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

NCT01484184 | Completed Phase 1 DMC

• 1 other identifier: SPIN-01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (1)

• Occurrence of rhythmic leg EMGs

  During 2 hours post-administration vs pre-administration

Study Arms (2)

buspirone or levodopa/carbidopa

ACTIVE COMPARATOR

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)

Placebo

PLACEBO COMPARATOR

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)

Interventions

SPINALON (buspirone + levodopa + cardidopa) DRUG

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.

Also known as: Apo-Buspirone 10 mg tablets (DIN 02211076), Sinemet 100/25 mg tablets (DIN 00513997)

Placebo; buspirone or levodopa/carbidopa

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• years of age
• Men and women
• Quebec Province residents only

You may not qualify if:

• 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

Sponsors & Collaborators

• Nordic Life Science Pipeline Inc.: lead
• United States Department of Defense: collaborator

Study Sites (1)

McGill University Health Centre (Montreal General Hospital)

Montreal, Quebec, H3G 1A4, Canada

Location

Related Publications (6)

• 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.

  PMID: 20952632 BACKGROUND

• 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.

  PMID: 20349462 BACKGROUND

• 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.

  PMID: 19720083 BACKGROUND

• 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.

  PMID: 19204052 BACKGROUND

• 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.

  PMID: 18480366 BACKGROUND

• 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.

  PMID: 16836640 BACKGROUND

MeSH Terms

Conditions

Spinal Cord Injuries; Paraplegia; Quadriplegia

Interventions

Buspirone; Levodopa; carbidopa, levodopa drug combination

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Spiro Compounds; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Polycyclic Compounds; Dihydroxyphenylalanine; Catecholamines; Amines; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Tyrosine

Study Officials

• Mohan Radhakrishna, MD

  McGill University Health Centre/Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

• Pierre Guertin, Ph.D.

  Nordic Life Science Pipeline/Université Laval

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2011
• First Posted: December 2, 2011
• Study Start: July 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: August 20, 2015

Record last verified: 2015-08

Locations

CA (1)