Randomized Placebo-controlled Phase II Cross-over Study on the Influence of Fampridine on Working Memory in Healthy Subjects
Phase: PHASE2
Conditions: Working Memory
Sponsor: Prof. Dominique de Quervain, MD

 
 
 
Study Protocol FamH  
 
 
 
 
 
 
 
                Version 7, 5thApril 2022 
Authors: de Quervain / Gerhards 
 
Page 1 of 48 
Randomized placebo-controlled phase II cross-over 
study on the influence of fampridine on working 
memory in healthy subjects 
 
Study-ID: FamH 
 
 
 
Clinical Study Protocol 
 
 
 
 
 
Study Type 
Clinical Trial with Investigational Medicinal Product (IMP) 
Study Categorization 
Risk category B according to HRA 
Study Registration 
NCT04652557 
Study ID 
FamH 
Sponsor-Investigator 
Prof. Dominique de Quervain, MD 
University of Basel 
Co-Director Transfaculty Research Platform Molecular and Cognitive 
Neurosciences 
Director Division of Cognitive Neuroscience 
Birmannsgasse 8, 4055 Basel 
E-Mail: dominique.dequervain@unibas.ch 
Phone: +41 61 207 02 37 
Sponsor 
Prof. Andreas Papassotiropoulos, MD 
University of Basel 
Co-Director Transfaculty Research Platform Molecular and Cognitive 
Neurosciences 
Director Division of Molecular Neuroscience 
Birmannsgasse 8, 4055 Basel 
E-Mail: andreas.papas@unibas.ch 
Phone: +41 61 207 05 99 
Investigational Product 
Fampridine (Fampyra®) 
Protocol Version and Date 
Version 7 (dated 05/04/2022) 
 
The information contained in this document is the property of the sponsors. The information may not – in 
full or in part – be transmitted, reproduced, or published without prior written authorization from the 
sponsors  
 

PRoToCOL SIGNATURE FORM
Study Title
Study number
Protocol Version
Basel,7th April2022
Randomized placebo-controlled phase ll cross-over study on the influence of
fampridine on working memory in healthy subjects
NCT04652557
Version 7 (dated 0510412022)
Sponsors
The sponsors have approved and confirm hereby to conduct the study according to the protocol, current
version of the World Medical Association Declaration of Helsinki, and ICH-GCP guidelines as well as the
local legally applicable requirements.
Prof. Dominique de Quervain, MD
Sponsor-lnvestigator
/,û-<
Place/Date
Signature
Prof. Andreas Papassotiropoulos, M D
Sponsor
Basel,7th April2022
Place/Date
Local Investigators and trial statistician at study site
I have read and understood this trial protocol and agree to conduct the trial as set out in this study protocol,
the current version of the World Medical Association Declaration of Helsinki, ICH-GCP guidelines and the
local legally applicable requirements.
Studv Site: University of Basel, Division of Cognitive Neuroscience, Birmannsgasse 8, CH-4055 Basel
Christiane Gerhards, MD
lnvestigator
?
Place/Date
Signature
Annette Harings-Kaim, MD
lnvestigator
{\or^-{_ c}. ùtl,x.F1L A"
(^"^-^.
Place/Datè
Signature
Nathalie Schicktanz, PhD
Trial statistician
Basel, 7th April2022
l/
Place/Date
4l?
S
Study Protocol FamH
Authors: de Quervain / Gerhards
Version 7, SthApril 2022
Page 2 of 48

 
 
 
Study Protocol FamH  
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE FORM 
2 
STUDY SYNOPSIS 
6 
GLOSSARY OF ABBREVIATIONS 
10 
STUDY SCHEDULE 
12 
1 
STUDY ADMINISTRATIVE STRUCTURE 
13 
2 
ETHICAL AND REGULATORY ASPECTS 
15 
2.1 
Study registration 
15 
2.2 
Categorization of study 
15 
2.3 
Competent Ethics Committee (CEC) 
15 
2.3.1 
Notification and reporting upon completion, discontinuation or interruption of the clinical trial 
(ClinO, Art. 38) 
15 
2.3.2 
Notification and reporting of safety and protective measures (ClinO, Art. 37 and 43) 
15 
2.4 
Competent Authority (CA) 
15 
2.4.1 
Notification and reporting upon completion, discontinuation or interruption of the clinical trial 
(ClinO, Art. 38) 
15 
2.4.2 
Notification and reporting of safety and protective measures (ClinO, Art. 37 and 43) 
16 
2.5 
Ethical Conduct of the Study 
16 
2.6 
Declaration of interest 
16 
2.7 
Patient Information and Informed Consent 
16 
2.8 
Participant privacy and confidentiality 
16 
2.9 
Early termination of the study 
17 
2.10 
Protocol amendments 
17 
2.10.1 
Reporting to the Competent Ethics Committee (CEC) 
17 
2.10.2 
Reporting to the Competent Authority (CA) 
17 
3 
BACKGROUND AND RATIONALE 
18 
3.1 
Background and Rationale 
18 
3.2 
Investigational Product (treatment) and Indication 
18 
3.3 
Preclinical Evidence 
19 
3.4 
Clinical Evidence to Date 
19 
3.5 
Dose Rationale 
19 
3.6 
Explanation for choice of placebo 
20 
3.7 
Risks / Benefits 
20 
Fampridine application 
20 
rMT measurement 
21 
3.8 
Justification of choice of study population 
22 
4 
STUDY OBJECTIVES 
23 
4.1 
Overall Objective 
23 
4.2 
Primary Objective 
23 
4.3 
Secondary Objectives 
23 
4.4 
Safety Objectives 
23 
5 
STUDY OUTCOMES 
24 
5.1 
Primary Outcome 
24 
5.2 
Secondary Outcomes 
24 
5.3 
Safety Outcomes 
24 
5.4 
Assessment of potential confounders 
24 
6 
STUDY DESIGN 
25 
6.1 
General study design and justification of design 
25 
6.2 
Methods of minimizing bias 
25 
6.2.1 
Randomization 
25 
6.2.2 
Blinding procedures 
25 
6.2.3 
Other methods of minimizing bias 
26 
6.3 
Unblinding Procedures (Code break) 
26 

 
 
 
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7 
STUDY POPULATION 
27 
7.1 
Eligibility criteria 
27 
7.2 
Recruitment and screening 
28 
7.3 
Assignment to study groups 
28 
7.4 
Criteria for withdrawal / discontinuation of participants 
28 
7.5 
Contraception and pregnancy 
29 
8 
STUDY INTERVENTION 
29 
8.1 
Identity of Investigational Products 
29 
8.1.1 
Experimental Intervention 
29 
8.1.2 
Control Intervention 
29 
8.1.3 
Packaging, Labelling and Supply (re-supply) 
29 
8.1.4 
Storage Conditions 
29 
8.2 
Administration of experimental and control interventions 
29 
8.2.1 
Experimental Intervention 
29 
8.2.2 
Control Intervention 
29 
8.3 
Dose 
30 
8.4 
Compliance with study intervention 
30 
8.5 
Data Collection and Follow-up for withdrawn participants 
30 
8.6 
Trial specific preventive measures 
30 
8.7 
Concomitant Interventions (treatments) 
30 
8.8 
Study Drug Accountability 
30 
8.9 
Return or Destruction of Study Drug 
30 
9 
STUDY ASSESSMENTS 
31 
9.1 
Study flow chart(s) / table of study procedures and assessments 
31 
9.2 
Assessments of outcomes 
31 
9.2.1 
Assessment of primary outcome 
31 
9.2.2 
Assessment of secondary outcomes 
31 
9.3 
Assessment of safety outcomes 
32 
9.4 
Procedures at each visit and during treatment periods 
32 
9.4.1 
Screening visit 
32 
9.4.2 
Test days (visits 2-5) 
33 
9.4.3 
Treatment periods 
34 
10 
SAFETY 
35 
10.1 
Definitions 
35 
10.1.1 
Adverse Event (AE) 
35 
10.1.2 
Serious Adverse Event (SAE) 
35 
10.1.3 
Unexpected Adverse Drug Reaction 
35 
10.1.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
35 
10.2 
Assessment of (Serious) Adverse Events and other safety related events 
36 
10.2.1 
Assessment of causality 
36 
10.2.2 
Assessment of Severity 
36 
10.3 
Documentation 
36 
10.3.1 
Serious Adverse Events (SAE) 
36 
10.3.2 
Adverse Events (AE) 
36 
10.4 
Reporting of serious adverse events (SAE) and other safety related events 
36 
10.4.1 
Reporting of SAEs 
36 
10.4.2 
Reporting of SUSARs 
36 
10.4.3 
Reporting of safety signals 
37 
10.4.4 
Reporting and handling of pregnancies 
37 
10.4.5 
Periodic reporting of safety 
37 
10.4.6 
Follow-up of (Serious) Adverse Events (AE) 
37 
11 
STATISTICAL METHODS 
38 
11.1 
Hypothesis 
38 
11.2 
Determination of Sample Size 
38 
11.3 
Statistical criteria of termination of trial 
38 

 
 
 
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11.4 
Planned Analyses 
38 
11.4.1 
Datasets to be analyzed, analysis populations 
38 
11.4.2 
Analysis for the primary outcome 
38 
11.4.3 
Analyses for secondary outcomes 
38 
11.4.4 
Interim analyses 
39 
11.4.5 
Safety analysis 
39 
11.4.6 
Deviation(s) from the original statistical plan 
39 
11.4.7 
Handling of missing data and drop-outs 
39 
12 
QUALITY ASSURANCE AND CONTROL 
40 
12.1 
Responsibilities 
40 
12.2 
Data handling and record keeping / archiving 
40 
12.2.1 
Case Report Forms (CRF) 
40 
12.2.2 
Specification of source documents 
40 
12.2.3 
Record keeping / Archiving 
41 
12.3 
Data management 
41 
12.3.1 
Pseudonymization and Coding 
41 
12.3.2 
Data Security and Access 
41 
12.3.3 
Data Management Systems, Back-up 
41 
12.3.4 
Analysis and Archiving 
42 
12.3.5 
Electronic and central data validation 
42 
12.4 
Monitoring 
42 
12.5 
Audits and inspections 
42 
12.6 
Confidentiality and Data Protection 
43 
13 
PUBLICATION AND DISSEMINATION POLICY 
44 
14 
FUNDING AND SUPPORT 
44 
15 
INSURANCE 
44 
16 
REFERENCES 
45 
16.1 
Regulatory Documents 
45 
16.2 
References 
45 
 
 
 

 
 
 
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STUDY SYNOPSIS 
Sponsor-
Investigator 
Prof. Dominique de Quervain, MD, 
Transfaculty Research Platform Molecular and Cognitive Neurosciences, 
University of Basel.  
Sponsor 
Prof. Andreas Papassotiropoulos, MD 
Transfaculty Research Platform Molecular and Cognitive Neurosciences, 
University of Basel.  
Study Title 
Randomized placebo-controlled phase II cross-over study on the influence 
of fampridine on working memory in healthy subjects  
Study ID 
FamH 
Protocol Version 
and Date 
Version 7 (dated 05/04/2022) 
Trial Registration 
NCT04652557 (Clinicaltrials.gov) 
Study Category and 
Rationale 
Risk category B according to ClinO Art. 19 
Fampridine is approved in Switzerland for treatment of gait problems in 
patients with MS. We will use fampridine for a different indication. 
Clinical Phase 
Phase II, proof of concept 
Background and 
Rationale  
Large genome-wide association studies for schizophrenia suggest that 
genetic variations (single nucleotide polymorphisms) in genes encoding 
potassium channels modify the risk for the development of this disorder. In 
healthy humans we found that genetic variations in the same genes are also 
associated with working memory, an established heritable cognitive 
component (endophenotype) of schizophrenia. 
Objectives 
To investigate the effects of fampridine - an inhibitor of voltage‐gated 
potassium (Kv) channels - on working memory in healthy participants.  
Outcomes 
Primary outcome will be  
• 
High-load working-memory performance: 3-back (d’) as assessed 
by a letter n-back task (Heck, Fastenrath et al. 2014) after repeated 
intake 
Secondary outcomes will be  
• 
High-load working-memory performance in a 3-back (d’) task after 
acute intake 
• 
Reaction time (for correct 3-back responses) after acute and 
repeated intake 
• 
Performance in a 0-back (d’) task as a measure of attention after 
acute and repeated intake 
• 
Processing speed task (Symbol Digit Modalities Test, SDMT; Smith 
1973) after acute and repeated intake 
• 
BOMAT - advanced (Hossiep/Turck/Hasella, 1999) after acute and 
repeated intake 
• 
Digit span forward and backward performance (von Aster 2006) 
after acute and repeated intake 
• 
Resting motor threshold (rMT) after repeated intake, measured by 
transcranial magnetic stimulation (TMS) 
Safety outcomes will be   
• 
Headache, gastrointestinal discomfort, dizziness  
• 
AE-recording 
• 
Vital signs 
Study Design 
Randomized, placebo-controlled, double blind, cross-over 

 
 
 
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Inclusion- / Exclusion 
Criteria 
Inclusion criteria: 
• 
male or female 
• 
generally healthy  
• 
normotensive (BP between 90/60mmHg and 140/90mmHg) 
• 
BMI between 19 and 29,9 kg/m2 
• 
aged between 18 and 30 years  
• 
fluent German-speaking  
• 
IC as documented by signature 
• 
At least double vaccination against Covid-19 
Exclusion criteria: 
• 
contraindications to the class of drugs under study, e.g. known 
hypersensitivity or allergy to 4-aminopyridine 
• 
use of potassium channel blockers within the last 3 months 
• 
concomitant treatment with OCT 2 inhibitors and substrates (e.g. 
cimetidine, propranolol) 
• 
acute or chronic psychiatric disorder (e.g. major depression, 
psychoses, somatoform disorder, suicidal tendency)  
• 
acute cerebrovascular condition 
• 
history of seizures 
• 
risk of lowered seizure threshold (due to e.g. sleep deprivation, 
withdrawal of alcohol after alcohol abuse) 
• 
renal impairment 
• 
history of malignant cancers 
• 
walking problems (e.g. due to dizziness) 
• 
other clinically significant concomitant disease states (e.g. hepatic 
dysfunction, cardiovascular disease, diabetes, asthma) 
• 
bradycardia < 50/min during clinical examination 
• 
clinically significant laboratory or ECG abnormality that could be a 
safety issue in the study  
• 
known or suspected non-compliance  
• 
drug or alcohol abuse 
• 
inability to follow the procedures of the study, e.g. due to language 
or psychological problems of the participant 
• 
participation in another study with an investigational drug within the 
30 days preceding and during the present study 
• 
prior participation (less than two years ago) in a study investigating 
working memory (notably the n-back task) 
• 
enrolment of the investigator, his/her family members, employees 
and other dependent persons 
• 
smoking (>3 cigarettes per day)  
• 
intake of psychoactive drugs (e.g. benzodiazepines, 
antidepressants, neuroleptics)  
• 
pregnancy or breast feeding  
• 
experiencing a syncope during basal rMT measuring 
 
Exclusion Criteria concerning TMS measurement 
• 
metal in the brain, skull or elsewhere in the body (e.g., splinters, 
fragments, clips, etc.) 
• 
implanted neurostimulator (e.g., DBS, epidural/subdural, VNS) 
• 
cardiac pacemaker or intracardiac lines 
• 
medication infusion device 
• 
piercings, pivot teeth (retainers are no exclusion criterion) 
• 
tattoos (head area) less than 3 months old or older than 20 years 
• 
condition after neurosurgery 

 
 
 
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• 
hearing problems or tinnitus 
• 
not able to sit still due to tremor, tics, itching 
• 
history of repeated syncope  
• 
head trauma diagnosed as concussion or associated with loss of 
consciousness 
• 
diagnosis of epilepsy, or a convulsion or a seizure in the past of the 
participant or his family 
• 
TMS in the past showing problems 
• 
MRI in the past showing problems 
• 
surgical procedures to spinal cord 
• 
spinal or ventricular derivations 
Measurements and 
procedures 
Assessment of efficacy: Performance in cognitive tasks at two time points 
(after acute and repeated administration) and rMT at one time point (after 
repeated administration) 
• 
Effect after acute administration (visits 2 and 4): the assessment 
will be performed 4 hours after intake of 10 mg fampridine or 
placebo. 
• 
Effect after repeated administration (visits 3 and 5): 3.5 days after 
intake of twice daily doses of 10 mg fampridine or placebo. The 
assessment will be performed 4 hours after the last intake of study 
medication 
• 
Assessment of safety: AE recording, vital signs 
Study Product  
Twice daily oral administration of 10 mg fampridine (Fampyra®) for 3.5 
days  
Control Intervention 
Twice daily oral administration of placebo for 3.5 days  
Number of 
Participants with 
Rationale 
Total of 44 participants, approx. 22 male and 22 females. There will be 
replacement of Drop-Outs until data from 44 participants are completed. 
The estimation of N=44 is based on a power analysis assuming to detect a 
medium effect size of a drug with a power of 90% at α=0.05. 
Study Duration 
Study duration is estimated to be 18 months. 
Study Schedule 
First participant in 09/2021 (planned) 
Last participant out 02/2023 (planned) 
Investigators 
Christiane Gerhards, MD 
Transfaculty Research Platform 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel  
Phone: +41 61 207 0244 
Fax: 
+41 61 207 0241 
Email: christiane.gerhards@unibas.ch 
Annette Harings-Kaim, MD 
Transfaculty Research Platform 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
Phone: +41 61 207 0251 
Fax: 
+41 61 207 0241 
E-Mail: annette.harings@unibas.ch 

 
 
 
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Study Centre 
University of Basel 
Transfaculty Research Platform Molecular and Cognitive Neurosciences 
Birmannsgasse 8 
4055 Basel 
Statistical 
Considerations 
Linear mixed models will be used to compare the effect of fampridine and 
placebo on primary and secondary outcome variables. 
GCP Statement 
This study will be conducted in compliance with the protocol, the current 
version of the Declaration of Helsinki, the ICH-GCP as well as all national 
legal and regulatory requirements. 
 
 
 
 

 
 
 
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GLOSSARY OF ABBREVIATIONS 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
4-AP 
 
4-Aminopyridine  
ASR 
 
Annual Safety Repot  
AST 
 
Aspartate Aminotransferase 
BASEC  
Business Administration System for Ethical Committees 
BMI 
 
Body Mass Index 
BOMAT 
Bochumer Matrizentest 
BP 
 
Blood Pressure 
Bpm 
 
Beats per minute 
CA 
 
Competent Authority 
CEC 
 
Competent Ethics Committee 
CTCAE  
Common Terminology Criteria for Adverse Events 
ClinO 
Ordinance on Clinical Trials in Human Research  
CRF 
Case Report Form 
CTU 
Clinical Trial Unit 
DS 
Digit Span Task 
ECG 
Electrocardiography 
eCRF  
Electronic Case Report Form 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
EMG 
Electromyography 
FADP  
Federal Act on Data Protection  
FOPH  
Federal Office of Public Health 
GCP 
 
Good Clinical Practice 
Gf 
 
Fluid Intelligence 
GGT 
 
Gamma-Glutamyltransferase 
GMP 
 
Good Manufacturing Practice 
GWAS  
Genome-wide association studies 
Ho 
 
Null hypothesis 
H1 
 
Alternative hypothesis 
hCG  
 
Human choriogonadotropin 
HR 
 
Heart Rate 
HRA 
 
Federal Act on Research involving Human Beings  
IC 
 
Informed Consent 
ICH 
 
International Conference on Harmonisation  
IEC 
 
Independent Ethics Committee 
IIT 
 
Investigator-initiated trial 
IMP 
 
Investigational Medicinal Product 
IR 
 
Immediate Release 
Kv 
 
Voltage‐gated potassium channel 
LDH 
 
Lactatdehydrogenase 
LTP 
 
Long-Term-Potentiation  
MADRS 
Montgomery Åsberg Depression Rating Scale 

 
 
 
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MEP 
 
Motor Evoked Potential   
MNI 
 
Montreal Neurological Institute 
MRHD  
Maximum Recommended Human Dose 
MS 
 
Multiple Sclerosis 
MSO 
 
Maximum Stimulator Output 
MTI 
 
Maximum Tolerated Imbalance 
OCT 2  
Organic Cation Transporter 2 
PI 
 
Principal Investigator 
PR 
 
Prolonged Release 
rMT 
 
resting Motor Threshold 
SADRS 
Serious Adverse Drug Reaction 
SAE 
 
Serious Adverse Event 
SD 
 
Source Data 
SDMT  
Symbol Digit Modalities Test 
SDV 
 
Source Data Verification 
SNCTP  
Swiss National Clinical Trials Portal 
SOP 
 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SR 
 
Sustained Release 
TMF 
 
Trial Master File 
TMS 
 
Transcranial Magnetic Stimulation 
V/P 
 
Verum/Placebo 
VAS 
 
Visual Analog Scale 
WI 
 
Working Instruction 
WIE 
 
Wechsler Intelligenztest für Erwachsene  
 
 

 
 
 
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STUDY SCHEDULE 
 
 
Duration 
 
Treatment period 1 
(3.5 days) 
 
Wash-out 
period 
8-82 days 
between V3 
and V4 
Treatment period 2 
(3.5 days) 
Visit 
 
Visit 1 
Visit 2  
 
Visit 3 
 
Visit 4 
 
Visit 5 
Description 
 
Screening 
Test day 
1 
P/V 
or 
V/P 
Test day 
2 
Wash-out 
period 
Test day 
3 
V/P 
or 
P/V 
Test day 
4 
Day 
 
within 14 
days before 
Visit 2 
1 
 
4 
 
12-30 
 
15-33 
Screening 
• 
Written informed consent, 
assignment of the subject 
number 
• 
Personal, family and 
medication history 
• 
Self-assessment mental health 
and sleeping habits, MADRS-S, 
EHI 
• 
Physical examination 
• 
ECG, Blood sample  
1.5 h 
x 
 
 
 
 
 
 
 
Treatment periods 
• 
Electronic intake diary 
• 
Electronic AE diary (VAS 
headache, gastrointestinal 
discomfort, dizziness; free text) 
3.5 days 
 
 
x 
 
 
 
x 
 
Wash-out period 
(8-82 days between V3 and V4) 
8-82 days 
 
 
 
 
x 
 
 
 
Test days 
 
 
 
 
 
 
 
 
 
Pre-examination test days 
• 
Vital signs 
• 
Flu-like symptoms, common 
cold symptoms 
• 
Pregnancy test (Visits 2 and 4) 
• 
Questionnaire drugs and 
alcohol consumption during last 
3 days resp. past 12 hours 
• 
Sleep duration last 24 hours 
• 
AE recording 
• 
VAS headache, gastrointestinal 
discomfort, dizziness; VAS 
tiredness, motivation 
15 min 
 
x 
 
x 
 
x 
 
x 
Assignment of the randomization 
number 
5 min 
 
x 
 
 
 
 
 
 
Intake of study medication 
5 min 
 
x 
x 
x 
 
x 
x 
x 
Waiting time  
(incl. continental breakfast 2 hours 
after intake of study medication) 
4 h 
 
x 
 
x 
 
x 
 
x 
Before start of testing 
• 
AE recording  
• 
VAS headache, gastrointestinal 
discomfort, dizziness; VAS 
tiredness, motivation  
15 min 
 
x 
 
x 
 
x 
 
x 
Testing Phase – part 1 
• 
n-Back  
• 
Processing speed task SDMT 
• 
Digit Span 
45 min 
 
x 
 
x 
 
x 
 
x 
Break 
15 min 
 
x 
 
x 
 
x 
 
x 
Testing Phase – part 2 
• 
BOMAT 
15 min 
 
x 
 
x 
 
x 
 
x 
rMT measurement using TMS 
15 min 
x 
 
 
x 
 
 
 
x 
Final Examination  
• 
AE recording 
• 
VAS headache, gastrointestinal 
discomfort, dizziness; VAS 
tiredness, motivation 
15-20 min 
 
x 
 
x 
 
x 
 
x 
 
 

 
 
 
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1 STUDY ADMINISTRATIVE STRUCTURE 
Function 
Address  
Sponsor Investigator 
Prof. Dominique de Quervain, MD 
University of Basel 
Co-Director Transfaculty Research Platform Molecular and Cognitive 
Neurosciences 
Director Division of Cognitive Neuroscience 
Birmannsgasse 8, 4055 Basel 
 
E-Mail: dominique.dequervain@unibas.ch  
Phone: +41 61 207 0237 
Sponsor 
Prof. Andreas Papassotiropoulos, MD 
University of Basel 
Co-Director Transfaculty Research Platform Molecular and Cognitive 
Neurosciences 
Director Division of Molecular Neuroscience 
Birmannsgasse 8, 4055 Basel 
 
E-Mail: andreas.papas@unibas.ch 
Phone: +41 61 207 0599 
Investigators 
Christiane Gerhards, MD 
Transfaculty Research Platform 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
 
E-Mail: christiane.gerhards@unibas.ch 
Phone: +41 61 207 0244 
 
Annette Harings-Kaim, MD 
Transfaculty Research Platform 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
 
E-Mail: annette.harings@unibas.ch 
Phone: +41 61 207 0251 
Trial statistician 
Nathalie Schicktanz, PhD 
Transfaculty Research Platform 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
 
E-Mail: nathalie.schicktanz@unibas.ch 
Phone: +41 61 207 0228 

 
 
 
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CTU / Monitoring Institution 
 
 
 
 
Contact person monitoring 
 
 
 
Contact person database 
administrator 
 
CTU Basel 
Universitätsspital Basel 
Schanzenstrasse 55 (BH 3)  
4031 Basel 
 
Klaus Ehrlich 
Phone:  +41 61 556 52 61 
E-mail: klaus.ehrlich@usb.ch 
 
Patrick Simon 
Phone: +41 61 556 50 55 
E-mail: patrick.simon@usb.ch 
PRU 
 
 
 
 
 
 
Contact Person 
Klinische Pharmakologie & Toxikologie (Forschung) 
Phase I Research Unit (PRU) 
Ambulantes Studienzentrum 
Universitätsspital Basel 
Schanzenstrasse 55 
4031 Basel 
 
Joyce Santos   
Study nurse 
Phone: +41 61 328 77 91 
E-Mail: joyce.santos@usb.ch 
Laboratory 
 
 
 
 
Contact Person 
Labormedizin 
Universitätsspital Basel 
Petersgraben 4  
4031 Basel 
 
Corinne Büeler 
Studienkoordinatorin Labormedizin 
Phone: +41 61 328 53 96 
Fax: +41 61 265 46 00 
E-Mail: studienkoordination.labor@usb.ch 
Pharmacy 
 
 
 
 
 
 
Contact Person 
Spital-Pharmazie 
Universitätsspital Basel 
Qualitätssicherung 
Rossetti-Bau 
Spitalstrasse 26 
4031 Basel 
 
Anne Henn 
Apothekerin / Studienkoordinatorin 
Phone: +41 61 328 42 78 
Fax: +41 61 265 32 75 
E-mail: anne.henn@usb.ch 
 
 
 

 
 
 
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2 ETHICAL AND REGULATORY ASPECTS 
The decision of the competent ethics committee (CEC) and the competent authority (CA) concerning the 
conduct of the study will be made in writing to the Sponsor-Investigator before commencement of this 
study. The clinical study can only begin once approval from all required authorities has been received. 
Any additional requirements imposed by the authorities shall be implemented. 
2.1 
Study registration  
The study will be registered in the registry clinicaltrial.gov and in the Swiss National Clinical Trials Portal 
(SNCTP) before the start of recruitment. 
2.2 
Categorization of study  
This clinical trial comes under Category B as fampridine (Fampyra®) is authorized in Switzerland and it 
is used in an indication different from that specified in the prescribing information. 
2.3 
Competent Ethics Committee (CEC)  
The sponsor-investigator will obtain approval from CEC (EKNZ) before the start of the clinical trial. 
No changes are made to the protocol without prior sponsor-investigator and CEC approval, except where 
necessary to eliminate apparent immediate hazards to study participants. 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse Reactions (SUSAR) are 
reported according to chapter 10.3. 
Amendments are reported according to chapter 2.10 
2.3.1 
Notification and reporting upon completion, discontinuation or interruption of the clinical trial 
(ClinO, Art. 38) 
The following notifications have to be made by the sponsor investigator to the CEC (EKNZ): 
• 
The completion of the study within 90 days. Completion of a clinical trial is marked by the last 
participant’s final visit.  
• 
The discontinuation or interruption of the clinical trial within 15 days. In the notification, the 
reasons for the discontinuation or interruption shall be stated.  
• 
The final report shall be submitted within two years after completion or discontinuation of the 
clinical trial. 
2.3.2 
Notification and reporting of safety and protective measures (ClinO, Art. 37 and 43) 
The following notifications and reporting have to be made by the sponsor-investigator to the CEC (EKNZ): 
• 
If immediate safety and protective measures have to be taken during the conduct of the clinical 
trial, a notification shall be submitted within 7 days. In the notification, these measures and the 
circumstances necessitating them shall be stated.  
• 
Annual safety report once a year. 
2.4 
Competent Authority (CA) 
The sponsor will obtain approval from the CA (Swissmedic) before the start of the clinical study.  
No changes are made to the protocol without prior Sponsor and CA approval, except where necessary to 
eliminate apparent immediate hazards to study participants. 
Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse Reactions (SUSAR) are 
reported according to chapter 10.3. 
Amendments are reported according to chapter 2.10.  
2.4.1 
Notification and reporting upon completion, discontinuation or interruption of the clinical trial 
(ClinO, Art. 38) 
The following notifications have to be made by the sponsor investigator to the CA (Swissmedic): 
• 
The completion of the study within 90 days. Completion of a clinical trial is marked by the last 
participant’s final visit. 

 
 
 
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• 
The discontinuation or interruption of the clinical trial within 15 days. In the notification, the 
reasons for the discontinuation or interruption shall be stated. 
• 
The final report shall be submitted within two years after completion or discontinuation of the 
clinical trial. 
2.4.2 
Notification and reporting of safety and protective measures (ClinO, Art. 37 and 43) 
The following notifications and reporting have to be made by the sponsor investigator to the CA 
(Swissmedic): 
• 
if immediate safety and protective measures have to be taken during the conduct of the clinical 
trial, a notification shall be submitted within 7 days. In the notification, these measures and the 
circumstances necessitating them shall be stated. 
• 
Annual Safety Report (ASR). 
2.5 
Ethical Conduct of the Study  
The study will be carried out in accordance to the protocol and with principles enunciated in the current 
version of the Declaration of Helsinki, the guidelines of Good Clinical Practice (GCP) issued by ICH, the 
Swiss Law and Swiss regulatory authority’s requirements. The CEC and the CA will receive annual safety 
and interim reports and they will be informed about study stop/end.  
2.6 
Declaration of interest  
The authors certify that they have no intellectual, financial or proprietary conflict and are independent. 
2.7 
Patient Information and Informed Consent 
The investigators will explain to each participant the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits and any discomfort it may entail. Each 
participant will be informed that the participation in the study is voluntary and that he/she may withdraw 
from the study at any time and that withdrawal of consent will not affect his/her subsequent medical 
assistance and treatment.  
The participant must be informed that his/her medical records may be examined by authorized individuals 
other than their treating physician. 
All interested persons will be provided with sufficient information to make an informed decision about their 
participation in the study. The “study information and informed consent form” will be sent by e-mail to 
interested persons before telephone screening. They will be given time (at least 24 hours) between the 
receipt of the “patient information and informed consent form” and screening for their decision to 
participate. For details of the recruiting procedures see chapter 7.2. 
The formal consent of a participant, using the approved consent form, must be obtained before the 
participant is submitted to any study procedure.   
The participant should read and consider the statement before signing and dating the informed consent 
form, and should be given a copy of the signed document. The consent form must also be signed and 
dated by the investigator (or his designee) at the same time as the participant sign, and it will be retained 
as part of the study records. 
2.8 
Participant privacy and confidentiality  
The investigators affirm and uphold the principle of the participant's right to privacy and that they shall 
comply with applicable privacy laws. Especially, anonymity of the participants shall be guaranteed when 
presenting the data at scientific meetings or publishing them in scientific journals.  
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality will be further ensured by utilizing subject 
identification code numbers to correspond to treatment data in the computer files. 
For data verification purposes, authorized representatives of the sponsor-investigator, a competent 
authority (e.g. Swissmedic), or the ethics committee may require direct access to parts of the medical 
records relevant to the study, including participants’ medical history. 

 
 
 
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2.9 
Early termination of the study  
The sponsor-investigator may terminate the study prematurely according to certain circumstances, for 
example: 
• 
ethical concerns; 
• 
insufficient participant recruitment; 
• 
when the safety of the participants is doubtful or at risk, respectively; 
• 
alterations in accepted clinical practice that make the continuation of a clinical trial unwise; 
• 
early evidence of benefit or harm of the experimental intervention.  
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the CEC and the CA respectively. 
Under emergency circumstances, deviations from the protocol to protect the rights, safety and well-being 
of participants may proceed without prior approval of the sponsor-investigator, the CEC and the CA. Such 
deviations shall be documented and reported to the sponsor-investigator, the CEC and the CA as soon 
as possible.  
Other reporting commitments are reported according to the chapters 2.3 and 2.4 and safety issues 
according to chapter 10. 
2.10.1 
Reporting to the Competent Ethics Committee (CEC) 
Substantial amendments: The following changes are considered to be significant and have to be reported 
to the CEC by the sponsor investigator (ClinO, Art. 29): 
• 
amendments with effect on the safety and health of the human participants as well as on their 
rights and obligations; 
• 
deviations from the protocol due to new scientific findings regarding the experimental design, 
methods, target criteria or statistical evaluation concepts; 
• 
changes of locations or use of additional locations for the implementation of the clinical trial; 
• 
changes of sponsor or investigators. 
The sponsor-investigator shall submit to the CEC any application documents specified in Annex 3 of the 
ClinO, which are affected by the change. At the same time, the sponsor-investigator shall provide 
information on the reasons for the change. The ethics committee shall reach a decision within 30 days. 
Non-substantial changes must be notified to the CEC in the Annual Safety Report (ASR).  
2.10.2 
Reporting to the Competent Authority (CA) 
Substantial amendments: The following changes are considered to be significant and have to be reported 
to the CA by the sponsor-investigator (ClinO, Art. 34): 
• 
changes of the study medication, its application or administration; 
• 
changes based on new preclinical or clinical data which may affect product safety; or 
• 
changes concerning the production of the IMP, which may affect product safety. 
The sponsor shall submit to the CA any application documents specified in Annex 4 of the ClinO, which 
are affected by the change. At the same time, the sponsor shall provide information on the reasons for 
the change. The CA shall reach a decision within 30 days after receipt of the complete application 
documents affected by the change. 
Non-substantial changes, which affect the documents submitted to CA, must be communicated to CA as 
soon as possible. 
 

 
 
 
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3 BACKGROUND AND RATIONALE 
3.1 
Background and Rationale  
We have shown previously that combining genome-wide association studies (GWAS) of disease with 
genetic studies of cognitive and behavioral endophenotypes (i.e. heritable disease components 
observable also in non-affected individuals) may lead to the identification of compounds that modulate 
cognitive and behavioral traits relevant to the respective disease (Papassotiropoulos, Gerhards et al. 
2013).  
Large GWAS of schizophrenia suggest that genetic variations (single nucleotide polymorphisms) in genes 
encoding potassium channels modify the risk for the development of this disorder (Pardinas, Nalmpanti 
et al. 2019) 
In healthy humans (for methods see (Papassotiropoulos, Stephan et al. 2006, Papassotiropoulos, Henke 
et al. 2009)) we found that genetic variations in the same genes are also associated significantly with 
working memory performance, an established cognitive endophenotype of schizophrenia. These findings 
suggest that this class of genes may play a role in working memory and, consequently, that a 
pharmacological agent that interacts with the respective gene products may modulate this cognitive trait 
in health and disease. For phenotype description see (de Quervain, Henke et al. 2003, de Quervain, 
Kolassa et al. 2007, Heck, Fastenrath et al. 2014). 
Here, we aim at investigating if the administration of Fampyra®, an inhibitor of voltage gated potassium 
channels, affects working memory in healthy humans.  
Furthermore we want to investigate whether fampridine has an influence on resting motor threshold (rMT). 
For the rMT measurement we will use single pulse TMS.  
In a study of our research group we could show that resting motor threshold correlated with working 
memory performance in healthy humans (Schicktanz et al. 2014). In a study investigating rMT in patients 
with schizophrenia a negative correlation between rMT and working memory was confirmed (Bridgman, 
Barr et al. 2016). 
Literature in relation to the effect of fampridine SR on rMT is scarce, and to our knowledge there is no 
study published examining healthy participants.  
Neurophysiological studies in MS patients are controversial. One placebo controlled study of 40 MS 
patients found no effect for any of the clinical or electrophysiological measures and esp. on rMT after 8 
weeks treatment of fampridine 10 mg bd (Marion, Leonid et al. 2020). Another one failed to show an effect 
on rMT after 14 days treatment with 10 mg fampridine bd in 20 MS patients (Ahdab, Shatila et al. 2019) 
Krushkov on the other hand found significant effects on rMT after treating 18 MS patients for 5 days with 
2x10mg fampridine i.m. (Krushkov, Shotekov et al. 2006). 
3.2 
Investigational Product (treatment) and Indication  
Active study medication consists of 7 tablets of fampridine 10mg sustained release (SR) formulated for 
oral administration (Fampyra®), manufactured by  
Alkermes Pharma Ireland Ltd, Monksland,  
Athlone, Co.  
Westmeath, Ireland 
Biogen Idec (Denmark)  
Manufacturing ApS, Biogen Idec Allé 1, Hillerod,  
DK-3400, Denmark 
Fampridine is a potassium channel blocker indicated to improve walking in patients with multiple sclerosis. 
This was demonstrated by an increase in walking speed (Jeffery and Pharr 2010). Fampyra® whose 
active ingredient is prolonged release 4-aminopyridine (4-AP), is a broad-spectrum voltage-dependent K+ 
channel blocker, which can increase action potential propagation in demyelinated axons (Chwieduk and 
Keating 2010). The compound, which is lipid soluble, crosses the axon membrane, blocking the exposed 
K+ channels; this decreases K+ loss, increases action potentials and conduction, and promotes synaptic 
and neuromuscular transmission of nerve signals (Chwieduk and Keating 2010). Prolonged release 

 
 
 
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fampridine is completely absorbed from the gastrointestinal tract and this more slowly than immediate 
release (IR) fampridine (Fernandez, Berger et al. 2012). This decreases peak plasma concentration by 
50%, which consequently reduces dose-related adverse effects. (Fernandez, Berger et al. 2012). SR 
fampridine should be administered under fasting conditions: administration with food increases peak 
plasma concentration, leading to increased risk of adverse effects (Weir, Torkin et al. 2013), see also 
prescribing information of Fampyra® SR. Tablets should only be taken whole; not divided, crushed, chew, 
or dissolved. 
Apparent first-order terminal elimination half-life t1/2 of fampridine SR is 5.2 to 6.5 h (Henney, Faust et al. 
2011). There will be a wash out period of at least 8 days equalling over 30 half-lives of the active substance 
fampridine SR (t1/2=6h). 
3.3 
Preclinical Evidence  
In rats, fampridine was found to improve short-term memory performance of old, but not young, animals 
(Barnes, Eppich et al. 1989). 
Further it was found to be able to enhance memory as demonstrated in a 72-h retention of passive 
avoidance task (Haroutunian, Barnes et al. 1985). The effect of fampridine was also investigated in a 
mouse model of HIV-1 encephalitis. These mice show impaired spatial memory in radial arm water maze 
tests. Electrophysiology studies revealed a reduction of long-term potentiation (LTP) in the CA1 region of 
the hippocampus. Systemic administration of fampridine blocked HIV-1-associated reduction of LTP and 
improved animal performance in the radial arm water maze (Keblesh, Dou et al. 2009).  
3.4 
Clinical Evidence to Date  
Fampridine was investigated in patients with Alzheimer disease. In one study it partially reversed memory 
deficits (Wesseling, Agoston et al. 1984). In a second study, results indicated no significant difference in 
total Alzheimer Disease Assessment Scale Scores (Davidson, Zemishlany et al. 1988).  
In patients with Multiple Sclerosis fampridine was investigated in several clinical studies. MS can cause 
progressive walking impairments, which are improved by Fampridine. Through a blockade of potassium 
channels, fampridine restores nerve impulse conduction (Tseng, Li et al. 2016), facilitates and enhances 
synaptic transmission, retards the postsynaptic action potential repolarization (Kasatkina 2016), and 
increases the release of acetylcholine (Lugaresi 2015).  
Fampridine also improves cognitive functions in MS. In a clinical trial MS patients receiving a maximum 
dose of 0.7 mg/kg of weight per day achieved significantly higher scores in attention span, verbal fluency, 
planning and graphics and constructive motion (Arreola-Mora, Silva-Pereyra et al. 2019). Another study 
showed improvement in information processing speed in MS patients receiving 10 mg twice daily for 12 
weeks (De Giglio, De Luca et al. 2019). In an earlier study the application of 7.5-52.5 mg of immediate 
release fampridine over 1-5 days showed motor and visual improvements in MS (Stefoski, Davis et al. 
1991). 
These findings are consistent with another study, where 40 mg/day led to improvements in attention and 
concentration in MS patients (Smits et al. 1994). In contrast, no cognitive improvement was reported with 
a dose of 30–32 mg/day (Rossini et al. 2001; Romani et al. 2004). Considering a long period of 
administration (9–12 months) at a dose of 20 mg per day, a beneficial effect on both processing speed 
and working memory has been observed (Pavsic, Pelicon et al. 2015). 
3.5 
Dose Rationale  
The maximum recommended dose of fampridine SR is 10 mg twice daily (approximately 12 hours apart) 
without food (see prescribing information Fampyra®). 
In healthy individuals a single dose of fampridine SR 10 mg achieved a mean maximum plasma 
concentration (Cmax) of 21.6 ± 3.89 ng/ mL, with a mean time to maximum plasma concentration (Tmax) of 
3.2 ± 1.5 hours (Smith, Swan et al. 2010). Steady state of fampridine SR will be reached after 5 half-lives 
of fampridine equalling approx. 30 h (Arzneimittelinformation Swissmedic Fampyra). 
Fampridine is lipid soluble and able to pass the blood–brain barrier (Lemeignan, Millart et al. 1984) and 
therefore able to reach structures of the prefrontal cortex involved in working memory functions. 

 
 
 
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Cerebrospinal fluid levels of fampridine peak 30–60 min following peak serum concentration (Donovan, 
Halter et al. 2000).  
Previous studies examining long-term use up to several weeks reported pro-cognitive effects with 10 mg 
fampridine SR twice daily (see 3.4).   
We are interested in the effects on working memory after acute administration of 10 mg fampridine SR as 
well as in effects after repeated administration of 10 mg fampridine SR  twice daily.  
We will therefore examine working memory after the first dose of 10 mg fampridine SR (i.e. after a 4 h 
waiting time to reach maximum plasma concentration)). 
Second testing will take place after 3.5 days of twice daily application of 10 mg fampridine SR.  
3.6 
Explanation for choice of placebo 
Placebo is chosen to assess effects of fampridine on memory processes in a cross-over design. Placebo 
consists of an identically looking tablet manufactured by  
Losan PharmaLosan Pharma GmbH 
Otto-Hahn-Straße 13 
79395 Neuenburg am Rhein 
Germany 
consisting of additives that are very similar to those used for the verum formulation: 
3.7 
Risks / Benefits 
Fampridine application 
Although a short term application of 10 mg fampridine twice daily in healthy participants is generally well 
tolerated (March and Cardi 2009), participants will be informed of the possible risks associated with taking 
fampridine. Specific risks that participants need to be aware of are listed below: 
• 
The most frequently occurring AEs included dizziness, headache, insomnia and gastrointestinal 
discomfort. No discontinuations due to AEs were reported in a study with healthy subjects after 
administration of a single 10 mg dose (Smith, Swan et al. 2010) as well as after 5 days of twice daily 
fampridine SR 10 mg in healthy subjects (March and Cardi 2009). 
• 
Fampridine is excreted primarily unchanged in the urine (Blight and Henney 2009). Tolerability and 
incidence of AEs appear to be dose related, occurring more frequently at plasma concentrations > 
100 ng/mL (Van Diemen, Polman et al. 1993). We will therefore exclude subjects with renal 
impairment to avoid higher plasma levels. To assess renal impairment, we will perform creatinine and 
uric acid levels in plasma. 

 
 
 
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• 
Fampridine is excreted primarily through the organic cation transporter 2 (OCT 2). OCT 2 inhibitors 
or substrates (e.g. Cimetidine, Carvedilol, Propranolol and Metformin) may inhibit elimination of 
fampridine and increase the risk of adverse events. Subjects with concomitant use of these drugs are 
excluded from participation. 
• 
Fampridine can cause seizures. We will exclude people with a history of seizures and subjects at risk 
of lowered seizure threshold due to e.g. sleep deprivation or alcohol withdrawal after alcohol abuse.  
• 
Despite the fact that fampridine at therapeutic and supratherapeutic doses is not associated with QT 
prolongation in healthy subjects (March and Cardi 2009) we will exclude subjects with any clinically 
significant ECG abnormalities or history of cardiovascular disease.  
• 
Fampridine might cause nausea and dizziness and have an additive effect with alcohol. Participants 
will be advised to avoid alcohol, illegal substances, and any medication (especially psychoactive) due 
to possible interactions during the course of the study.  
• 
An increased risk of bacterial and viral infections is described in the prescribing information. In a study 
with 47 healthy subjects receiving 10 mg twice daily doses of fampridine SR over 5 days no viral or 
bacterial infections were reported (March and Cardi 2009). 
• 
Subjects will be warned about engaging in activities requiring mental alertness, such as driving a car 
or operating appliances, machinery, etc. Driving a motor vehicle or operating machinery is not allowed 
during each intervention period of 4 days (96 h) and subjects have to agree to use public 
transportation or taxi after medication intake for this time period.  
• 
In several in vivo and in vitro studies there was no evidence of drug-related carcinogenicity or 
mutagenicity (prescribing information Fampyra®). 
• 
Administration of fampridine to animals during pregnancy and lactation resulted in decreased 
offspring viability and growth at doses 6.8 times  the maximum recommended human dose (MRHD) 
of 20 mg/day. In developmental toxicity studies in rats and rabbits, fampridine was administered orally 
at doses up to 10 and 5 mg/kg/day, respectively, during the period of organogenesis. These doses 
are approximately 5 times the MRHD. No evidence of developmental toxicity was found in either 
species at the highest doses tested, which were maternally toxic. In addition, a case study about a 
favorable outcome of a pregnancy after exposure with fampridine in the first month of conception is 
available (Maillart, Gout et al, 2016) For additional safety data, we refer to the prescribing information 
Fampyra®. 
All female of childbearing potential should use adequate contraception starting 10 days before each 
intervention period and during intervention period, such as an oral, injectable, or implantable 
contraceptive or contraceptive devices (IUP). To minimize the risk of exposure to IMP we will perform 
a pregnancy test before administration of study drug on test day 1 and 3.  
• 
All subjects will be informed about possible side effects of medication and advised to inform the 
investigator about observed side effects due to possible individual differences in metabolism of study 
medication. 
rMT measurement 
• 
Seizures are the most serious possible TMS-related adverse events. Only few cases of TMS induced 
seizures have been reported so far out of hundreds of thousands examined subjects, and the vast 
majority of seizures were induced during repetitive TMS (Rossi, Antal et al. 2021). Single-pulse TMS, 
the method used here, is considered to have no significant risk (Rossi et al., 2009) and studies 
investigating physiological mechanisms of corticocortical plasticity in healthy subjects, which did not 
require repeated sessions over several days in order to reach a clinical effect did not show major AE, 
including seizure occurrence, Thus, there should not be any special concern in studies of this type 
(Rossi, Antal et al. 2021). We will exclude all persons having experienced a seizure in the past and/or 
with positive family history (first-degree relatives) of seizures.  
• 
A number of medications have been reported to increase risk of seizure in clinical populations (Stultz, 
Osburn, et al. 2020) and it was previously assumed that their use in combination with repetitive TMS 
may confer heightened risk for seizure induction (Rossi et al., 2009). However, empirical evidence for 
this risk is lacking, and the observed seizure rate even in repetitive TMS patients is extremely low 
overall despite that the majority of them were on CNS-active medications (Rossi, Antal et al. 2021). 

 
 
 
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• 
Risks concerning single pulse rMT measurement in combination with fampridine SR were monitored 
in MS patients: In  recent studies no SAEs during TMS measurements were reported (Marion, Leonid 
et al 2020), (Ahdab, Shatila et al. 2019), (Krushkov, Shotekov et al. 2006). 
• 
Compared to seizure, syncope is more likely to occur during a TMS investigation, but this is a rare 
event too. No systematic studies addressed the relative incidence of the two phenomena during TMS, 
but this is a common experience in many labs (Groppa, 2012). Vasodepressor (neurocardiogenic) 
syncope is a common reaction to anxiety and physical discomfort and it can take place following TMS, 
as with many other non-invasive or minimally invasive medical procedures. The cardinal feature that 
distinguishes syncope from seizure is rapid recovery of full consciousness within few seconds and 
not minutes (Lin, Ziegler et al. 1982). We will exclude individuals with a history of repeated syncope.  
• 
Other side effects of single-pulse TMS investigations are mild and, when present, transient. Most of 
subjects do not complain about discomfort, especially when they are familiarized with the TMS 
procedure. Some may experience surprise looking at their hand/arm twitching (personal 
communication Schicktanz 2021). 
• 
Both, patient and examiner will always wear earplugs during diagnostic TMS to prevent transient 
auditory threshold changes, which are more likely to occur during repetitive TMS, but are theoretically 
possible even with single pulse application (Rossi, Antal et al. 2021). We  will exclude persons with 
hearing impairment or tinnitus. 
• 
For safety reasons we added a list of exclusion criteria concerning TMS in general (single-pulse, 
paired-pulse and repetitive TMS). We will use the questionnaire for screening of subjects before TMS 
investigations that has been developed on a consensus conference by considering the safety and 
ethical guidelines for the use of TMS in clinical practice and research (Rossi, Hallett et al. 2011) 
(Groppa, Oliviero et al. 2012). 
• 
All TMS investigations will be performed by specially trained persons.  
• 
The participant is always allowed to stop the TMS measuring if he/she feels ill at ease. 
Benefits 
The benefit of the study lies in the gain of knowledge regarding the translation of human genetic studies 
in pharmacological intervention studies and, more specifically, in the potential to find working memory 
improvements by fampridine. Such a finding may have important clinical implications with regard to 
treatment of working memory deficits in neuropsychiatric disorders.     
3.8 
Justification of choice of study population  
Genetic variability in genes encoding potassium channels are related to differences in working memory 
performance in healthy young subjects (Heck, Fastenrath et al. 2014). We therefore decided to investigate 
the effects of fampridine on working memory in healthy young subjects.  
 
 

 
 
 
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4 STUDY OBJECTIVES  
4.1 
Overall Objective 
The overall objective of this study is to evaluate if fampridine has an influence on cognitive functions in 
healthy young participants. 
4.2 
Primary Objective 
The primary objective of this study is to evaluate if fampridine has an influence on working memory in 
healthy young participants. 
4.3 
Secondary Objectives 
The secondary objectives are to assess the influence of fampridine on different working memory functions, 
attention, processing speed, fluid intelligence and resting motor treshold (rMT).   
4.4 
Safety Objectives 
The study aims to assess tolerability of study medication in terms of incidence of side effects e.g. 
headache, gastrointestinal discomfort and dizziness and the rate of AEs. 
 
 

 
 
 
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5 STUDY OUTCOMES 
5.1 
Primary Outcome 
• 
High-load working memory performance (3-back (d’) as assessed by a letter n-back task) after 
repeated intake of study medications (visit 3 and 5). 
5.2 
Secondary Outcomes 
• 
High-load working memory performance (3-back (d’) as assessed by a letter n-back task) after 
acute intake of study medication (visit 2 and 4) 
• 
rMT measurement using TMS after repeated intake of study medication (visit 3 and 5) 
Performance in other working memory-related tasks and other n-back outcomes after acute and repeated 
intake of study medication  
• 
Reaction time (for correct 3-back responses) 
• 
Performance in a 0 back task as a measure of attention 
• 
Symbol Digit Modalities Test, SDMT (Smith 2013, 13th edition) 
• 
BOMAT - advanced (Hossiep/Turck/Hasella, 1999)  
• 
Digit span forward and backward performance (von Aster 2006) 
5.3 
Safety Outcomes 
• 
Headache, dizziness and gastrointestinal discomfort (see chapter 10.1.1) will be recorded and 
rated by the participants using visual analogue scales. 
• 
AE-recording 
• 
Vital signs  
5.4 
Assessment of potential confounders 
• 
Tiredness and motivation will be rated by the participant using visual analogue scales.  
 
 
 

 
 
 
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6 STUDY DESIGN 
6.1 
General study design and justification of design  
Pharmacological proof-of-concept study on the effects of 10 mg fampridine (twice daily oral 
administration) on physiological processes, in particular working memory, in healthy participants using 
the following design: 
• 
randomized 
• 
double-blind (participant, study team) 
• 
placebo-controlled  
• 
cross-over 
• 
counter-balanced 
The duration of the study from first participant in to last participant out is approx. 24 months. Duration for 
an individual study participant will be at most 7 to max. 15 weeks, depending on the duration of the wash 
out period. 
There will be two intervention periods of 3.5 days during which medication (fampridine /placebo) will be 
applied separated by a wash out period of 8 (days between Visit 3 and Visit 4; equivaling over 30 half-
lives of the study drug) up to 82 days (12 weeks). 
Two test days will take place during each intervention period: one on the first day and one on the last day 
of each period during which cognitive functions under the influence of fampridine/placebo will be assessed 
using parallel versions of tests.  
At the beginning of test day 1 (visit 2), each subject will be randomized to receive either placebo or 
fampridine first.  
After the administration of study medication (visits 2-5) there will be a 4-h waiting period allowing the 
medication to reach peak cerebrospinal fluid levels (Hayes 2004). After this time period, the cognitive test 
battery will be administered. 
At the end of each visit, participants will be asked about their actual wellbeing. If there are no complaints 
or symptoms, participants can be dismissed. In case of minor health problems, the participant will have 
to stay in the study center until recovery under medical supervision. In case of more severe incidents staff 
acts according to chapter 10.4.6. 
The study will end for the subjects in the evening of the second test day of the second intervention period 
(visit 5). The duration for the different study parts see table 1 (Duration of Study parts, page 12). 
6.2 
Methods of minimizing bias  
To minimize bias, participants will be randomly allocated to treatment groups (e.g. starting with fampridine 
or placebo) and study will be double-blinded. 
6.2.1 
Randomization  
After pre-examination on visit 2, each participant will be assigned to a randomization number. Each 
eligible participant will be allocated to one of the two randomization groups (Placebo/Verum or 
Verum/Placebo) according to the maximum tolerated imbalance (MTI) procedures. This allocation will be 
generated automatically by secuTrial®. This procedure ensures that participants will be randomly 
allocated to the two groups, while accounting for sex as a covariate of potential importance. 
The replacement of all Drop-Outs will be carried out after assignment of all 44 medication kits is 
completed. There will be replacement of Drop-Outs until data of approximately 44 participants are 
completed. 
6.2.2 
Blinding procedures  
The IMP and the placebo are identically looking tablets to ensure double-blind conditions.  
The pharmacy will prepare one kit of study medication per participant. Each kit will consist of two 
intransparent plastic containers, each containing either seven tablets of blistered fampridine and a drying 
agent or unblistered placebo and a drying agent. It is necessary to keep Fampyra® blistered as long as 
possible to prevent any contact of fampridine with humidity. After unblistering Fampridin® will stay stable 

 
 
 
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for seven days in a closed container while adding a drying agent (professional / prescribing information 
Germany Fampyra® SR). Each kit of study medication will be labelled with a randomization number. A 
staff member not involved in the conduct of the study will open the kit and the plastic container 
corresponding to the respective intervention period in a separate room. If Verum is inside he will unblister 
all the verum tablets and hand over the first tablet to the subject, who is waiting in a different room. If 
Placebo is inside the staff member may directly hand over the first tablet to the subject, who is waiting in 
a different room. Afterwards the subject will be handed over the reclosed container for the intake of the 
study medication at home. During each intervention period a tablet must be taken every 12 hours for 5 
times at home. The last (7th) intake of the study medication will be again in the study center. Therefore, 
the subject must bring along the container including the last tablet at the second study day of each 
intervention period.  
6.2.3 
Other methods of minimizing bias  
The investigators of the test days will be trained and will follow detailed working instructions to ensure that 
each test day will be conducted in a highly standardized way. 
Study team members involved in testing, data acquisition or data analysis are blinded. The study team 
member preparing the IMP at the testing days has no other outcome-related tasks in the study.  
The administration of medication will take place at the same time frame (8-9 a.m.) for each participant. 
Testing will take place in the same location at the premises of the Division of Cognitive Neuroscience of 
the University of Basel for each participant and during the same time of the day to minimize the influence 
of diurnal differences in cognitive test performance. 
6.3 
Unblinding Procedures (Code break)  
Unblinding will be permitted under these circumstances 
• 
SAE  
• 
AE if knowledge is crucial for further medical approach  
The investigator or a representative can perform the unblinding of the participant at any time. To ensure 
that unblinding is possible at any time, there is a unblinding procedure implemented in secuTrial®. The 
investigator or a representative will report to the sponsor-investigator and document the unblinding. Not 
involved study team members will not be informed about the result. 
 
 

 
 
 
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7 STUDY POPULATION 
7.1 
Eligibility criteria  
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
• 
male or female 
• 
generally healthy  
• 
normotensive (BP between 90/60mmHg and 140/90mmHg) 
• 
BMI between 19 and 29,9 kg/m2 
• 
aged between 18 and 30 years  
• 
fluent German-speaking  
• 
IC as documented by signature 
• 
At least double vaccination against Covid-19 
The presence of any one of the following exclusion criteria will lead to exclusion of the participant: 
• 
contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to 4-
aminopyridine 
• 
use of potassium channel blockers within the last 3 months 
• 
concomitant treatment with OCT 2 inhibitors and -substrates (e.g. cimetidine, propranolol) 
• 
acute or chronic psychiatric disorder (e.g. major depression, psychosis, somatoform disorder, 
suicidal tendency)  
• 
acute cerebrovascular condition 
• 
history of seizures 
• 
risk of lowered seizure threshold (due to e.g. sleep deprivation, withdrawal of alcohol after alcohol 
abuse) 
• 
renal impairment 
• 
history of malignant cancers 
• 
walking problems (e.g. due to dizziness) 
• 
other clinically significant concomitant disease states (e.g. hepatic dysfunction, cardiovascular 
disease, diabetes, asthma, 
• 
bradycardia < 50/min during clinical examination 
• 
clinically significant laboratory or ECG abnormality that could be a safety issue in the study  
• 
known or suspected non-compliance  (e.g. missing more than one dose of study medication per 
intervention phase) 
• 
drug or alcohol abuse 
• 
inability to follow the procedures of the study, e.g. due to language or psychological problems of 
the participant 
• 
participation in another study with an investigational drug within the 30 days preceding and during 
the present study 
• 
prior participation (less than two years ago) in a study investigating working memory (notably the 
n-back task) 
• 
enrolment of the investigator, his/her family members, employees and other dependent persons 
• 
smoking (>3 cigarettes per day)  
• 
intake of psychoactive drugs (e.g. benzodiazepines, antidepressants, neuroleptics) 
• 
pregnancy or breast feeding  
• 
experiencing a syncope during basal rMT measuring 
Exclusion Criteria concerning TMS measurement 
• 
metal in the brain, skull or elsewhere in the body (e.g., splinters, fragments, clips, etc.) 
• 
implanted neurostimulator (e.g., DBS, epidural/subdural, VNS) 
• 
cardiac pacemaker or intracardiac lines 
• 
medication infusion device 
• 
piercings, pivot teeth (retainers are no exclusion criterion) 
• 
tattoos (head area) less than 3 months old or older than 20 years 
• 
condition after neurosurgery 
• 
hearing problems or tinnitus 

 
 
 
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• 
not able to sit still due to tremor, tics, itching 
• 
History of repeated syncope  
• 
head trauma diagnosed as concussion or associated with loss of consciousness 
• 
diagnosis of epilepsy, or a convulsion or a seizure in the past of the participant or his family  
• 
TMS in the past showing problems 
• 
MRI in the past showing problems 
• 
surgical procedures to spinal cord 
• 
spinal or ventricular derivations 
Remark: It is necessary to ensure that the metal nose piece of surgical masks, if they have to be worn 
as protection against Covid-19 infection, is not ferromagnetic (Bikson, Hanlon et al. 2020). 
7.2 
Recruitment and screening  
Study participants will be searched in the German speaking part of Switzerland using the following 
websites mcn.unibas.ch and markt.unibas.ch,.  
We may also invite former participants of unrelated studies of the Divisions of Cognitive and Molecular 
Neuroscience interested in further study participation by e-mail.  
After contacting us, the interested person will be sent the “Participant information and informed consent 
form” together with some administrative information. If the person is still interested in participating, a study 
team member will call the interested person to inform him/her about the study and answer his/her 
questions. Afterwards, a pre-screening with a check of the main in- and exclusion criteria will be 
performed. If the interested person meets all inclusion criteria and none of the exclusion criteria and is 
interested in participating, the screening visit will be fixed.  
All interested persons will be advised not to come to the study center in case of common cold or flu like 
symptoms but fix an alternative date. The telephone screening documents will be filed as part of the 
Source Data (SD) in the participant’s dossier. The telephone screening documents of participants not 
eligible for a study participation will be shredded. All steps will be documented and we will assess the 
number of participants, who were not eligible during pre-screening.  
For screening procedures see chapter 9.4.1. 
A study compensation of CHF 800 including travel expenses will be paid at the end of the second test 
period. Screening Failures and Drop-Outs receive a pro rata temporis compensation.  
7.3 
Assignment to study groups  
After informed consent, each participant will be assigned to a participant number. Then, eligible 
participants will be allocated to the treatment group (i.e. either fampridine or placebo first) following the 
order of the randomization list. The randomization number will be listed in the SD, in the eCRF and in the 
Drug Accountability Log. 
7.4 
Criteria for withdrawal / discontinuation of participants  
Participants have the right to withdraw from the study at any time for any reason without being obliged to 
give reason. There will be a final examination after withdrawal for whatever reason. The investigator also 
has the right to withdraw participants from the study if it is in the best interest of the participant. 
The following reasons result in withdrawal: 
• 
Adverse events challenging the health of the participant if continuing the study 
• 
Adverse events prohibiting cognitive testing or rMT-measurement, e.g.  
o 
headache, dizziness and nausea more than mild or 
o 
having slept less than 4 hours during the last night (Visits 3 and 5). 
• 
Participant being ill at ease during rMT measuring 
• 
Intake of psychoactive substances within 3 days before test days (e.g. benzodiazepines, 
antidepressants, neuroleptics, cannabis) 
• 
Non-Compliance  
• 
Severe protocol violations 
• 
Administrative troubles 
• 
Positive pregnancy test (test day 1 or test day 3) 

 
 
 
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• 
Alcohol intake within 12 hours before start of all visits 
Withdrawal date and reason will be listed in the participant enrolment log. Safety data will be analyzed for 
all participants, who received at least one dose of study medication. There will be no anonymization of 
the data. For information about data handling see chapter 12.3. 
7.5 
Contraception and pregnancy 
All female participants of childbearing potential should use adequate contraception starting 10 days before 
each intervention period and during intervention period, such as an oral, injectable, or implantable 
contraceptives or contraceptive devices (IUP). To minimize the risk of exposure to IMP we will perform a 
pregnancy test before administration of study drug on test day 1 and 3.  
If against all demanded contraception, a pregnancy should occur the pregnant participant must be 
withdrawn immediately from the clinical study. Any pregnancy during the treatment phase of the study 
and within 30 days after discontinuation of study medication will be reported to the Sponsor-Investigator 
within 24 hours.  
The pregnancy will be followed-up like an SAE. A document for the initial registration is available, as well 
as one for the end of the first trimenon. All other relevant information that we should receive from the 
participant will be documented. Information about course and outcome of pregnancy from the treating 
gynecologist might be asked after release from the confidentiality by the participant. 
A follow-up of mother and child after the first trimenon is not foreseen, as no risks are expected for the 
development of the unborn thereafter.  
 
8 STUDY INTERVENTION 
8.1 
Identity of Investigational Products  
8.1.1 
Experimental Intervention  
Active study medication consists of 7 tablets of fampridine 10 mg formulated for oral administration taken 
in the morning and evening 12 h apart without food. Tablets must be administered whole: do not divide, 
crush, chew, or dissolve Fampyra® retard tablets. 
There will be a washout period of at least 8 days equaling over 30 half-lives of the active substance 
fampridine (t½ = 6 h) between experimental and control intervention and up to 82 days (12 weeks) 
depending on the individual scheduling of each subject.  
8.1.2 
Control Intervention  
Identically looking placebo tablets consisting of widely identical additives formulated for oral 
administration. 
8.1.3 
Packaging, Labelling and Supply (re-supply)  
Packaging, labelling and supply will be provided by the Pharmacy of the University Hospital Basel (see 
chapter 6.2.2). 
8.1.4 
Storage Conditions  
The IMP will be stored under 25° C and protected from light and humidity until initiation at the pharmacy 
Thereafter the IMP will be stored for the entire study until last participant out at the same conditions in our 
division. The storage temperature will be controlled with LogTag temperature recorder.  
8.2 
Administration of experimental and control interventions  
8.2.1 
Experimental Intervention  
See chapter 8.1.1 
8.2.2 
Control Intervention 
See chapter 8.1.2.  

 
 
 
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8.3 
Dose  
No modifications needed. 
8.4 
Compliance with study intervention  
Each subject will be provided with a personal login to secuTrial® to be able to document the intake of the 
investigational product at a time. A study team member will send a note if entry is missing to remind the 
subject of intake of the investigational product. 
All subjects have to return the container on the following test days in order to control the container for not 
used tablets and for correct disposal of remaining tablets after study end.  
Blinding is warranted (see chapter 7.6, Randomization and Blinding). 
8.5 
Data Collection and Follow-up for withdrawn participants  
Not needed. Subject withdrawn because of (S)AE will be followed up until resolution or stabilization. 
8.6 
Trial specific preventive measures 
In case of headache, pain or fever, paracetamol is allowed and has to be recorded as concomitant 
medication. 
8.7 
Concomitant Interventions (treatments)  
Treatments with OCT 2 inhibitors or substrates (e.g. cimetidine, propranolol) are prohibited during the 
course of the study as they may inhibit elimination of fampridine and increase the risk of adverse events. 
All concomitant treatment will be recorded in the eCRF. 
8.8 
Study Drug Accountability  
The supplies from and the returns to the pharmacy of the USB for destruction will be documented at the 
pharmacy and also by the study coordinator on the site in the IMP accountability log. This log documents 
the IMPs received from the pharmacy, the kits used by each participant, and the return to the pharmacy 
of used and unused kits.  
This documentation includes the following information: delivery date, delivered kits, batch number, expiry 
date. 
The administration of the IMP to the participants is recorded in the participant dossier.  
8.9 
Return or Destruction of Study Drug  
Used and unused kits will be returned to the pharmacy of the USB for destruction. The pharmacy will 
destroy and dispose them duly in accordance to hospital policy and the local directives. 
 
 

 
 
 
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9 STUDY ASSESSMENTS 
9.1 
Study flow chart(s) / table of study procedures and assessments 
See study schedule (Table 1, Duration of study parts, page 12) 
9.2 
Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
• 
High-load working memory performance will be measured as follows: 
We will use the letter n-back task (Heck, Fastenrath et al. 2014)) which includes a 3-back task 
assessing working memory. The 3-back task requires participants to respond to a letter repeat 
with two intervening letters (for example, S−m−b−s−g…). Performance will be quantified with the 
d’ measure controlling for false positives. We will use parallel versions (different sequences) for 
the four test days. Primary outcome will be performance after repeated intake of study medication. 
9.2.2 
Assessment of secondary outcomes 
• 
High-load working memory performance( see above) after acute intake of study medication. 
• 
Resting motor threshold (rMT) will be measured during screening procedures and after repeated 
intake  with a biphasic magstim Rapid2 stimulator (The MAGSTIM® Company Ltd, Whitland, UK) 
and a 70 mm figure-of-eight coil.  
rMT will be determined by measuring the motor evoked potential (MEP) in the abductor digiti 
minimi according to (Rossini 2001). rMT will be defined as the lowest stimulation intensity by 
stimulating the primary motor cortex of the left or right hemisphere required to induce an MEP in 
the abductor digiti minimi of the dominant hand in at least 5 out of 10 trials. In case of a relaxed 
target muscle, a positive MEP is defined as an MEP with ⩾50 µV peak-to-peak amplitude (Rossini 
2001). 
The coil will be held tangentially to the skull over M1, approximately four cm lateral and one cm 
anterior to the Vertex. Additionally, the coil-handle points backwards at an angle of 45° to the 
corresponding parasagittal line. Then the coil will be shifted systematically in steps of 
approximately one cm in anterior, posterior, lateral and medial direction. Stimulation will be 
performed at an initial output intensity of 30% of maximum stimulator’s output (MSO) and will be 
increased in steps of 10% until a twitch is detected. Thereafter, 10 pulses will be applied. If less 
than five MEPs are observed, stimulator output intensity will be increased by 5 %. Depending on 
the result, intensity will be further decreased or again increased by steps of two and then one 
percent until the lowest stimulator intensity is found. Otherwise stimulator output intensity is first 
decreased 5% and thereafter increased or decreased by steps of two and then one percent until 
rMT is found. The participant is always allowed to stop the measuring, if he/she feels ill at ease. 
Performance in other working memory-related tasks and other n-back outcomes will be measured both 
after acute and repeated study medication as follows: 
• 
Reaction time (for correct 3-back responses). 
• 
Performance in a 0-back task (d’ measure controlled) as a measure of attention. We will use 
parallel versions (different sequences) for the four test days  
• 
Symbol Digit Modalities Test, SDMT (Smith 2013, 13th edition), a processing speed test. The test 
consists of the presentation of a series of 9 symbols, each of them is paired with a single digit, 
labelled 1–9, in a key at the top of a sheet. The remainder of the page has a pseudorandomized 
sequence of the symbols and the participant must respond with the digit associated with each of 
these as quickly as possible. The score is the number of correct answers in 90 seconds. The 
administration of SDMT will be preceded by a learning sequence at both timepoints. We will use 
parallel versions for all test days.  
• 
Bochumer Matrizentest (BOMAT – advanced; Hossiep/Turck/Hasella, 1999, 1st edition), matrix 
reasoning. We will administer the BOMAT to measure fluid intelligence (Gf) consisting of 40 items. 
Parallel versions will be used for the four test days. To create four versions, we divided the original 
BOMAT versions A and B each into two versions (every second item) with 20 items each. We will 
use a time-limited version (15 instead of 40 minutes) to avoid a ceiling effect. The total score is 
calculated by summing the correct solutions, ranging between 0 to 20. 

 
 
 
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• 
Working memory will be also assessed with the digit span task, a subtest of the “Wechsler 
Intelligenztest für Erwachsene“ (WIE; (von Aster 2006)). Total scores for digit span forward and 
backward will be calculated as described in the manual of the WIE. Parallel version will be used 
for the four test days.  
9.3 
Assessment of safety outcomes 
The following known side effects will be recorded using visual analog scales: headache, gastrointestinal 
discomfort, dizziness 
Adverse events: All clinically relevant (S)AEs occurring after the participant has signed the informed 
consent until follow up visit will be fully recorded in the participants eCRF. Description of (S)AE, time of 
onset, duration and resolution. Assessment of intensity, relationship to study drug and measures taken. 
For documentation of (S)AEs see section 10. 
Laboratory parameters: No laboratory parameters will be assessed after screening. 
Vital signs: Vital signs (BP, HR) will be taken as described in screening procedures. Blood pressure and 
heart rate will be used as baseline before intake of study medication, during waiting period, before testing 
and before end of visit to control for side effects of the medication.  
9.4 
Procedures at each visit and during treatment periods 
9.4.1 
Screening visit  
During the screening visit the investigator explains to the participant the aims of the study, the study 
procedures, the drug under investigation and potential risks (see also chapter 3.7 risks and benefits). 
Written informed consent will be obtained from all participants without limiting time for signature. 
Participants who are candidates for enrolment into the study will be evaluated for eligibility during the 
screening visits by the investigator (inclusion, exclusion criteria). Screening visit will take place within 2 
weeks before first test visit and consists of  
• 
Assessment of personal and family history  
• 
Psychosocial assessment 
• 
Assessment of medication history 
• 
Physical examination 
The following questionnaires will be used to assess psychiatric disorders:  
• 
Depressive symptoms will be assessed with the self-rating questionnaire MADRS-S based on the 
MADRS (Schmidtke, 1988). This scale consists of 9 items assessing subjects' mood, feelings of 
unease, sleep, appetite, ability to concentrate, initiative, emotional involvement, pessimism and 
zest for life. Each item is scored between 0 and 3. The total score is calculated by summing the 
answers of the nine items, ranging between 0 and 27 (higher scores indicate increased 
impairment). A score of ≥8 results in exclusion. In case of suicidal tendency (Item 9 > 1), the 
subject is excluded and advised to consult a psychologist/psychiatrist. We will provide subjects 
with addresses. 
• 
Self-assessment questionnaire covering mental health, drug and alcohol consumption, sleeping 
habits and some sociodemographic information. 
The investigator decides, whether there are contraindications for the administration of study medication.  
The medical examination performed covers: 
Vital signs (blood pressure / heart rate) will be taken with the participant having been in a seated position 
for at least 5 minutes.  
• 
Height / weight (for calculation of BMI)  
• 
Physical examination; findings will be recorded as “normal” or “abnormal”. 
• 
Twelve lead ECG with formal readings (Wilson, Einthoven, Goldberger), device: Schiller AT10, 
will be taken and rated by a specialist familiar with the study medication at the Phase I Research 
Unit (PRU) University Hospital Basel (see contract with PRU). 
• 
Venous blood samples (2,7 ml and 4.7 ml) will be taken at the Phase I Research Unit University 
Hospital Basel to measure:  

 
 
 
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o 
Blood count (incl. platelets) / hemoglobin / hematocrit 
o 
Blood chemistry including: sodium, potassium, chloride, calcium, phosphate, creatinine, 
uric acid, bilirubin, alkaline phosphatase, LDH, AST, ALT, GGT, pancreatic amylase, 
albumin, total protein (+Alb./Glob.), C-reactive protein, creatine kinase.  
Laboratory values outside the reference range of the laboratory and considered clinically relevant will lead 
to exclusion of the subject from study participation. 
Blood samples will be analyzed by the laboratory of University Hospital Basel. Blood samples will be 
discarded directly after analysis. 
Clinically significant abnormal ECG readings will result in exclusion of the subject. 
Resting Motor Threshold (rMT) will be determined as described in chapter 9.2.2. During screening a 
handedness questionnaire (short version of Edinburgh Handedness Inventory (EHI)) will be administered, 
as rMT will be measured at the dominant hand.   
All female of childbearing potential will be requested to use adequate contraception starting 10 days 
before each intervention period and during intervention period, such as an oral, injectable, or implantable 
contraceptive or contraceptive devices (IUP). To minimize the risk of exposure to IMP we will perform a 
pregnancy test before administration of study drug on test day 1 and 3.  
Screening failures equal to participants not meeting all inclusion criteria or meeting one or more of the 
exclusion criteria. Excluded participants will be listed on a screening failure log. The whole screening will 
be repeated if the wash out period (time between test day 2 and 3) lasts more than 26 days. 
9.4.2 
Test days (visits 2-5) 
At the beginning of the test days 1 and 3, all female participants will perform a pregnancy test. Pregnancy 
test will be performed in a urine sample according to instructions of Axaclear, Axapharm. Axaclear is a 
one-step hCG (monoclonal anti-hCG antibodies) urine pregnancy test used for qualitative (visual) 
determination of hCG in urine specimen for early detection of pregnancy. The pregnancy tests will be 
stored with IMP at the same conditions. Additionally women will be requested again to use an adequate 
contraception during the wash-out period. 
There will be a short examination consisting of vital signs, assessment of concomitant medication, sleep 
duration, self-assessment questionnaire covering drugs and alcohol consumption and adverse events.  
Intake of study medication will take place at the same time point for each subject. We will provide a 
continental breakfast to be eaten 2 hours after intake of study medication. The breakfast consists of two 
rolls, butter and jam. After breakfast study participants will be provided with fruits and crackers (e.g. 
Darvida). Whole day water and herbal and fruit tea (no green or black tea) will be available. Caffeine 
containing beverages are only allowed during breakfast. 
Testing will take place at the same time for each subject to minimize the influence of diurnal differences 
in cognitive test performance. 
There will be a 4-h waiting period allowing the medication to reach high cerebrospinal fluid concentration. 
After this time period, the cognitive test battery will be administered. A parallel version of the test battery 
will be administered on each test day.  
For the duration of the different study parts see table 1 (Duration of Study parts, page 12).  
At the end of each test day, participants will be asked about their actual wellbeing. If there are no 
complaints / symptoms they will be dismissed. In case of minor health problems the participant will have 
to stay in the study center until recovery under medical control. In case of more severe incidents staff will 
act according to chapter 10. 
Assessments in participants who prematurely stop the study: There will be a final examination after 
withdrawal during test days for whatever reason. The examination consists of recording adverse events 
and assessing vital signs. 
The study including assessment of inclusion and exclusion criteria (other than laboratory parameters and 
ECG that will be assessed at the Phase I Research Unit of the University Hospital Basel), medication 
intake and assessment of study outcomes will be conducted at the Transfaculty Research Platform 
Molecular and Cognitive Neurosciences, University of Basel. 

 
 
 
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9.4.3 
Treatment periods 
During the visits 2 and 4 (test days 1 and 3) every subject will be supplied with a plastic container 
containing the remaining 6 tablets of IP to be taken twice per day during the following 3 days, the first 
tablet in the evening of visit 1 (resp. 3) and the last tablet in the morning of the visits 3 and 5 (test days 2 
and 4). Each subject receives a total of 7 verum tablets and 7 placebo tablets.  
During the treatment days, the participants document the intake of the tablets and – if any – adverse 
events via a separate personal login directly in secuTrial® (s. chapter 8.4, Compliance with study 
intervention).  
 

 
 
 
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10 SAFETY 
10.1 Definitions  
10.1.1 
Adverse Event (AE) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or a clinical investigation 
participant administered a pharmaceutical product and which does not necessarily have a causal 
relationship with the study procedure. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of a medicinal investigational product, whether or not related to the medicinal investigational product.  
In this study, the following very common AEs being already described in the prescribing information 
Fampyra® (version from May 2019) are excluded from recording, but will be measured as possible 
confounding factor using VAS: 
• 
headache  
• 
gastrointestinal disturbances such as dyspepsia, abdominal pain, constipation and nausea 
• 
dizziness 
All other clinically relevant AEs will be fully recorded by describing the AE, time of onset, duration and 
resolution, assessment of intensity, relationship to study drug and measures taken 
10.1.2 
Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is classified as any untoward medical occurrence that: 
• 
results in death, 
• 
is life-threatening, 
• 
requires in-patient hospitalization or prolongation of existing hospitalization, 
• 
results in persistent or significant disability/incapacity, or 
• 
is a congenital anomaly/birth defect. 
In addition, important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization, but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed above should also usually be considered serious. (ICH E2A)  
SAEs should be followed until resolution or stabilization. Participants with ongoing SAEs at study 
termination (including safety visit) will be further followed up until recovery or until stabilization of the 
disease after termination.  
10.1.3 
Unexpected Adverse Drug Reaction 
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g. investigator’s brochure for drugs that are not yet 
approved and prescribing information for approved drugs, respectively). (ICH E2A) 
10.1.4 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
The Sponsor-Investigator evaluates any SAE that has been reported regarding seriousness, causality 
and expectedness. If the event is related to the investigational product and is both serious and 
unexpected, it is classified as a SUSAR. In order to determine a SUSAR unblinding is needed. 
 
 

 
 
 
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10.2 Assessment of (Serious) Adverse Events and other safety related events 
10.2.1 
Assessment of causality 
Both Investigator and Sponsor-investigator make a causality assessment of the event to the study drug, 
based on the criteria listed in the ICH E2A guidelines: 
Relationship 
Description 
Definitely 
Temporal relationship 
Improvement after dechallenge* 
Recurrence after rechallenge 
(or other proof of drug cause) 
Probably 
Temporal relationship 
Improvement after dechallenge 
No other cause evident 
Possibly 
Temporal relationship 
Other cause possible 
Unlikely 
Any assessable reaction that does not fulfil the above conditions 
Not related 
Causal relationship can be ruled out 
*Improvement after dechallenge (stop administering a drug, to see whether its suspected effects cease to occur) 
only taken into consideration, if applicable to reaction 
10.2.2 
Assessment of Severity 
Adverse events will be categorized as 1=mild, 2= moderate, 3=severe, 4=life-threatening, 5= death. 
10.3 Documentation 
10.3.1 
Serious Adverse Events (SAE) 
The sponsor’s SOPs provide more detail on safety reporting. 
During the entire duration of the study all serious adverse events (SAEs) are collected, fully investigated 
and documented in source documents and electronic case report forms (eCRF). Study duration 
encompassed the time from when the participant signs the informed consent until the final examination.    
10.3.2 
Adverse Events (AE) 
The following information needs to be collected for adverse events:  
• 
time of onset,  
• 
duration,  
• 
resolution,  
• 
action to be taken,  
• 
assessment of intensity, and  
• 
relationship with study treatment.  
For assessment of safety outcomes see  
chapters 9.3 
10.4 Reporting of serious adverse events (SAE) and other safety related events  
10.4.1 
Reporting of SAEs 
All SAEs must be reported immediately and within a maximum of 24 hours to the sponsor-investigator of 
the study. The sponsor-investigator will re-evaluate the SAE and return the form to the site. 
SAEs resulting in death are reported to the EKNZ within 7 days. 
10.4.2 
Reporting of SUSARs 
A SUSAR needs to be reported to the CEC (EKNZ) and to the CA (Swissmedic) (via Sponsor-Investigator) 
within 7 days, if the event is fatal, or within 15 days (all other events). 

 
 
 
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10.4.3 
Reporting of safety signals 
All suspected new risks and relevant new aspects of known adverse reactions that require safety-related 
measures, i.e. so called safety signals, must be reported to the sponsor-investigator within 24 hours. The 
sponsor-investigator must report the safety signals within 7 days to the CEC (EKNZ) and to the CA 
(Swissmedic). 
10.4.4 
Reporting and handling of pregnancies 
Pregnant participants must be withdrawn immediately from the clinical study. Any pregnancy during the 
treatment phase of the study and within 30 days after discontinuation of study medication will be reported 
to the Sponsor-Investigator within 24 hours.  
The course and outcome of the pregnancy will be followed up until the end of the first trimenon, and any 
abnormal outcome regarding the mother or the child be documented and reported. For further information 
see Chapter 7.5. 
10.4.5 
Periodic reporting of safety 
An annual safety report is submitted once a year to the local Ethics Committee via BASEC and to the CA 
via sponsor-investigator. 
10.4.6 
Follow-up of (Serious) Adverse Events (AE) 
In case of minor health problems the participant will have to stay under medical control in our department.  
In case of major health problems the participant will be transferred to the emergency department in the 
University Hospital of Basel (USB). The responsible investigator will inform the health care provider about 
the participation in the study. For unblinding see 6.3. 
Information about the outcome in all above-mentioned cases will be collected until full recovery.  
 
 
 

 
 
 
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11 STATISTICAL METHODS 
11.1 Hypothesis 
Fampridine improves working memory performance in healthy humans. 
11.2 Determination of Sample Size  
We are interested to detect a drug effect with at least medium effect size. The estimation of N=44 is based 
on a power analysis using dependent two-tailed t-tests assuming to detect a medium effect size (Cohens 
dz = 0.5) with a power of 90% at α=0.05 (software: G-power 3).  
11.3 Statistical criteria of termination of trial  
As soon as 44 participants will have completed the entire study. For subjects still enrolled at that time 
point see 11.4.1. 
11.4 Planned Analyses  
All analyses will be performed with the software R. The differences between the experimental conditions 
(placebo, verum) will be analyzed using linear mixed models in combination with analysis of variance (SS 
II). Subjects will be included as the random effect of the mixed model. Sex and age will be inserted as 
covariates.  
In case of significant interactions between covariates and experimental condition, post-hoc tests will be 
applied to describe the interaction.  
To control for an influence of other variables, possible confounders will be entered into the model as 
covariate (each possible confounder entering the statistical analyses separately and corrected for multiple 
comparisons with the Bonferroni method).   
11.4.1 
Datasets to be analyzed, analysis populations 
We will apply a Per-Protocol-Analysis, i.e. the analysis of the primary and secondary outcome measures 
will be only performed with those participants, who completed all tests and investigations. There will be 
replacement of Drop-Outs until data of 44 participants are completed. Drop-Outs will be thoroughly 
described to assess the reason(s) for dropping out.  
We will recruit up to 4 subjects more towards the end of the trial to prevent under-recruitment due to Drop-
Outs. If more then 44 subjects will complete all tests and investigations their data will also be analyzed.  
11.4.2 
Analysis for the primary outcome  
A significance level of p < 0.05 will be considered as significant.  
The dependent variable is the primary outcome (i.e.3-back (d`)) after repeated administration of study 
medication). The independent variable of interest is the experimental condition (placebo or verum). 
To control for possible confounders or moderators, we will also consider tiredness, motivation, headache, 
gastrointestinal discomfort, dizziness, mood as assessed by MADRS-S, potassium blood concentration 
at screening, body weight, duration of washout period and vital signs as covariates (each covariate 
entering the statistical analysis separately). In case of a significant (i.e. after Bonferroni correction for 
multiple comparisons) interaction between independent variables of interest and covariates, post-hoc 
analysis will be applied to describe the interaction effect.  
11.4.3 
Analyses for secondary outcomes  
Behavioral secondary outcomes will be treated statistically the same way as the primary outcome, but a 
Bonferroni correction (i.e. corrected for the number of behavioral secondary outcomes) will apply 
separately for the main effect (i.e. drug vs. placebo) and the interaction effect (i.e. main effect x acute vs. 
repeated administration). In the case of a significant (i.e. Bonferroni-corrected) interaction effect, post-hoc 
analysis will be applied to describe the interaction effect. 
The measure of the non-behavioral secondary outcome (i.e. rMT) will be treated statistically the same 
way as the primary outcome measure. 

 
 
 
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11.4.4 
Interim analyses 
No interim analyses are planned. 
11.4.5 
Safety analysis 
Safety data will be analyzed for all participants, who received at least one dose of study medication. 
11.4.6 
Deviation(s) from the original statistical plan  
Deviations from the original statistical plan will be justified and reported to the ethical committee and 
regulatory authorities. 
Deviation from the original statistical plan will be performed, if reviewers demand specific analyses. If in 
the meantime other studies find important effects or confounding effects related to our study, we will 
include these found confounders (if we have assessed those) as an additional analysis in our statistical 
plan beside our planned analyses. 
11.4.7 
Handling of missing data and drop-outs  
Missing data will be recorded as NA. 
Drop-Outs see chapter 11.4.1. 
 
 

 
 
 
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12 QUALITY ASSURANCE AND CONTROL 
12.1 Responsibilities 
The sponsor-investigator has an overall responsibility for the implementation and conduct of the study. 
He is allowed to delegate tasks to the research team as specified in the authorization list. Adequate 
information and training of the involved staff is in his charge and should be documented. 
12.2 Data handling and record keeping / archiving  
12.2.1 
Case Report Forms (CRF) 
Study data is recorded with electronic Case Report Forms (eCRF). secuTrial® will be used for the eCRF 
(see contract with CTU). For each enrolled study participant a eCRF will be maintained. The eCRF will 
be kept current, as it has to reflect participant status at each phase during the course of study. For 
confidentiality reasons eCRFs must not contain any personal data of study participants. It will be used a 
coded identification consisting of a participant number (see chapter 12.3.1). Authorized for eCRF entries 
is mainly the study coordinator and additionally the investigators (especially for medical issues). 
secuTrial® has a detailed audit trail so that every relevant change is traceable and assignable to the 
person who made it. Data is entered into the eCRF and can be validated for completeness and 
discrepancies automatically.  
We will perform single data entry. Entries in the eCRF must be consistent with information recorded in the 
source documents. eCRF data should be accurate, consistent, complete and reliable.  
The n-back Tasks and the Digit Span Task will not be entered in the eCRF (secuTrial®). These tests will 
be performed with Presentation® respectively SoSci-Survey and the generated logfiles will be transferred 
to a secure electronical archive (LabKey®) to guarantee originality and to prepare the data for data 
analysis. The data collected with Presentation® (n-Back Task) and SoSci-Survey (Digit Span) will be 
transferred to LabKey® according to the procedures described in chapter 12.3.3.  
12.2.2 
Specification of source documents  
Source data are all information in original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in 
source documents (e.g. hospital records, laboratory notes, recorded data from automated instruments, 
and records kept at the pharmacy and other departments involved in the clinical trial). (GCP 1.51/2) 
Source data will consist of the following documents: 
Paper documentation:  
• 
Informed Consent Form 
• 
Screening documentation, incl. telephone screening 
• 
Sociodemographic questionnaire 
• 
AE-log, concomitant medication 
• 
SDMT (visits 2 to 5) 
• 
Administrative documents: visit checklists, visit plan, randomization number, rMT-value, etc. 
Direct data entry with secuTrial®: 
• 
Questionnaire at the beginning of the test days (visits 2 to 5) 
• 
Questionnaires during the test days (before and after testing; visits 2 to 5) 
• 
BOMAT (visits 2 to 5) 
• 
Visual Analog Scales and documentation of the intake of the IP at home (treatment periods)  
Direct data entry with Presentation® (https://www.neurobs.com/): 
• 
n-back tasks  
Direct data entry with SoSci-Survey: 
• 
Digit Span task 
Data recording with Brainsight® (TMS-software): 
• 
Location of rMT assessment (MNI-coordinates) 
• 
Electromyography (EMG) during rMT (MEP information: peak-to-peak amplitude, EMG waveform 
information; accuracy specifications such as: distance to associated target, target error).  

 
 
 
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12.2.3 
Record keeping / Archiving  
All study related data (essential documents and site documents) will be archived for a minimum of 10 
years after study termination or premature termination of the clinical trial in the archives of Division of 
Cognitive and Molecular Neuroscience and in case of the eCRF in the electronic archive-system of the 
University Hospital Basel. Electronically captured data with presentation® (n-back task), SoSci-Survey 
(Digit Span) and Brainsight® (EMG) will be archived in a read only status in LabKey® for at least 10 years 
(for further information to LabKey® see chapter 12.3.4).  
The study team will archive all essential data, such as a printout version of the eCRFs, medical records 
including logs for concomitant medication, laboratory reports, informed consent documents, IP disposition 
records including randomization and decryption lists, safety reports, information regarding participants 
who discontinued, and other pertinent data.  
12.3 Data management  
12.3.1 
Pseudonymization and Coding 
Each subject will be assigned to a numeric code in the following way: 81-0001-01. The first two digits 
identify the study, the 4 four digits in the middle are the subject number and the last two digits are reserved 
for the sample number.  
The telephone screening will be performed before assignment of the subject code as described above. 
This document will be coded with a separate numeric code and the date of birth.  
The participant identification list will be kept under lock and key. During the course of the study the study 
coordinator is responsible for the list. Access to the participant identification list will have only authorized 
study team members. After the monitoring close out visit the study documentation will be transferred to 
our archive (s. 12.3). Access will have only persons authorized by the sponsor-investigator of the project. 
12.3.2 
Data Security and Access 
Trial and participant data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the study. On the eCRFs, 
participants are only identified by a unique participant number and additionally the year of birth can be 
noted (see chapter 12.3.1).  
All Source Data are kept under lock and key. All electronic systems used in this study are password 
protected, to ensure that only authorized persons can enter the system to view, add or modify data 
according to their permissions within the scope of the study. 
The investigators will permit study related monitoring visits, audits, EC reviews, and regulatory 
inspections, and provide direct access to all source data.  
12.3.3 
Data Management Systems, Back-up 
SecuTrial® (eCRF) runs on a server maintained by the IT-department of the University Hospital Basel. 
The data management group at the Clinical Trial Unit (CTU) of the University Hospital Basel implements 
the eCRF. The user administration and user training is performed by the CTU according to predefined 
processes. Back-up of eCRF data is performed according to the processes of the IT-department of the 
University Hospital Basel. SecuTrial® has a detailed audit trail so that every relevant change is traceable 
and assignable to the person who made it. 
LabKey® (https://www.labkey.com; nBack tasks (Presentation), Digit Span task (SoSci-Survey), TMS-
Logfiles (Brainsight®)) runs on a server maintained by the IT-department of the University of Basel. The 
data manager of the Division of Cognitive Neuroscience is responsible for the implementation of the tasks, 
for the user administration and for the user training. Back-up is performed according to processes of the 
IT-department of the University of Basel. LabKey® has a detailed audit trail so that every relevant change 
is traceable and assignable to the person who made it. Back-up of the LabKey® database is done by 
sciCORE, University of Basel, on daily bases. An additional text-file-based database dump is stored within 
the Linux or Macintosh file-system deployed by the Psychology IT-Department. This is done occasionally, 
e.g. when the data collection is finished. 
The source data (including Presentation®-, SoSci-Survey- and TMS-logfiles) will be stored on a Linux or 
Macintosh file-system with restricted user access (main file-system). The meta-information of the source 

 
 
 
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data (SHA-1 hashes as file id, file modification time, path to the file on the file-system, date and time 
information logged in the log-file) is stored in LabKey® in a study specific folder (main study folder). The 
relevant content of the source data that is necessary for creating an analytical database is additionally 
uploaded to LabKey® (main study folder). The analytical database is created as text-files with time-stamps 
based on the uploaded or manually entered raw data. These text-files are stored and accessible within 
the LabKey® file-system in the main study folder. 
For source data, we don’t expect that any changes will be done. Therefore, we store the meta-information 
of the source data to be able to verify that the files are in the original state. All other information is 
documented and stored within LabKey®. 
For source data (including the Presentation®-, SoSci-Survey- and Brainsight®-logfiles) we use different 
levels of validation: As a first step, we evaluate for each subject, visit and computer if all expected files or 
entries are available and stored in the correct sequence (via the time-stamp). If this basis checks fail, we 
manually curate the source data, if possible; manual data curation is documented in text-files stored 
together with the source data or in LabKey®. After performing these basic checks, the data is copied and 
stored in the final storage space of a study in the main file-system (deployed by Psychology IT-
department). At the same time-point the meta-information of each file is stored in LabKey®. When 
uploading the relevant content of the raw data, we further validate if the file-content corresponds to the 
expected design of a task or survey, if possible (this is data-dependent). Furthermore, within LabKey® 
we track for each subject, visit and task if there are exclusion reasons (filter-variables). While creating the 
final analytical database we apply these filter-variables to the data. An audit trail system maintains a 
record of initial entries and changes (time and date of changes, user identification of entry and changes). 
Reasons for changes can be added by a commentary. The data entered or uploaded in the LabKey® 
study folder will be reviewed by the investigator.  
12.3.4 
Analysis and Archiving 
The eCRF will be locked after all data was monitored and all raised queries have been resolved. Data is 
exported and transferred to the investigator by the CTU according to internally defined processes. The 
exported data will be archived by the study coordinator (see 12.2.3). 
12.3.5 
Electronic and central data validation  
Data is entered into the eCRF and can be validated for completeness and discrepancies automatically. 
An audit trail system maintains a record of initial entries and changes (reasons for changes, time and date 
of changes, user identification of entry and changes). 
An independent monitor from the CTU Basel will review the data entered into the eCRF. The monitor will 
raise queries using the query management system implemented. Designated investigators and the study 
coordinator have to respond to the query and confirm or correct the corresponding data. Thereafter the 
monitor can close the query. 
12.4 Monitoring 
The aim of monitoring is to evaluate the progress of the study, to verify the accuracy and completeness 
of CRFs, to ensure that all protocol requirements, applicable local authority regulations and investigator’s 
obligations are being fulfilled, and to resolve any inconsistencies in the study records. The investigator 
will allow the sponsor to periodically monitor at mutually convenient times during and after the study and 
they will answer questions during monitoring.  
Monitoring will be provided by the CTU Basel (see contract). Monitoring will be performed according to 
the separate monitoring plan.  
12.5 Audits and inspections  
Audits by the CEC or the sponsor or inspections by regulatory authorities during study or after study 
closure may be performed to ensure proper study conduct and data handling procedures according to 
ICH-GCP guidelines and regulatory requirements. Audits and inspections may include verification of all 
source documents, check of CRFs and site files and a visual inspection of the study site. Direct access 
to all documents and places at study site is mandatory. In case of an announced audit or inspection 
immediate notification of the respective other party is necessary. 

 
 
 
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The investigators will permit study related monitoring visits, audits, IEC reviews, and regulatory 
inspections, and provide direct access to all essential documents including the source data. Essential 
documents permit individually and collectively an evaluation of the conduct of a study and the quality of 
the data produced. Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
All involved parties must keep the participant data strictly confidential. 
12.6 Confidentiality and Data Protection  
Participant’s confidentiality will be maintained at all times. Personnel from the sponsor, CTU Basel, from 
the Department of Pharmacology (PRU USB) and Toxicology (USB), laboratory (USB), from regulatory 
authorities and members of IEC are obliged to respect medical secrecy and to refrain from divulging the 
participant’s identity or any other personal information they might fortuitously be aware of. 
The participants name or other personal identifiable data are not recorded in the eCRF. 
Direct access to source documents will be permitted for purposes of monitoring (chapter 12.4), audits and 
inspections (chapter 12.5). People who will have access to protocol, dataset, statistical code, etc. during 
and after the study (publication, dissemination) will be declared. 
 
 

 
 
 
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13 PUBLICATION AND DISSEMINATION POLICY 
The main publication will be created by Prof. Dominique de Quervain and Prof. Andreas 
Papassotiropoulos. Subsequent publications of subgroups can follow thereafter and will have to be 
approved by Prof. de Quervain and Prof. Andreas Papassotiropoulos. 
No unpublished data given to the investigator may be transmitted to a third party without prior written 
approval by Prof. de Quervain and Prof. Andreas Papassotiropoulos. No publication or communication 
involving the results of the study is authorized without prior written consent from the Prof. de Quervain 
and Prof. Andreas Papassotiropoulos. In view of patent and confidentiality issues, however, the 
investigator must accept requirements on the timing of early publication. The investigator’s name should 
not be used in any publication without the prior written permission of Prof. de Quervain and Prof. Andreas 
Papassotiropoulos.  
 
14 FUNDING AND SUPPORT 
Funding the trial: Funds of the Swiss National Science Foundation and the Transfaculty Research 
Platform, University of Basel. 
 
15 INSURANCE 
The sponsor-investigator declares that he has taken out an insurance policy for the total study length, 
covering the participants in respect of the risks involved in this study. In case of injury or disability deriving 
from participation in the study, the subject is requested to inform without delay the investigator responsible 
for the study.  
 
 
 
 

 
 
 
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16 REFERENCES 
16.1 Regulatory Documents 
Declaration of Helsinki, Version October 2013, 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-
involving-human-subjects/ 
Federal Act on Medicinal Products and Medical Devices (Therapeutic Products Act, TPA) of 15 December 
2000 
(Status 
as 
of 
1 
January 
2020). 
https://www.admin.ch/opc/en/classified-
compilation/20002716/index.html 
Federal Act on Research involving Human Beings (Human Research Act, HRA) of 30 September 2011 
(Status as of 1 January 2014). https://www.admin.ch/opc/en/classified-compilation/20061313/index.html 
Federal Act on Data Protection (FADP) of 19 June 1992 (Status as of 1 March 2019). 
https://www.admin.ch/opc/en/classified-compilation/19920153/index.html 
Ordinance on Clinical Trials in Human Research (Clinical Trials Ordinance, ClinO) of 20 September 2013 
(Status as of 24 April 2018). https://www.admin.ch/opc/en/classified-compilation/20121176/index.html 
International 
Conference 
on 
Harmonization 
E6(R2) 
Guideline 
for 
Good 
Clinical 
Practice 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_Step_4_20
16_1109.pdf 
Common Terminology Criteria for Adverse Events (CTCAE) 
https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
International Conference on Harmonization  E2A Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002749.p
df 
International Conference on Harmonization (ICH, 1997) E8 Guideline: General Considerations for Clinical 
Trials 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guidelin
e.pdf 
16.2 References 
Ahdab, R., Shatila, M. M., Shatila, A. R., Khazen, G., Freiha, J., Salem, M., Makhoul, K., El Nawar, R., El 
Nemr, S., Ayache, S. S., & Riachi, N. (2019). Cortical Excitability Measures May Predict Clinical Response 
to Fampridine in Patients with Multiple Sclerosis and Gait Impairment. Brain sciences, 9(12), 357. 
https://doi.org/10.3390/brainsci9120357 
Arreola-Mora, C., J. Silva-Pereyra, T. Fernandez, M. Paredes-Cruz, B. Bertado-Cortes and I. Grijalva 
(2019). "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 
28: 117-124. 
Arzneimittelinformation 
Swissmedic 
Fampyra. 
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Barnes, C. A., C. Eppich and G. Rao (1989). "Selective improvement of aged rat short-term spatial 
memory by 3,4-diaminopyridine." Neurobiol Aging 10(4): 337-341. 
Bikson, M., C. A. Hanlon, A. J. Woods, B. T. Gillick, L. Charvet, C. Lamm, G. Madeo, A. Holczer, J. 
Almeida, A. Antal, M. R. Ay, C. Baeken, D. M. Blumberger, S. Campanella, J. A. Camprodon, L. 
Christiansen, C. Loo, J. T. Crinion, P. Fitzgerald, L. Gallimberti, P. Ghobadi-Azbari, I. Ghodratitoostani, 
R. H. Grabner, G. Hartwigsen, A. Hirata, A. Kirton, H. Knotkova, E. Krupitsky, P. Marangolo, E. M. 
Nakamura-Palacios, W. Potok, S. K. Praharaj, C. C. Ruff, G. Schlaug, H. R. Siebner, C. J. Stagg, A. 
Thielscher, N. Wenderoth, T. F. Yuan, X. Zhang and H. Ekhtiari (2020). "Guidelines for TMS/tES clinical 
services and research through the COVID-19 pandemic." Brain Stimul 13(4): 1124-1149. 
Blight, A. R. and H. R. Henney, 3rd (2009). "Pharmacokinetics of 14C-radioactivity after oral intake of a 
single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers." Clin Ther 31(2): 328-335. 

 
 
 
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Bridgman, A. C., M. S. Barr, M. S. Goodman, R. Chen, T. K. Rajji, Z. J. Daskalakis and T. P. George 
(2016). "Deficits in GABAA receptor function and working memory in non-smokers with schizophrenia." 
Schizophr Res 171(1-3): 125-130. 
Chwieduk, C. M. and G. M. Keating (2010). "Dalfampridine extended release: in multiple sclerosis." CNS 
Drugs 24(10): 883-891. 
Davidson, M., Z. Zemishlany, R. C. Mohs, T. B. Horvath, P. Powchik, J. P. Blass and K. L. Davis (1988). 
"4-Aminopyridine in the treatment of Alzheimer's disease." Biol Psychiatry 23(5): 485-490. 
De Giglio, L., F. De Luca, F. Gurreri, I. Ferrante, L. Prosperini, G. Borriello, E. Quartuccio, C. Gasperini 
and C. Pozzilli (2019). "Effect of dalfampridine on information processing speed impairment in multiple 
sclerosis." Neurology 93(8): e733-e746. 
de Quervain, D. J., K. Henke, A. Aerni, D. Coluccia, M. A. Wollmer, C. Hock, R. M. Nitsch and A. 
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