Clinical trial NCT01484184: Study to Assess Safety, Tolerability and MTD of a Central Pattern Generator-activating Tritherapy (SPINALON) in Patients With Chronic Spinal Cord Injury
Official title: Tri-therapy (SPINALON)-Elicited Spinal Locomotor Network Activation: Phase I-IIa Clinical Trial in Patients With Chronic Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Spinal Cord Injury
Keywords: Completely paralyzed
Chronically injured
Central Pattern Generator
Locomotion
Secondary complications
Activity-based training
Treadmill training
Spinal cord injury
Paraplegia
Tetraplegia
Lead sponsor: Nordic Life Science Pipeline Inc.
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2011-12-02
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Heart rate
timeFrame: Steadily during 4 hours post-single administration vs pre-administration
measure: Tolerability of common AEs
timeFrame: During 4 hours post-single administration vs pre-administration
measure: Pharmacokinetics
timeFrame: 15, 30, 60, 120 and 240 min post-administration vs pre-administration
measure: Blood pressure
timeFrame: During 4 hours post-single administration vs pre-administration
measure: Respiration rate
timeFrame: During 4 hours post-single administration vs pre-administration
measure: Oxygen saturation
timeFrame: During 4 hours post-single administration vs. pre-administration
measure: Temperature
timeFrame: During 4 hours post-single administration vs. pre-administration
measure: Change in hematology and biochemistry laboratory parameters
timeFrame: Once at 4 hours post-single administration vs pre-administration
Secondary outcomes:
measure: Occurrence of rhythmic leg EMGs
timeFrame: During 2 hours post-administration vs pre-administration
Other outcomes:
Locations:
city: Montreal
country: Canada
facility: McGill University Health Centre (Montreal General Hospital)
state: Quebec
Study officials:
affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: Mohan Radhakrishna, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nordic Life Science Pipeline/Université Laval
name: Pierre Guertin, Ph.D.
role: STUDY_DIRECTOR
References:
citation: Guertin PA, Ung RV, Rouleau P, Steuer I. Effects on locomotion, muscle, bone, and blood induced by a combination therapy eliciting weight-bearing stepping in nonassisted spinal cord-transected mice. Neurorehabil Neural Repair. 2011 Mar-Apr;25(3):234-42. doi: 10.1177/1545968310378753. Epub 2010 Oct 15.
citation: Guertin PA, Ung RV, Rouleau P. Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: proof-of-concept of efficacy. Biotechnol J. 2010 Apr;5(4):421-6. doi: 10.1002/biot.200900278.
citation: Guertin PA. The mammalian central pattern generator for locomotion. Brain Res Rev. 2009 Dec 11;62(1):45-56. doi: 10.1016/j.brainresrev.2009.08.002. Epub 2009 Aug 29.
citation: Lapointe NP, Rouleau P, Ung RV, Guertin PA. Specific role of dopamine D1 receptors in spinal network activation and rhythmic movement induction in vertebrates. J Physiol. 2009 Apr 1;587(Pt 7):1499-511. doi: 10.1113/jphysiol.2008.166314. Epub 2009 Feb 9.
citation: Lapointe NP, Guertin PA. Synergistic effects of D1/5 and 5-HT1A/7 receptor agonists on locomotor movement induction in complete spinal cord-transected mice. J Neurophysiol. 2008 Jul;100(1):160-8. doi: 10.1152/jn.90339.2008. Epub 2008 May 14.
citation: Landry ES, Lapointe NP, Rouillard C, Levesque D, Hedlund PB, Guertin PA. Contribution of spinal 5-HT1A and 5-HT7 receptors to locomotor-like movement induced by 8-OH-DPAT in spinal cord-transected mice. Eur J Neurosci. 2006 Jul;24(2):535-46. doi: 10.1111/j.1460-9568.2006.04917.x. Epub 2006 Jul 12.