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

Sponsor

Coordinación de Investigación en Salud, Mexico (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03899584

Collaborator

(none)

150

Enrollment

Location

Arms

52.5

Anticipated Duration (Months)

2.9

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injuries Chronic	Drug: 4-Aminopyridine Drug: Placebo oral capsule	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 17, 2019

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Treatment with 4-aminopyridine 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 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. Other Names: 4-AP
Placebo Comparator: Placebo oral capsule 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 The placebo arm will include a placebo of microcrystalline cellulose. Other Names: Microcrystalline cellulose

Arm

Intervention/Treatment

Active Comparator: Treatment with 4-aminopyridine

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

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.

Other Names:

4-AP

Placebo Comparator: Placebo oral capsule

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

The placebo arm will include a placebo of microcrystalline cellulose.

Other Names:

Microcrystalline cellulose

Outcome Measures

Primary Outcome Measures

Changes in Sensory Function [From baseline at 6 months after treatment]
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.
Changes in Motor function [From baseline at 6 months after treatment]
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).
Changes in the functional assement of Spinal Cord Independence [From baseline at 6 months after treatment]
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).
Changes in the Sphincters function [From baseline at 6 months after treatment]
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.
Change of overall quality of life score as measured by Short Form-36 (SF-36) [From baseline at 6 months after treatment]
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".
Changes in Mean International Index of Erectile Function [From baseline at 6 months after treatment]
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.
Incidence of Treatment-Emergent Adverse Events (Safety) [6 months]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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.

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital de Especialidades, CMN Siglo XXI	Mexico City		Mexico	06725

Sponsors and Collaborators

Coordinación de Investigación en Salud, Mexico

Investigators

Principal Investigator: Martín Paredes Cruz, MSc, Instituto Mexicano del Seguro Social
Study Director: Israel Grijalva Otero, PhD, Instituto Mexicano del Seguro Social