Clinical trial NCT02280096: Efficacy and Safety of 4-aminopyridine on Cognitive Performance and Motor Function of Patients With Multiple Sclerosis
Official title: Efficacy and Safety of 4-aminopyridine on Cognitive Performance and Motor Function of Patients With Multiple Sclerosis. Randomized, Blinded, Placebo-controlled Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: Cognitive function
Multiple sclerosis
4-aminopyridine
Fatigue
Lead sponsor: Coordinación de Investigación en Salud, Mexico
Sponsor class: OTHER_GOV
First posted: 2014-10-31
Enrollment: 24
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: Twenty four relapsing-remitting multiple sclerosis (RRMS) patients over the age of 18, with similar degree of disability, and with an evolution of at last 6 months, who are in first-line immunomodulatory therapy and have a stable disease (no more than one outbreak per year) will be included in the present study. Patients will be administered a neuropsychological test battery selected for this study and divided into two sessions of one and a half-hour each. Emotional state will be assessed with the Beck Depression Inventory in a different session. Cognitive impairment is defined as the alteration of two or more neuropsychological tests. Patients will be divided randomly into two groups where one will receive placebo and the other one 4-Aminopyridine (4-AP) for a period of 22 weeks in increasing doses.

Detailed description: Consecutive patients with stable multiple sclerosis are being recruited from the neurological services of Social Security Mexican Institute (IMSS) at the National Medical Center (CMN) "Siglo XXI" Specialties Hospital over the period of 1 year. Of those meeting inclusion criteria, 24 will be selected for the study. After signing an informed consent, they will be randomized into 12 for the intervention arm and 12 for the placebo arm. All patients will receive capsules for daily consumption according to their assignment, with no visible difference between capsules. Dosage will be 6.5-7.5 mg/kg to a limit of 50 mg. These capsules will be taken for a period of 22 weeks. A battery of neuropsychological tests will be administered at baseline, after 22 weeks, and after an additional 22 weeks of follow-up to assess cognitive performance and motor function. Emotional state will be assessed with the Beck Depression Inventory at each of the three afore mentioned points.

After the follow-up period, all test results will be analyzed and compared to determine the efficacy and safety of 4-aminopyridine on the cognitive performance and motor function of patients. Mann-Whitney U will be used for statistical analysis.

Eligibility criteria: Inclusion Criteria: Patients with multiple sclerosis (MS) are eligible for the study if they meet the following criteria:

1. Relapsing recurrent MS with an evolution of at last 6 months before the study began.
2. Both males and females, aged 20 - 65 years
3. Neurologic Expanded Disability Status Scale (EDSS) 3 - 7
4. Who are in first-line immunomodulatory therapy and have a stable disease
5. No more than one outbreak per year.
6. The absence of antiepileptic antecedent and electroencephalogram without epileptic activity.
7. For females: postmenopausal or surgically sterile, or using an acceptable method of birth control

Exclusion Criteria:

1. 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
2. Known allergy to pyridine-containing drugs
3. Neurologic, degenerative, or psychiatric disorders that would impair the patient's ability to complete the protocol
4. Any illness or abnormality that would jeopardize patient safety or interfere with the conduct of the study
5. History of substance abuse
6. Inability to discontinue excluded concomitant drug therapy

Primary outcomes:
measure: The Brief Repeatable Battery of Rao
timeFrame: 10-15 minutes
measure: Integrated Program of Neuropsychological Exploration Test Barcelona
timeFrame: 7-10 min
measure: Rey-Osterrieth Complex Figure Test (ROCF)
timeFrame: 10-15 minutes
measure: Five Digit Test (FDT). Processing Speed
timeFrame: 8-10 min
measure: Wisconsin Card Sorting Test (WCST)
timeFrame: 10-15 minutes
measure: Color Trails Test (CTT)
timeFrame: 5-8 minutes
measure: Tower Of London (TOL). Total Moves and Total Correct Moves
timeFrame: 25-30 minutes
measure: Tower Of London (TOL). Execution Time and Problem-solving Time
timeFrame: 25-30 minutes
Secondary outcomes:
measure: Improved Physical Capacity
timeFrame: 15-20 minutes
measure: Fatigue
timeFrame: 10 minutes
measure: Walk
timeFrame: 5-10 minutes
measure: Number of Participants With Abnormal Studies
timeFrame: 22 weeks
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Hospital de Especialidades, CMN Siglo XXI
state: Distrito Federal
Study officials:
affiliation: Instituto Mexicano del Seguro Social
name: Claudia Arreola Mora, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Mexicano del Seguro Social
name: Israel Grijalva, PhD
role: STUDY_DIRECTOR
References:
citation: Ruck T, Bittner S, Simon OJ, Gobel K, Wiendl H, Schilling M, Meuth SG. Long-term effects of dalfampridine in patients with multiple sclerosis. J Neurol Sci. 2014 Feb 15;337(1-2):18-24. doi: 10.1016/j.jns.2013.11.011. Epub 2013 Nov 16.
citation: Amato MP, Portaccio E, Zipoli V. Are there protective treatments for cognitive decline in MS? J Neurol Sci. 2006 Jun 15;245(1-2):183-6. doi: 10.1016/j.jns.2005.07.017. Epub 2006 Apr 27.
citation: Romani A, Bergamaschi R, Candeloro E, Alfonsi E, Callieco R, Cosi V. Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment. Mult Scler. 2004 Aug;10(4):462-8. doi: 10.1191/1352458504ms1051oa.
citation: Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, Carlesimo GA, Zibellini G, Caltagirone C. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler. 2001 Dec;7(6):354-8. doi: 10.1177/135245850100700602.
citation: Smits RC, Emmen HH, Bertelsmann FW, Kulig BM, van Loenen AC, Polman CH. The effects of 4-aminopyridine on cognitive function in patients with multiple sclerosis: a pilot study. Neurology. 1994 Sep;44(9):1701-5. doi: 10.1212/wnl.44.9.1701.
citation: Arreola-Mora C, Silva-Pereyra J, Fernandez T, Paredes-Cruz M, Bertado-Cortes B, Grijalva I. Effects of 4-aminopyridine on attention and executive functions of patients with multiple sclerosis: Randomized, double-blind, placebo-controlled clinical trial. Preliminary report. Mult Scler Relat Disord. 2019 Feb;28:117-124. doi: 10.1016/j.msard.2018.12.026. Epub 2018 Dec 19.