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

Primary Purpose

Spinal Cord Injury

Status
Completed
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
SPINALON (buspirone + levodopa + cardidopa)
Sponsored by
Nordic Life Science Pipeline Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Cord Injury focused on measuring Completely paralyzed, Chronically injured, Central Pattern Generator, Locomotion, Secondary complications, Activity-based training, Treadmill training, Spinal cord injury, Paraplegia, Tetraplegia

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • McGill University Health Centre (Montreal General Hospital)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

buspirone or levodopa/carbidopa

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Heart rate
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
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
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
Systolic and diastolic blood pressure values as a safety measure will be measured as mmHg during 4 hours
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
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)
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)
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).

Secondary Outcome Measures

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.

Full Information

First Posted
November 25, 2011
Last Updated
August 19, 2015
Sponsor
Nordic Life Science Pipeline Inc.
Collaborators
United States Department of Defense
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1. Study Identification

Unique Protocol Identification Number
NCT01484184
Brief Title
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

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
July 2013 (undefined)
Primary Completion Date
August 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nordic Life Science Pipeline Inc.
Collaborators
United States Department of Defense

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Cord Injury
Keywords
Completely paralyzed, Chronically injured, Central Pattern Generator, Locomotion, Secondary complications, Activity-based training, Treadmill training, Spinal cord injury, Paraplegia, Tetraplegia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Factorial Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
buspirone or levodopa/carbidopa
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
SPINALON (buspirone + levodopa + cardidopa)
Other Intervention Name(s)
Apo-Buspirone 10 mg tablets (DIN 02211076), Sinemet 100/25 mg tablets (DIN 00513997)
Intervention Description
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.
Primary Outcome Measure Information:
Title
Heart rate
Description
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
Title
Tolerability of common AEs
Description
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
Title
Pharmacokinetics
Description
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
Title
Blood pressure
Description
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
Title
Respiration rate
Description
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
Title
Oxygen saturation
Description
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
Title
Temperature
Description
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
Title
Change in hematology and biochemistry laboratory parameters
Description
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
Secondary Outcome Measure Information:
Title
Occurrence of rhythmic leg EMGs
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mohan Radhakrishna, MD
Organizational Affiliation
McGill University Health Centre/Research Institute of the McGill University Health Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Pierre Guertin, Ph.D.
Organizational Affiliation
Nordic Life Science Pipeline/Université Laval
Official's Role
Study Director
Facility Information:
Facility Name
McGill University Health Centre (Montreal General Hospital)
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3G 1A4
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
20952632
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.
Results Reference
background
PubMed Identifier
20349462
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.
Results Reference
background
PubMed Identifier
19720083
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.
Results Reference
background
PubMed Identifier
19204052
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.
Results Reference
background
PubMed Identifier
18480366
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.
Results Reference
background
PubMed Identifier
16836640
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.
Results Reference
background
Links:
URL
http://nordiclifesciencepipeline.com
Description
Sponsor's website

Learn more about this trial

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

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