High Doses of 4-aminopyridine in Clinically Complete Chronic Spinal Cord Injury Patients.

NCT03899584 | Unknown Phase 3 DMC

• 1 other identifier: 2010-785-073
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

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.

Conditions

Spinal Cord Injuries; Chronic

Keywords

4-Aminopyridine; erectile function; tetraplegia; rehabilitation; questionnaires; paraplegia

Outcome Measures

Primary Outcomes (7)

• Changes in Sensory Function

  This function will be examined using the ASIA International Standards for the Neurological and Functional Classification of Spinal Cord Injury. Sensory function will be evaluated and qualify for two modes, pin prick / light touch in all dermatomes. The first one will be measured with the sharp and blunt end of a safety pin and the last one will be evaluated with a cotton ball. A scale of 3 points (0- 2) will be used depending on whether the modality is normal (2), diminished (1) or absent (0). A score of 2 for each of the 28 key sensory points tested on each side of the body would result in a maximum score of 56 for pin prick, 56 for light touch, and a total of 112, higher values represent a better outcome.

  From baseline at 6 months after treatment

• Changes in Motor function

  Motor function will be examined using the ASIA International Standards for the Neurological and Functional Classification of Spinal Cord Injury. Muscle strength will be evaluated in each of the 20 key muscles, five in each limb, representing segments of the spinal cord C5 through T1 and L2 through S1, using a six-point rating scale (0-5). There is a maximum score of 25 for each extremity, totaling 50 for the upper limbs and 50 for the lower limbs. Changes in motor score (total range from 0 to 100, higher values represent a better outcome).

  From baseline at 6 months after treatment

• Changes in the functional assement of Spinal Cord Independence

  The Spinal Cord Independence Measure version III (SCIM III) has 16 questions on self-care, respiratory and sphincter management and mobility in and out of home, which ranges from 0 (total dependence) to 100 points (total Independence).

  From baseline at 6 months after treatment

• Changes in the Sphincters function

  The function of the anal sphincter and the bladder will be evaluated. The anal function will be qualified as a sensation when the patient can differentiate when the rectum is full and ready to empty and control when the patient can stop the fecal evacuation with enough time to reach the bathroom and eliminate the fecal material. The function of the bladder will be classified in the same way as the anal function. Positive or negative will be the final result of sensation and control.

  From baseline at 6 months after treatment

• Change of overall quality of life score as measured by Short Form-36 (SF-36)

  The Short Form-36 (SF-36) has 36 questions. Each question has a score, which will be transformed into a 0 to 100 scale, where 0 corresponds to "the worst health state" and 100 to "the best health state".

  From baseline at 6 months after treatment

• Changes in Mean International Index of Erectile Function

  The international Index of Erectile Function (IIEF) contains 15 questions, rated from 0 or 1 to 5, yielding an overall score of 5-75 points. A score of 1-10 indicates severe erectile dysfunction, 11-16 moderate dysfunction, 17-25 mild dysfunction, and greater than 25 "normal" function.

  From baseline at 6 months after treatment

• Incidence of Treatment-Emergent Adverse Events (Safety)

  Safety will be measured by occurrence of Treatment-Emergent Adverse Events (TRAEs); data will represent the number of participants with abnormal laboratory values and/or adverse events that are related to treatment.

  6 months

Study Arms (2)

Treatment with 4-aminopyridine

ACTIVE COMPARATOR

The 4-aminopyridine will be administered in the form of gelatin capsules containing 4-aminopyridine 10 mg and microcrystalline cellulose as excipient. The dose of 4-aminopyridine will increase 10 mg / every 2 to 4 weeks until reaching the maximum dose proposed by weight ( maximum 1 mg / kg / d).

Drug: 4-Aminopyridine

Placebo oral capsule

PLACEBO COMPARATOR

Patients randomized to the placebo sequence will receive placebo in the same way as those who will take 4-AP. They will be blinded to the fact that they are taking placebo and the capsules will be identical in appearance to the intervention capsules.

Drug: Placebo oral capsule

Interventions

4-Aminopyridine DRUG

Each patient will take 10 mg per kilogram of weight (example: a person weighing 60 kg, will take two capsules three times a day after meals, for a total of 6 capsules / day). Each capsule will contain 10 milligrams of 4-Aminopyridine that will allow to be administered sequentially at progressively higher doses / day. The dose of 4-aminopyridine will increase 10 mg / 2 to 4 weeks.

Also known as: 4-AP

Treatment with 4-aminopyridine

Placebo oral capsule DRUG

The placebo arm will include a placebo of microcrystalline cellulose.

Also known as: Microcrystalline cellulose

Placebo oral capsule

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Pressure ulcers, skin infections, or phlebitis
• 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
• Know allergy to pyridine-containing drugs
• Neurologic, degenerative, or psychiatric disorders that would impair the patient's ability to complete the protocol
• Any illness or abnormality that would jeopardize patient safety or interfere with the conduct of the study
• Inability to discontinue excluded concomitant drug therapy
• Were pregnant or lactating
• Had received any other investigational drug less tan 30 days before the study
• History of drug or alcohol abuse
• Treatment with and anti-spasticity compound and could not maintain a stable daily dosage
• Had received any drug known to cause significant major organ toxicity less tan 3 months before the study
• Peripheral neuropathy
• Treatment with corticosteroids

Sponsors & Collaborators

• Coordinación de Investigación en Salud, Mexico: lead

Study Sites (1)

Hospital de Especialidades, CMN Siglo XXI

Mexico City, 06725, Mexico

Location

Related Publications (16)

• 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.

  PMID: 8320728 BACKGROUND

• 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.

  PMID: 8320729 BACKGROUND

• 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.

  PMID: 8493036 BACKGROUND

• 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.

  PMID: 7837283 BACKGROUND

• 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.

  PMID: 8938604 BACKGROUND

• 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.

  PMID: 9554012 BACKGROUND

• 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.

  PMID: 21551756 BACKGROUND

• 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.

  PMID: 10762192 BACKGROUND

• 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.

  PMID: 11569894 BACKGROUND

• 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.

  PMID: 11526982 BACKGROUND

• 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.

  PMID: 12885095 BACKGROUND

• 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.

  PMID: 14970964 BACKGROUND

• 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.

  PMID: 15356676 BACKGROUND

• 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.

  PMID: 16773037 BACKGROUND

• 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.

  PMID: 21167397 BACKGROUND

• 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.

  PMID: 24216616 BACKGROUND

MeSH Terms

Conditions

Spinal Cord Injuries; Bronchiolitis Obliterans Syndrome; Quadriplegia; Paraplegia

Interventions

4-Aminopyridine; microcrystalline cellulose

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aminopyridines; Amines; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Martín Paredes Cruz, MSc

  Instituto Mexicano del Seguro Social

  PRINCIPAL INVESTIGATOR

• Israel Grijalva Otero, PhD

  Instituto Mexicano del Seguro Social

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2019
• First Posted: April 2, 2019
• Study Start: July 17, 2019
• Primary Completion: December 1, 2022
• Study Completion: December 1, 2023
• Last Updated: February 21, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)