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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Nordic Life Science Pipeline Inc.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Nordic Life Science Pipeline Inc.
ClinicalTrials.gov Identifier:
NCT01484184
First received: November 25, 2011
Last updated: July 19, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Spinal Cord Injury
Drug: SPINALON (buspirone + levodopa + cardidopa)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Tri-therapy (SPINALON)-Elicited Spinal Locomotor Network Activation: Phase I-IIa Clinical Trial in Patients With Chronic Spinal Cord Injury

Resource links provided by NLM:


Further study details as provided by Nordic Life Science Pipeline Inc.:

Primary Outcome Measures:
  • Heart rate [ Time Frame: Steadily during 4 hours post-single administration vs pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: During 4 hours post-single administration vs pre-administration ] [ Designated as safety issue: No ]
    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 [ Time Frame: 15, 30, 60, 120 and 240 min post-administration vs pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: During 4 hours post-single administration vs pre-administration ] [ Designated as safety issue: Yes ]
    Systolic and diastolic blood pressure values as a safety measure will be measured as mmHg during 4 hours

  • Respiration rate [ Time Frame: During 4 hours post-single administration vs pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: During 4 hours post-single administration vs. pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: During 4 hours post-single administration vs. pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Once at 4 hours post-single administration vs pre-administration ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: During 2 hours post-administration vs pre-administration ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 51
Study Start Date: July 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 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.
Drug: SPINALON (buspirone + levodopa + cardidopa)
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.
Other Names:
  • Apo-Buspirone 10 mg tablets (DIN 02211076)
  • Sinemet 100/25 mg tablets (DIN 00513997)
Placebo Comparator: 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.
Drug: SPINALON (buspirone + levodopa + cardidopa)
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.
Other Names:
  • Apo-Buspirone 10 mg tablets (DIN 02211076)
  • Sinemet 100/25 mg tablets (DIN 00513997)

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

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01484184

Contacts
Contact: Mohan Radhakrishna, MD 514-934-1934 ext 44185 mohan.radhakrishna@muhc.mcgill.ca

Locations
Canada, Quebec
McGill University Health Centre (Montreal General Hospital) Recruiting
Montreal, Quebec, Canada, H3G 1A4
Contact: Mohan Radhakrishna, MD    514-934-1934 ext 44185    mohan.radhakrishna@muhc.mcgill.ca   
Sponsors and Collaborators
Nordic Life Science Pipeline Inc.
Investigators
Principal Investigator: Mohan Radhakrishna, MD McGill University Health Center
Study Director: Pierre Guertin, Ph.D. Nordic Life Science Pipeline/Université Laval
  More Information

Additional Information:
Publications:
Responsible Party: Nordic Life Science Pipeline Inc.
ClinicalTrials.gov Identifier: NCT01484184     History of Changes
Other Study ID Numbers: SPIN-01
Study First Received: November 25, 2011
Last Updated: July 19, 2013
Health Authority: Canada: Health Canada
Canada: Olympia Monitoring

Keywords provided by Nordic Life Science Pipeline Inc.:
Completely paralyzed
Chronically injured
Comorbid problems
Central Pattern Generator
Locomotion
Secondary complications
Activity-based training
Treadmill training

Additional relevant MeSH terms:
Spinal Cord Injuries
Wounds and Injuries
Spinal Cord Diseases
Central Nervous System Diseases
Nervous System Diseases
Trauma, Nervous System
Buspirone
Levodopa
Anti-Anxiety Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Psychotropic Drugs
Serotonin Receptor Agonists
Serotonin Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antiparkinson Agents
Anti-Dyskinesia Agents
Dopamine Agents

ClinicalTrials.gov processed this record on September 14, 2014