Efficacy and Safety of 4-aminopyridine on Cognitive Performance and Motor Function of Patients With Multiple Sclerosis

NCT02280096 | Completed Phase 2 Results DMC

• 1 other identifier: 2012-785-091
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis

Keywords

Cognitive function; Multiple sclerosis; 4-aminopyridine; Fatigue

Outcome Measures

Primary Outcomes (8)

• The Brief Repeatable Battery of Rao

  Neuropsychological tests to assess: verbal fluency. Participants have to say as many words as possible from a category in a given time 60 Sec (F, A, S) Max score 72 and min score 19 words. Higher scores indicate a better cognitive performance.

  10-15 minutes

• Integrated Program of Neuropsychological Exploration Test Barcelona

  Integrated Program of Neuropsychological Exploration Test Barcelona: Digit Span Forward (DSF), (attention spam and improved scoring metrics significantly enhance the precision of DSF assessments of short-term verbal memory). Digit sequences are presented beginning with a length of two digits and two trials are presented at each increasing list length. Max score 8 and min score 0 digits. Higher scores indicate a better cognitive performance.

  7-10 min

• Rey-Osterrieth Complex Figure Test (ROCF)

  The purpose of this test is to assess visual-spatial constructional ability and visual memory. The time required to copy the drawing is recorded. Less time indicates a better performance and more time indicates a worse outcome (min score 60 and max score 300 seconds).

  10-15 minutes

• Five Digit Test (FDT). Processing Speed

  Processing speed information (which includes reading, count, and alternation speed). Cards with a different number of stimuli are shown to the patient, who has to read, count, and respond to a change of instructions (alternation). Reading speed (min 12, max 31+ seconds), counting speed (min 14, max 28+ seconds), and alternation speed (min 26, max 56+ seconds) are recorded. Less speed corresponds to a better outcome.

  8-10 min

• Wisconsin Card Sorting Test (WCST)

  Is used primarily to assess perseveration and abstract thinking, allows the clinician to assess the following 'frontal' lobe functions: strategic planning, organised searching, utilising environmental feedback to shift cognitive sets, directing behaviour toward achieving a goal. WCST measures abstract reasoning and ability to alter problem solving strategies. Patients are given 128 response cards and 4 stimulus cards and asked to match each stimulus card to 1 pile of response cards. The patient is not told how to match the cards, only "right" or "wrong" to each placement. The examiner may change matching rules during the test. Perseveration errors occur when subject repeats the same error no matter how many times they are told the placement is wrong. Higher scores indicate a worse cognitive performance (min=0-3, max=58-126)

  10-15 minutes

• Color Trails Test (CTT)

  Measure sustained attention. The CTT uses numbered coloured circles and universal sign language symbols. The circles are printed with vivid pink or yellow backgrounds that are perceptible to colourblind individuals. For the Colour Trails 1 trial, the respondent uses a pencil to rapidly connect circles numbered 1 through 25 in sequence. Less time indicates better performance (min=10, max= 240).

  5-8 minutes

• Tower Of London (TOL). Total Moves and Total Correct Moves

  Measures higher order problem-solving ability. The information it provides is not only useful when assessing frontal lobe damage, but also when evaluating attention disorders and executive functioning difficulties. The administrator arranges red, green, and blue beads on a peg board to match the configuration in the diagram. The patient is asked to replicate the configuration on a second peg board. Scores are calculated for Total Correct Moves and Total Moves. Total moves: higher scores indicate a worse cognitive performance (min= 0, max=58+); Total correct higher scores indicate a better cognitive performance (min=0, max=10).

  25-30 minutes

• Tower Of London (TOL). Execution Time and Problem-solving Time

  Measures higher-order problem-solving ability. The information it provides is not only useful when assessing frontal lobe damage, but also when evaluating attention disorders and executive functioning difficulties. The administrator arranges red, green, and blue beads on a peg board to match the configuration in the diagram. The patient is asked to replicate the configuration on a second peg board. Scores are calculated for Total Execution Time (since the patient performs the first move until he ends the test), Total Problem-Solving Time (the sum of planning and execution times). Total execution time higher scores indicate a worse outcome (min= 0-78, max=564+ seconds), Total problem-solving time higher scores indicate a worse outcome (min= 0-56, max=500+ seconds).

  25-30 minutes

Secondary Outcomes (4)

• Improved Physical Capacity

  15-20 minutes

• Fatigue

  10 minutes

• Walk

  5-10 minutes

• Number of Participants With Abnormal Studies

  22 weeks

Study Arms (2)

4-aminopyridine treatment

ACTIVE COMPARATOR

4-aminopyridine is given as gelatin capsules containing 4-aminopyridine 10 mg and microcrystalline cellulose as the excipient. Each patient will take two capsules every 8 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study.

Drug: 4-aminopyridine

Placebo

PLACEBO COMPARATOR

Patients randomized to the placebo sequence will receive placebo for 20 weeks after the run-in period. They will be blinded to the fact that they are taking placebo, and capsules will be identical in appearance to the intervention capsules.

Drug: Placebo

Interventions

4-aminopyridine DRUG

Each patient will take two capsules every 8 hours after meals, for a total of 6 capsules/day. The 4-aminopyridine dosage will increase 10 mg/4 weeks by substitution of placebo instead of 4-aminopyridine capsules; such that patients will receive from 40 to 60 mg. distribute in 6capsules/day throughout the study.

Also known as: 4-AP

4-aminopyridine treatment

Placebo DRUG

The placebo arm will include Microcrystalline Cellulose placebo

Also known as: Microcrystalline Cellulose

Placebo

Eligibility Criteria

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

You may qualify if:

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

You may not qualify if:

• 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
• Known 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
• History of substance abuse
• Inability to discontinue excluded concomitant drug therapy

Sponsors & Collaborators

• Coordinación de Investigación en Salud, Mexico: lead

Study Sites (1)

Hospital de Especialidades, CMN Siglo XXI

Mexico City, Mexico City, 06725, Mexico

Location

Related Publications (6)

• 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.

  PMID: 24290498 BACKGROUND

• 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.

  PMID: 16643949 BACKGROUND

• 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.

  PMID: 15327047 BACKGROUND

• 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.

  PMID: 11795455 BACKGROUND

• 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.

  PMID: 7936300 BACKGROUND

• 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.

  PMID: 30593980 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis; Fatigue

Interventions

4-Aminopyridine; microcrystalline cellulose

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

As the sample size is very small, it is recommended to increase the number of patients. The heterogeneity in cognitive processes would imply a greater restriction criteria in the selection of patients to avoid the ceiling effect.

Results Point of Contact

• Title: Dr. Israel Grijalva
• Organization: Instituto Mexicano del Seguro Social. Unidad de Investigación Médica en Enfermedades Neurológicas.

igrijalvao@yahoo.com

(01152) 5555780240

Study Officials

• Claudia Arreola Mora, MS

  Instituto Mexicano del Seguro Social

  PRINCIPAL INVESTIGATOR

• Israel Grijalva, PhD

  Instituto Mexicano del Seguro Social

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2014
• First Posted: October 31, 2014
• Study Start: October 1, 2014
• Primary Completion: February 1, 2016
• Study Completion: February 1, 2017
• Last Updated: September 12, 2019
• Results First Posted: September 12, 2019

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)