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Multiple SclerosisPhase 2NCT02280096

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

A Phase 2 study testing 4-aminopyridine in people with Multiple Sclerosis, run by Coordinación de Investigación en Salud, Mexico at 1 site in Mexico.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 60 years
Conditions the study is for
Multiple Sclerosis
What is being tested?
4-aminopyridine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
24 participants
Where
1 siteMexico
Study dates
Oct 2014to Feb 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

None listed.

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

Mexico1 site

  • Hospital de Especialidades, CMN Siglo XXI

    Mexico City, Mexico City, 06725

Other trials in Mexico

About this study

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.

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.

Read the 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.

Being tested
4-aminopyridine, Placebo
Keywords
Cognitive function, Multiple sclerosis, 4-aminopyridine, Fatigue
Medical subject headings
Multiple Sclerosis, Fatigue

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • 4-aminopyridineDrug

    Also called 4-AP

    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.

  • PlaceboDrug

    Also called Microcrystalline Cellulose

    The placebo arm will include Microcrystalline Cellulose placebo

Study groups in NCT02280096
Study groupRoleWhat they receive
4-aminopyridine treatmentActive comparator4-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.
Receives: Drug: 4-aminopyridine
PlaceboPlacebo comparatorPatients 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.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 10-15 minutes

  2. 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.

    Measured: 7-10 min

  3. 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).

    Measured: 10-15 minutes

  4. 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.

    Measured: 8-10 min

  5. 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)

    Measured: 10-15 minutes

  6. 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).

    Measured: 5-8 minutes

  7. 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).

    Measured: 25-30 minutes

  8. 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).

    Measured: 25-30 minutes

Secondary outcomes (4)

  1. Improved Physical Capacity

    The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. It is widely used in clinical trials and in the assessment of people with MS. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist. The first levels 1.0 to 4.5 refers to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refers to the loss of ambulatory ability. It also provides eight subscale measurements called Functional System (FS) scores. The levels of function within each category refer to the eight FS affected by MS: The FS are scored on a scale of 0 (low level of problems) to 5 (high level of problems) to best reflect the level of disability observed clinically.

    Measured: 15-20 minutes

  2. Fatigue

    The Fatigue Severity Scale (FSS) is one of the most frequently used inventories for measuring fatigue in people with chronic illnesses. The FSS questionnaire is comprised of nine statements inquiring about the examinee's sleep habits over the preceding week. Ratings are on a 7-point Likert scale, where higher scores indicate how strongly the patient agrees with the nine statements.Scale. Scoring using a bimodal response system or a Likert score with weights assigned to each response choice. Likert or bimodal rating scales with 4 response options. For the Likert Scale: better than usual= 0, no more than usual= 1, worse than usual= 2, much worse than usual= 3. For the bimodal scale: better than usual= 0, no more than usual= 0, worse than usual= 1, much worse than usual= 1. Sum all items for a total score. Score range. Range is 0 -11 for bimodal response format. Interpretation of scores. Higher score indicates more fatigue. Self report scale

    Measured: 10 minutes

  3. Walk

    Timed 25 Foot Walk Test (T25-FW). The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the instruction to start and ends when the patient has reached the 25-foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. TIME LIMIT PER TRIAL (2) 3 minutes (180 seconds) per trial.

    Measured: 5-10 minutes

  4. Number of Participants With Abnormal Studies

    Safety surveillance will be done every two weeks from the beginning of the study, intentionally searching for adverse events (AE). EEG (Diffuse or focal cerebral dysfunction through demonstration of background slowing or presence of epileptiform activity assessed by a neurophysiologist) and laboratory tests (Presence of values higher of the normal value established by local laboratory and related to the administration of treatments), blood and urine samples: creatinine, blood urea nitrogen, total cholesterol, triglycerides, total direct, and indirect bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine kinase, lactic acid dehydrogenase, amylase and lipase. A complete blood cell count with differentials and a routine urinalysis and urine culture also obtained at each visit, will be done before the patients take 40, 50 and 60 mg/day. The number of participants with abnormal studies were reported.

    Measured: 22 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Oct 2014 (estimated)
  2. Study startOct 2014
  3. Primary completionFeb 2016
  4. Study completionFeb 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02280096
Sponsor's protocol ID
2012-785-091
Status last verified
Feb 2017
First submitted
10 Oct 2014
Last updated
12 Sep 2019
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • 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.

    PubMed 24290498

  • 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.

    PubMed 16643949

  • 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.

    PubMed 15327047

  • 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.

    PubMed 11795455

  • 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.

    PubMed 7936300

  • 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.

    PubMed 30593980

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 4-aminopyridine in people with Multiple Sclerosis, run by Coordinación de Investigación en Salud, Mexico at 1 site in Mexico.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 0 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Mexico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 12 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Brief Repeatable Battery of Rao (time frame: 10-15 minutes). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02280096, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Sep 2019.

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