The objective of the present investigator-initiated mono-center trial to be performed at the Department of Neurology of the University Hospital Zurich is a detailed characterization of the effects of prolonged-release fampridine on walking function of 50-70 patients with MS. In a randomized, double-blind, placebo-controlled study with cross-over design, changes of essential gait elements such as stability, coordination, correct loading, posture or endurance in addition to walking speed after treatment with prolonged-release fampridine will be investigated using a comprehensive kinematic gait analysis protocol. This protocol comprises outcome parameters ranging from very specific and sensitive biomechanical measures to clinically meaningful indicators of improved ambulatory function. Kinematic, kinetic and electromyographic gait parameters will be assessed during treadmill walking (primary outcome parameters). Changes in overground walking capacity will be investigated by means of different functional walking tests (e.g. six minute walk test). Furthermore, the patient's perception of the effects of the treatment on walking function will be evaluated by a standardized questionnaire. Changes of global ambulatory activity will be assessed (Actimeter) indicating a successful translation of improved gait (sub-)functions due to prolonged-release fampridine treatment into everyday life. The study will last for a period of 18 weeks, excluding the screening period. Based on the mechanism of action, the investigators hypothesize that treatment with prolonged-release fampridine will not only improve walking speed, but also clinically more meaningful features of walking function in patients with MS.

• Trial with medicinal product

Inclusion Criteria:

1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
2. Male or female subjects must be 18 to 65 years old, inclusive, at the time of informed consent.
3. Must have a diagnosis of either primary progressive, secondary progressive, progressive remitting, or relapsing remitting MS as defined by the revised McDonald Committee criteria [Lublin et al. 1996; McDonald et al. 2001; Polman et al. 2005; Section 22.4, Appendix L] of at least 3 months duration.
4. Must be able to walk at least 50 meters (with or without a walking aid) at each individual 6minWT conducted pre-randomization.
5. Must have an impaired walking function demonstrated by a mild gait ataxia (Functional System (FS) score = 2 in the cerebellar system component of the EDSS) or a FS score of > 2 in the pyramidal system component of the EDSS based only on evaluation of the lower limbs (hip flexors, knee flexors, knee extensors, and ankle dorsiflexors)or a restricted ambulation (< 1h walking duration) at the Screening Visit.
6. Female subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 30 days after their last dose of study treatment.
7. Subjects must be able to understand the patient information sheet and comply with the requirements of the protocol.

Main Exclusion Criteria:

• Any history of seizure, epilepsy, or other convulsive disorder, with the exception of febrile seizures in childhood.
• Any prior treatment with anti-epileptic medications specifically prescribed for the treatment of epilepsy.
• Onset of MS exacerbation within the 60 days prior to the Screening Visit.
• Use of mitoxantrone, cyclophosphamide, rituximab, alemtuzumab, daclizumab, cladribine or any other immune suppressant (except FTY720) or antibody (except natalizumab) within 3 months prior to the Screening Visit, or scheduled use during study participation.
• Pulsed steroid treatment within the 60 days prior to the Screening Visit, or at any time during the screening period.
• Women who are pregnant or breast feeding,
• Clinically significant concomitant disease states such as renal failure, (e.g., moderate or severe renal impairment), hepatic dysfunction (e.g., acute or chronic hepatitis), cardiovascular or pulmonary disease, malignant disease (tumor, neoplasia) etc.
• Participation in another study with investigational drug within the 30 days preceding and during the present study.
• Contraindications to the class of drugs under study, e.g. known allergy to pyridine-containing substances.
• Any prior treatment with fampridine (4-aminopyridine; 4 AP) or 3,4-diaminopyridine in any formulation.
• Patients with an acute urinary tract infection at the Screening Visit as indicated by symptoms like painful urination/dysuria, urinary frequency, urinary urgency, pollakiuria, suprapubic pain, flank pain, costovertebral angle tenderness or fever >38°C in combination with a clinically significant pathological finding in the urine analysis (e.g., positive for leukocytes) at the Screening.