Clinical trial NCT03899584: High Doses of 4-aminopyridine in Clinically Complete Chronic Spinal Cord Injury Patients.
Official title: Quality of Life, Efficacy and Safety of High Doses of 4-aminopyridine in Patients With Clinically Complete Chronic Spinal Cord Injury: Multicenter, Randomized, Double Blind, Placebo Controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Spinal Cord Injuries
Chronic
Keywords: 4-Aminopyridine
erectile function
tetraplegia
rehabilitation
questionnaires
paraplegia
Lead sponsor: Coordinación de Investigación en Salud, Mexico
Sponsor class: OTHER_GOV
First posted: 2019-04-02
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 150 patients with clinically complete chronic spinal cord Injury will be included in a randomized, parallel, placebo controlled, multi-centric, phase III trial. Patients will be evaluated before starting the medication, and at the end of the treatment in the locomotor, sensory, grade of independence, sensitivity and control of bladder and anal sphincters, quality of life, and psychogenic erection in males. Patients will be divided randomly into two groups where one will receive placebo and the other one 4-Aminopyridine (4-AP) in a maximum of 30 weeks in increasing doses.

Detailed description: Consecutive patients with chronic AIS A tetraplegic or paraplegic with an MRI showing cord continuity will be recruited in the departments of neurology, neurosurgery or rehabilitation from hospitals of Social Security Mexican Institute (IMSS) in 8 states . Just patients who meeting inclusion criteria, will be selected for the study until reach 150. After signing an informed consent, they will be randomized into 75 for the intervention arm and 75 for the placebo arm. All patients will receive capsules for daily consumption according to their assignment. They will receive ascending doses of the drug starting with 10 milligrams and progressively increasing every 2 to 4 weeks 10 mg until reaching the maximum dose proposed according to weight (maximum 1 mg/kg/d). Questionnaires and functional evaluations will be administered at the beginning of the study, and at the end of the treatment to evaluate the efficacy. The evaluations include the International Standards for Neurological Classification of Spinal Cord Injury motor and sensory Scale, the Spinal Cord Injury Independence Measure (SCIM III), quality of life (SF-36), sphincter bladder/anal sensation/control in both genders and psychogenic erection in males as primary outcomes.

After the follow-up period, all test results will be analyzed and compared to determine the efficacy and safety of 4-aminopyridine. The Mann-Whitney U and Chi-square test will be used for statistical analysis.

Eligibility criteria: Inclusion Criteria: Patients with spinal cord injury (SCI) will be eligible for the study if they meet the following criteria:

1. Chronic AIS A tetraplegia or paraplegia for more tan 2 years before the study begin.
2. MRI showing cord continuity.
3. Neurologic Injury level of C4-T12.
4. Medically stable and able to breathe independently.
5. Stable neurologic deficits for more than 60 days before the study.
6. The absence of antiepileptic antecedent and electroencephalogram without epileptic activity.
7. They have maintained some type of rehabilitation after injury in the affected limbs and paralyzed extremities without passive limitations (healthy joints)
8. For females: postmenopausal or surgically sterile, or using an acceptable method of birth control.

Exclusion Criteria:

1. Pressure ulcers, skin infections, or phlebitis
2. History of cardiovascular disease (syncope, arrhythmia, or myocardial infarction within the last two years), systolic blood pressure greater than 150 or less than 70 mm Hg, diastolic blood pressure greater than 110 or less than 50 mm Hg, or heart rate greater than 110 or less than 50 beats/minute; impaired hepatic function (total hepatic enzyme or bilirubin levels greater than 2 times the upper limits of normal) or impaired renal function (creatinine level greater than 2 times the upper limits of normal) less than 6 months before the study
3. Know allergy to pyridine-containing drugs
4. Neurologic, degenerative, or psychiatric disorders that would impair the patient's ability to complete the protocol
5. Any illness or abnormality that would jeopardize patient safety or interfere with the conduct of the study
6. Inability to discontinue excluded concomitant drug therapy
7. Were pregnant or lactating
8. Had received any other investigational drug less tan 30 days before the study
9. History of drug or alcohol abuse
10. Treatment with and anti-spasticity compound and could not maintain a stable daily dosage
11. Had received any drug known to cause significant major organ toxicity less tan 3 months before the study
12. Peripheral neuropathy
13. Treatment with corticosteroids

Primary outcomes:
measure: Changes in Sensory Function
timeFrame: From baseline at 6 months after treatment
measure: Changes in Motor function
timeFrame: From baseline at 6 months after treatment
measure: Changes in the functional assement of Spinal Cord Independence
timeFrame: From baseline at 6 months after treatment
measure: Changes in the Sphincters function
timeFrame: From baseline at 6 months after treatment
measure: Change of overall quality of life score as measured by Short Form-36 (SF-36)
timeFrame: From baseline at 6 months after treatment
measure: Changes in Mean International Index of Erectile Function
timeFrame: From baseline at 6 months after treatment
measure: Incidence of Treatment-Emergent Adverse Events (Safety)
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Hospital de Especialidades, CMN Siglo XXI
Study officials:
affiliation: Instituto Mexicano del Seguro Social
name: Martín Paredes Cruz, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Mexicano del Seguro Social
name: Israel Grijalva Otero, PhD
role: STUDY_DIRECTOR
References:
citation: Hansebout RR, Blight AR, Fawcett S, Reddy K. 4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. J Neurotrauma. 1993 Spring;10(1):1-18. doi: 10.1089/neu.1993.10.1.
citation: Waxman SG. Aminopyridines and the treatment of spinal cord injury. J Neurotrauma. 1993 Spring;10(1):19-24. doi: 10.1089/neu.1993.10.19. No abstract available.
citation: Hayes KC, Blight AR, Potter PJ, Allatt RD, Hsieh JT, Wolfe DL, Lam S, Hamilton JT. Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury. Paraplegia. 1993 Apr;31(4):216-24. doi: 10.1038/sc.1993.40.
citation: Hayes KC, Potter PJ, Wolfe DL, Hsieh JT, Delaney GA, Blight AR. 4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. J Neurotrauma. 1994 Aug;11(4):433-46. doi: 10.1089/neu.1994.11.433.
citation: Zeidman SM, Ling GS, Ducker TB, Ellenbogen RG. Clinical applications of pharmacologic therapies for spinal cord injury. J Spinal Disord. 1996 Oct;9(5):367-80.
citation: Potter PJ, Hayes KC, Hsieh JT, Delaney GA, Segal JL. Sustained improvements in neurological function in spinal cord injured patients treated with oral 4-aminopyridine: three cases. Spinal Cord. 1998 Mar;36(3):147-55. doi: 10.1038/sj.sc.3100559.
citation: Hayes KC. 4-Aminopyridine and spinal cord injury: a review. Restor Neurol Neurosci. 1994 Jan 1;6(4):259-70. doi: 10.3233/RNN-1994-6401.
citation: Donovan WH, Halter JA, Graves DE, Blight AR, Calvillo O, McCann MT, Sherwood AM, Castillo T, Parsons KC, Strayer JR. Intravenous infusion of 4-AP in chronic spinal cord injured subjects. Spinal Cord. 2000 Jan;38(1):7-15. doi: 10.1038/sj.sc.3100931.
citation: van der Bruggen MA, Huisman HB, Beckerman H, Bertelsmann FW, Polman CH, Lankhorst GJ. Randomized trial of 4-aminopyridine in patients with chronic incomplete spinal cord injury. J Neurol. 2001 Aug;248(8):665-71. doi: 10.1007/s004150170111.
citation: Wolfe DL, Hayes KC, Hsieh JT, Potter PJ. Effects of 4-aminopyridine on motor evoked potentials in patients with spinal cord injury: a double-blinded, placebo-controlled crossover trial. J Neurotrauma. 2001 Aug;18(8):757-71. doi: 10.1089/089771501316919120.
citation: Grijalva I, Guizar-Sahagun G, Castaneda-Hernandez G, Mino D, Maldonado-Julian H, Vidal-Cantu G, Ibarra A, Serra O, Salgado-Ceballos H, Arenas-Hernandez R. Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial. Pharmacotherapy. 2003 Jul;23(7):823-34. doi: 10.1592/phco.23.7.823.32731.
citation: Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil. 2004 Jan;85(1):29-34. doi: 10.1016/s0003-9993(03)00651-8.
citation: DeForge D, Nymark J, Lemaire E, Gardner S, Hunt M, Martel L, Curran D, Barbeau H. Effect of 4-aminopyridine on gait in ambulatory spinal cord injuries: a double-blind, placebo-controlled, crossover trial. Spinal Cord. 2004 Dec;42(12):674-85. doi: 10.1038/sj.sc.3101653.
citation: Cardenas DD, Ditunno J, Graziani V, Jackson AB, Lammertse D, Potter P, Sipski M, Cohen R, Blight AR. Phase 2 trial of sustained-release fampridine in chronic spinal cord injury. Spinal Cord. 2007 Feb;45(2):158-68. doi: 10.1038/sj.sc.3101947. Epub 2006 Jun 13.
citation: Grijalva I, Garcia-Perez A, Diaz J, Aguilar S, Mino D, Santiago-Rodriguez E, Guizar-Sahagun G, Castaneda-Hernandez G, Maldonado-Julian H, Madrazo I. High doses of 4-aminopyridine improve functionality in chronic complete spinal cord injury patients with MRI evidence of cord continuity. Arch Med Res. 2010 Oct;41(7):567-75. doi: 10.1016/j.arcmed.2010.10.001.
citation: Cardenas DD, Ditunno JF, Graziani V, McLain AB, Lammertse DP, Potter PJ, Alexander MS, Cohen R, Blight AR. Two phase 3, multicenter, randomized, placebo-controlled clinical trials of fampridine-SR for treatment of spasticity in chronic spinal cord injury. Spinal Cord. 2014 Jan;52(1):70-6. doi: 10.1038/sc.2013.137. Epub 2013 Nov 12.