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.
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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
50
The proposed study is a combination of 1 and 2-arm designs. First, a 2-arm design will be used, the first arm being composed of 3 subjects receiving the lowest dose of the study drug, and the second arm being composed of 1 subject receiving a placebo. This 2-arm design will be repeated consecutively (not simultaneously) with increasing doses of SPINALON, as long as the dose is well tolerated. Six (6) groups are expected to be tested with this 2-arm design.This will be followed by a 2-arm composed of 1 group with 1 subject receiving placebo and 1 larger group (10 subjects) who will receive SPINALON at MTD as identified in the previous 2-arm groups.
McGill University Health Centre (Montreal General Hospital)
Montreal, Quebec, Canada
Heart rate
Heart rate as a safety measure will be measured as beats per minute during 4 hours post-administration during the only administration
Time frame: Steadily during 4 hours post-single administration vs pre-administration
Tolerability of common AEs
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
Time frame: During 4 hours post-single administration vs pre-administration
Pharmacokinetics
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)
Time frame: 15, 30, 60, 120 and 240 min post-administration vs pre-administration
Blood pressure
Systolic and diastolic blood pressure values as a safety measure will be measured as mmHg during 4 hours
Time frame: During 4 hours post-single administration vs pre-administration
Respiration rate
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
Time frame: During 4 hours post-single administration vs pre-administration
Oxygen saturation
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)
Time frame: During 4 hours post-single administration vs. pre-administration
Temperature
Temperature measured in degrees Celsius will be measured during 4 hours post-administration on the day of testing compared with baseline value (pre-administration)
Time frame: During 4 hours post-single administration vs. pre-administration
Change in hematology and biochemistry laboratory parameters
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).
Time frame: Once at 4 hours post-single administration vs pre-administration
Occurrence of rhythmic leg EMGs
EMG activities of leg muscles will be measured with surface electrodes during 2 hours post-administration on the day of testing compared with baseline values pre-administration. Possible occurrence of involuntary rhythmic and bilateral movements assessed quantitatively will be sought.
Time frame: During 2 hours post-administration vs pre-administration
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