- •Are given monoamine oxidase (MAO) inhibitors (two weeks prior and after Spinalon administration)
- •Had seizures
- •Had tumor(s) (malignant or non-malignant) or in situ carcinoma in the last five (5) years
- •Allergic or hypersensitive to buspirone, levodopa or carbidopa
- •Can not take sympathomimetic amines (e.g., epinephrine, pseudoephedrine)
- •Currently suffering of heart problems, blood related diseases, endocrine disease, liver disease, lung disease, or kidney disease
- •Receiving antihypertensive drugs
- •Receiving tricyclic antidepressant
- •Receiving dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone)
- •Receiving phenytoin and papaverine
- •With glaucoma
- •With psychiatric or mental disorder(s)
- •Had gastrointestinal ulcer(s) in the last five (5) years
- •Pregnant or lactating woman (all women between 18 and 50 year-old not yet confirmed as pregnant, will be tested (urine test - TestPak Plus, Abbott Laboratories) on medical exam-day due to the teratogenic potential of levodopa/carbidopa.
- •Children (younger than 18 year-old) or elderly (older than 65 year-old)
- •Not resident of Quebec Province
研究组 & 干预措施
Placebo
First, a 2-arm design will be used, the first arm being composed of 3 subjects receiving the lowest dose of SPINALON, the second arm being composed of 1 subject receiving a placebo. This 2-arm design will be repeated consecutively with increasing doses, as long as the dose is well tolerated. Six (6) groups are expected to be tested with this 2-arm design.
干预措施: SPINALON (buspirone + levodopa + cardidopa) (Drug)
buspirone or levodopa/carbidopa
Another 2-arm design will be tested composed of 16 subjects receiving drug A or drug B at MTD dose of the combined study drug as identified in the previous 2-arm groups.
干预措施: SPINALON (buspirone + levodopa + cardidopa) (Drug)
结局指标
主要结局
Heart rate
时间窗: Steadily during 4 hours post-single administration vs pre-administration
Heart rate as a safety measure will be measured as beats per minute during 4 hours post-administration during the only administration
Tolerability of common AEs
时间窗: During 4 hours post-single administration vs pre-administration
Frequent AEs such as nausea and hypotension will be specifically measured to assess tolerability and maximum tolerated dose. No more than 20% of subjects experiencing nausea with \> grade 2 severity. Dose schedule without ≥ grade 3 hypotension. No potentiation of other AEs possibly found for each molecule administered separately
Pharmacokinetics
时间窗: 15, 30, 60, 120 and 240 min post-administration vs pre-administration
Blood samples will be repeatedly obtained post-administration on the day of testing. HPLC analysis will be conducted to assess typical PK values (Cmax, Tmax, AUC) in order to determine whether or not the known PK profile of each active molecule (levodopa, carbidopa, buspirone) is changed once administered concomitantly (SPINALON)
Blood pressure
时间窗: During 4 hours post-single administration vs pre-administration
Systolic and diastolic blood pressure values as a safety measure will be measured as mmHg during 4 hours
Respiration rate
时间窗: During 4 hours post-single administration vs pre-administration
Respiration rate as number per minute will be measured as a safety issue during 4 hours post-administration compared with baseline value pre-administration on the day of testing
Oxygen saturation
时间窗: During 4 hours post-single administration vs. pre-administration
Oxygen saturation measured as CO2 level and O2 level in percentage will be measured on the day of testing during 4 hours post-administration compared with baseline level (pre-administration)
Temperature
时间窗: During 4 hours post-single administration vs. pre-administration
Temperature measured in degrees Celsius will be measured during 4 hours post-administration on the day of testing compared with baseline value (pre-administration)
Change in hematology and biochemistry laboratory parameters
时间窗: Once at 4 hours post-single administration vs pre-administration
Blood samples at 4 hours post-administration will be analyzed for standard hematology (CBC) and biochemistry (liver and kidney markers) values and compared with baseline values (medical exam day sample).
次要结局
- Occurrence of rhythmic leg EMGs(During 2 hours post-administration vs pre-administration)