Study to Assess Safety, Tolerability and MTD of a Central Pattern Generator-activating Tritherapy (SPINALON) in Patients With Chronic Spinal Cord Injury

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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).

Official Title
-----------------
Tri-therapy (SPINALON)-Elicited Spinal Locomotor Network Activation: Phase I-IIa Clinical Trial in Patients With Chronic Spinal Cord Injury

Conditions
-----------------
Spinal Cord Injury

Intervention / Treatment
-----------------
* Drug: SPINALON (buspirone + levodopa + cardidopa)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: buspirone or levodopa/carbidopa<br>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. | Drug: SPINALON (buspirone + levodopa + cardidopa)<br>* 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.<br>* Other names: Sinemet 100/25 mg tablets (DIN 00513997);|
| Placebo Comparator: Placebo<br>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. | Drug: SPINALON (buspirone + levodopa + cardidopa)<br>* 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.<br>* Other names: Sinemet 100/25 mg tablets (DIN 00513997);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart rate | Heart rate as a safety measure will be measured as beats per minute during 4 hours post-administration during the only administration | 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 | 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) | 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 | 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 | 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) | 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) | 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). | Once at 4 hours post-single administration vs pre-administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | During 2 hours post-administration vs pre-administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Completely paralyzed, Chronically injured, Central Pattern Generator, Locomotion, Secondary complications, Activity-based training, Treadmill training, Spinal cord injury, Paraplegia, Tetraplegia