Randomized Placebo-controlled Phase II Cross-over Study on the Influence of Fampridine on Working Memory in Mild to Moderate Depression
Phase: PHASE2
Conditions: Working Memory, Mild to Moderate Depression
Sponsor: University of Basel

 
 
CONFIDENTIAL 
 
 
Study Protocol FamD_2025 
Version 7 – 17/11/2025 
 
 
Page 1 of 53 
 
 
Clinical Study Protocol 
 
Randomized placebo-controlled phase II cross-over study on the 
influence of fampridine on working memory in mild to moderate 
depression 
 
Study-ID: FamD_2025 
 
 
Study Type 
Clinical Trial with Investigational Medicinal Product (IMP) 
Study Categorization 
Risk category B according to ClinO 
Study Registration 
NCT0675178 
HumRes66269 
Study ID 
FamD_2025 
Sponsor 
Research Cluster Molecular and Cognitive Neurosciences 
UNIVERSITY OF BASEL 
Birmannsgasse 8, 4055 Basel 
Contact persons: 
Prof. Dominique de Quervain, MD 
Co-Director Research Cluster Molecular and Cognitive Neurosciences 
Director Division of Cognitive Neuroscience 
E-Mail: dominique.dequervain@unibas.ch 
Phone: +41 61 207 02 37 
Prof. Andreas Papassotiropoulos, MD 
Co-Director Research Cluster Molecular and Cognitive Neurosciences 
Director Division of Molecular Neuroscience 
E-Mail: andreas.papas@unibas.ch 
Phone: +41 61 207 05 99 
Prof. Annette Brühl, MD 
Chief physician Zentrum für Affektive -, Stress- und Schlafstörungen & Zentrum 
für Alterspsychiatrie, Universitäre Psychiatrische Kliniken (UPK) Basel 
E-Mail: annette.bruehl@upk.ch  
Phone: +41 61 325 50 97 
Principal Investigators  
Dr. Christiane Gerhards, MD 
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 
Investigational Product 
Fampridine (Fampyra®) 
Protocol Version and Date 
Version 7 (dated 17/11/2025) 
 
 
 
The information contained in this document is the property of the sponsor and the principal investigator. The 
information may not – in full or in part – be transmitted, reproduced, or published, or disclosed to others than the 
applicable Competent Ethics Committee (EKNZ) and Regulatory Authority (Swissmedic) without prior written 
authorization from the sponsor except to the extent necessary to obtain informed consent from those who will 
participate in the study.  

SIGNATURE PAGE
Study Title
Study number
ProtocolVersion
Randomized placebo-controlled phase ll cross-over study on the
fampridine on working memory in mild to moderate depression
NCT06751 784
HumRes66269
Version 7 (dated 1711112025)
-4,/7, t r
influence of
The sponsors' the principal investigator, the trial statistician and the psychologist have approved the
protocol and confirm hereby to conduct the study according to the protocol, current version of the World
Medical Association Declaration of Helsinki, the ICH-GCP guidelines and the local legally applicable
requirements.
The principal investigator has received the ICF and consider it appropriate for use.
Prof. Dominiquq de Quervain, MD
*B; d,
Place/Date
Prof. Andreas Papassotiropoulos, MD
2r
Signature
Signature
Signature
Signature
1
Prof. Annette Bnihl, MD
Sponsor
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PI
Place/Date
Christiane Gerhards, MD
Principal lnvestigator
Nathalie Schicktanz, PhD
Trial statistician
/t.?o7{
Place/Date
Magdalena Ridder, M. Sc.
Psychologist
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Place/Date
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Study Protocol FamD 2025
Signature
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Page 2 of 53
CO N FID E NTIA L
Version 7 - 1711112025

 
 
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Study Protocol FamD_2025 
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TABLE OF CONTENTS 
Signature Page .................................................................................................................................................. 2 
Study synopsis .................................................................................................................................................. 6 
Assessment of potential confounders .................................................................................................................... 7 
Abbreviations ................................................................................................................................................. 10 
Summary of the Revision History in Case of Amendments ............................................................................... 12 
Study Schedule ............................................................................................................................................... 13 
1 
Study Administrative Structure ................................................................................................................ 15 
2 
Ethical and Regulatory Aspects ................................................................................................................ 17 
2.1 
Study registration .................................................................................................................................... 17 
2.2 
Categorization of study ............................................................................................................................ 17 
2.3 
Competent Ethics Committee (CEC) ......................................................................................................... 17 
2.3.1 
Notification and reporting for the first visit and for completion, premature termination, 
interruption and resumption of the clinical trial (ClinO, Art. 38) .................................................................... 17 
2.3.2 
Notification and reporting on the safety of participants and protective measures (ClinO, Art. 37 and 
43) 
17 
2.4 
Competent Authority (CA) ........................................................................................................................ 17 
2.4.1 
Notification and reporting for the first visit and for completion, discontinuation, interruption and 
resumption of the clinical trial (ClinO, Art. 38) ................................................................................................ 18 
2.4.2 
Notification and reporting of safety and protective measures (ClinO, Art. 37 and 43) ..................... 18 
2.5 
Ethical Conduct of the Study .................................................................................................................... 18 
2.6 
Declaration of interest ............................................................................................................................. 18 
2.7 
Patient Information and Informed Consent ............................................................................................. 18 
2.8 
Participant privacy and confidentiality .................................................................................................... 19 
2.9 
Premature termination of the study ........................................................................................................ 19 
2.10 
Protocol amendments .............................................................................................................................. 19 
2.10.1 Reporting to the Competent Ethics Committee (CEC) ....................................................................... 19 
2.10.2 Reporting to the Competent Authority (CA) ...................................................................................... 20 
3 
Background and Rationale ....................................................................................................................... 21 
3.1 
Background and Rationale ....................................................................................................................... 21 
3.2 
Investigational Product (treatment) and Indication ................................................................................ 21 
3.3 
Preclinical Evidence .................................................................................................................................. 22 
3.4 
Clinical Evidence to Date .......................................................................................................................... 22 
3.5 
Dose Rationale ......................................................................................................................................... 22 
3.6 
Explanation for choice of placebo ............................................................................................................ 23 
3.7 
Risks / Benefits ......................................................................................................................................... 23 
3.8 
Justification of choice of study population ............................................................................................... 24 
4 
STUDY OBJECTIVES .................................................................................................................................. 25 
4.1 
Primary Objective .................................................................................................................................... 25 
4.2 
Secondary Objectives ............................................................................................................................... 25 
4.3 
Safety Objectives ...................................................................................................................................... 25 
5 
Study Outcomes ...................................................................................................................................... 25 
5.1 
Primary Outcome ..................................................................................................................................... 25 
5.2 
Secondary Outcomes ............................................................................................................................... 25 
5.3 
Safety Outcomes ...................................................................................................................................... 25 

 
 
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5.4 
Assessment of potential confounders ...................................................................................................... 25 
6 
Study Design ........................................................................................................................................... 26 
6.1 
General study design and justification of design ..................................................................................... 26 
6.2 
Methods of minimizing bias ..................................................................................................................... 27 
6.2.1 
Randomization ................................................................................................................................... 27 
6.2.2 
Blinding procedures ........................................................................................................................... 27 
6.2.3 
Other methods of minimizing bias ..................................................................................................... 27 
6.3 
Unblinding Procedures (code break) ........................................................................................................ 27 
7 
Study Population ..................................................................................................................................... 29 
7.1 
Eligibility criteria ...................................................................................................................................... 29 
7.1.1 
Inclusion criteria ................................................................................................................................ 29 
7.1.2 
Exclusion criteria ................................................................................................................................ 29 
7.2 
Recruitment and pre-screening ................................................................................................................ 30 
7.3 
Criteria for withdrawal / discontinuation of participants ........................................................................ 30 
7.4 
Contraception and pregnancy ................................................................................................................. 30 
8 
Study Intervention .................................................................................................................................. 32 
8.1 
Identity of Investigational Products ......................................................................................................... 32 
8.1.1 
Experimental Intervention ................................................................................................................. 32 
8.1.2 
Control Intervention .......................................................................................................................... 32 
8.1.3 
Packaging, Labelling and Supply (re-supply) ...................................................................................... 32 
8.1.4 
Storage Conditions ............................................................................................................................. 32 
8.2 
Administration of experimental and control interventions ...................................................................... 32 
8.2.1 
Experimental Intervention ................................................................................................................. 32 
8.2.2 
Control Intervention .......................................................................................................................... 32 
8.3 
Dose ......................................................................................................................................................... 32 
8.4 
Compliance with study intervention ........................................................................................................ 32 
8.5 
Data Collection and Follow-up for withdrawn participants ..................................................................... 33 
8.6 
Trial specific preventive measures ........................................................................................................... 33 
8.7 
Concomitant Interventions (treatments) ................................................................................................. 33 
8.8 
Study Drug Accountability ....................................................................................................................... 33 
8.9 
Return or Destruction of Study Drug ........................................................................................................ 33 
9 
Study Assessments .................................................................................................................................. 34 
9.1 
Study flow chart(s) / table of study procedures and assessments ........................................................... 34 
9.2 
Assessments of outcomes ........................................................................................................................ 34 
9.2.1 
Assessment of primary outcome ....................................................................................................... 34 
9.2.2 
Assessment of secondary outcomes .................................................................................................. 34 
9.2.3 
Assessment of potential confounders ............................................................................................... 35 
9.2.4 
Assessment of safety outcomes ........................................................................................................ 35 
9.3 
Procedures at each visit ........................................................................................................................... 35 
9.3.1 
Screening visit (visit 1) ....................................................................................................................... 35 
9.3.2 
Test days (visits 2 - 5) ......................................................................................................................... 37 
9.3.3 
Treatment periods ............................................................................................................................. 38 
9.3.4 
Safety follow-up ................................................................................................................................. 39 
10 Safety ...................................................................................................................................................... 40 
10.1 
Definitions ................................................................................................................................................ 40 
10.1.1 Adverse Event (AE) ............................................................................................................................ 40 
10.1.2 Serious Adverse Event (SAE) .............................................................................................................. 40 
10.1.3 Unexpected Adverse Drug Reaction .................................................................................................. 40 
10.1.4 Suspected Unexpected Serious Adverse Reactions (SUSARs) ............................................................ 40 

 
 
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10.2 
Assessment of (Serious) Adverse Events and other safety related events ............................................... 41 
10.2.1 Assessment of causality ..................................................................................................................... 41 
10.2.2 Assessment of Severity ...................................................................................................................... 41 
10.3 
Documentation ........................................................................................................................................ 41 
10.3.1 Serious Adverse Events (SAE) ............................................................................................................ 41 
10.3.2 Adverse Events (AE) ........................................................................................................................... 41 
10.4 
Reporting of serious adverse events (SAE) and other safety related events ............................................ 41 
10.4.1 Reporting of SAEs ............................................................................................................................... 41 
10.4.2 Reporting of SUSARs .......................................................................................................................... 41 
10.4.3 Reporting of immediate safety and protective measures ................................................................. 42 
10.4.4 Reporting and handling of pregnancies ............................................................................................. 42 
10.4.5 Periodic reporting of safety and general progress of the clinical trial ............................................... 42 
10.4.6 Follow-up of (Serious) Adverse Events (AE) ....................................................................................... 42 
11 Statistical Methods .................................................................................................................................. 43 
11.1 
Hypothesis ............................................................................................................................................... 43 
11.2 
Determination of Sample Size .................................................................................................................. 43 
11.3 
Statistical criteria of termination of trial ................................................................................................. 43 
11.4 
Planned Analyses ..................................................................................................................................... 43 
11.4.1 Datasets to be analyzed, analysis populations .................................................................................. 43 
11.4.2 Analysis for the primary outcome ..................................................................................................... 44 
11.4.3 Analyses for secondary outcomes ..................................................................................................... 44 
11.4.4 Interim analyses ................................................................................................................................. 44 
11.4.5 Safety analysis .................................................................................................................................... 44 
11.4.6 Deviation(s) from the original statistical plan .................................................................................... 44 
11.4.7 Handling of missing data and drop-outs ............................................................................................ 44 
12 Quality Assurance and Control ................................................................................................................ 45 
12.1 
Responsibilities ........................................................................................................................................ 45 
12.2 
Pseudonymization and Coding ................................................................................................................. 45 
12.3 
Data handling and record keeping / archiving ........................................................................................ 45 
12.3.1 Case Report Forms (CRF) ................................................................................................................... 45 
12.3.2 Logfiles psychological testing ............................................................................................................. 46 
12.3.3 Specification of source documents .................................................................................................... 46 
12.3.4 Record keeping / Archiving ................................................................................................................ 47 
12.4 
Data management ................................................................................................................................... 47 
12.4.1 Data management systems ............................................................................................................... 47 
12.4.2 Data security, access and back-up ..................................................................................................... 48 
12.4.3 Analysis and Archiving ....................................................................................................................... 48 
12.4.4 Electronic and central data validation ............................................................................................... 48 
12.5 
Monitoring ............................................................................................................................................... 49 
12.6 
Audits and inspections ............................................................................................................................. 49 
12.7 
Confidentiality and Data Protection ........................................................................................................ 49 
13 Publication and Dissemination Policy ...................................................................................................... 50 
14 Funding and Support ............................................................................................................................... 50 
15 Insurance ................................................................................................................................................ 50 
16 References .............................................................................................................................................. 51 
16.1 
Regulatory Documents ............................................................................................................................ 51 
16.2 
References ............................................................................................................................................... 51 

 
 
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STUDY SYNOPSIS 
Sponsor 
 
Research Cluster Molecular and Cognitive Neurosciences 
UNIVERSITY OF BASEL 
Birmannsgasse 8, 4055 Basel 
Contact persons: 
Prof. Dominique de Quervain, MD 
Co-Director Research Cluster Molecular and Cognitive Neurosciences 
Director Division of Cognitive Neuroscience 
E-Mail: dominique.dequervain@unibas.ch 
Phone: +41 61 207 02 37 
Prof. Andreas Papassotiropoulos, MD 
Co-Director Research Cluster Molecular and Cognitive Neurosciences 
Director Division of Molecular Neuroscience 
E-Mail: andreas.papas@unibas.ch 
Phone: +41 61 207 05 99 
Prof. Annette Brühl, MD 
Chief physician Zentrum für Affektive -, Stress- und Schlafstörungen & 
Zentrum für Alterspsychiatrie, Universitäre Psychiatrische Kliniken (UPK) 
Basel 
E-Mail: annette.bruehl@upk.ch  
Phone: +41 61 325 50 97 
Study Title 
Randomized placebo-controlled phase II cross-over study on the influence of 
fampridine on working memory in mild to moderate depression  
Study ID 
FamD_2025 
Protocol Version 
and Date 
Version 6 (dated 06/10/25) 
Trial Registration 
The trial will be registered on clinicaltrials.gov and on HumRes.  
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  
Cognitive deficits, including working memory deficits, are often present in 
depression and there are currently no effective pharmacological treatments 
targeting working memory deficits. We have recently demonstrated that 
fampridine, a potassium channel blocker, can enhance working memory in 
healthy individuals with lower baseline performance, suggesting it may hold 
potential for addressing cognitive deficits in clinical populations. The primary 
aim of this study is to evaluate whether fampridine improves working memory 
performance in mild to moderate depression.  
Objectives 
The primary objective of this study is to evaluate if fampridine improves working 
memory in mild to moderate depression. Additionally, we aim to assess whether 
baseline working memory performance or subjective working memory deficits 
moderate the drug’s effect. 
The secondary objectives are to assess the influence of fampridine on different 
working memory functions, attention, cognitive flexibility, affective working 
memory, and mood. 

 
 
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Outcomes 
Primary outcome measure:  
• 
High-load working-memory performance: d’ 3-back as assessed by a 
letter n-back task (Heck et al., 2022) 
Secondary outcome measures:  
• 
Reaction time (3-back hits) 
• 
d’ 0-back (Heck et al., 2022) 
• 
Adaptive verbal working memory capacity test (SPAN), backward 
(SCHUHFRIED, 2024). 
• 
Verbal episodic memory performance (15 words) measured by 
immediate and delayed word-list recall task. Adapted from a subtest 
of the “Verbaler Lern- und Merkfähigkeits-Test” (VLMT; 
Helmstaedter/Lendt/Lux, 2001). 
• 
Accuracy in emotion recognition during the 0-back and 2-back 
conditions (Affective WM Task). 
• 
Depression (MADRS-s (Svanborg/Åsberg, 1994; Svanborg/Åsberg, 
2001), self-rating version).  
• 
Tower of London (ToL) (Phillips et al., 2001; Shallice, 1982). 
• 
Intra-Extra Dimensional Set Shift (IED; Fray, Robbins & Sahakian, 
1996). Adapted version for this study from GitHub (Sochat, V., 2016–
2017). 
Lexical ability measured using a phonemic verbal fluency task (S-words). 
Adapted from a subtest of the Regensburger Wortflüssigkeits-Test (RWT; 
Aschenbrenner/Tucha/Lange, 2001). Safety outcome measures will be   
• 
The most common side effects of fampridine (headache, dizziness and 
gastrointestinal complaints) are recorded by the participants during the 
treatment periods at home and at the study centre at the visits using 
VAS.  
• 
AE-recording  
Assessment of potential confounders 
• 
Tiredness and motivation will be rated by the participant using visual 
analogue scales.  
Study Design 
Randomized, placebo-controlled, double blind, cross-over 
Inclusion- / 
Exclusion Criteria 
Inclusion criteria: 
• 
Male or female  
• 
Major depressive episode confirmed by the Mini-DIPS. Currently mild 
to moderate (MADRS: 7-30). 
• 
Normotensive. BP: 90/60mmHg - 140/90mmHg. Sufficiently treated 
hypertensive subjects will be included. 
• 
BMI: 19-34.9 kg/m2 
• 
Age: 18-55 years 
• 
Fluent in German  
• 
IC as documented by signature 
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 
• 
treatment with OCT 2 inhibitors and -substrates (e.g. cimetidine, 
propranolol) 
• 
Treatment with antidepressants or antipsychotics within the last 3 
months and throughout the study period 
• 
Current intake of psychoactive drugs (e.g. benzodiazepines, 
antidepressants, neuroleptics).  
• 
Other acute or chronic psychiatric disorder (e.g. psychosis, 
somatoform disorder, alcohol or drug abuse disorder)  

 
 
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• 
Cognitive impairment (MoCA score < 25) 
• 
MADRS item 10 > 1 (suicidal tendency) 
• 
Risk of lowered seizure threshold (due to e.g. sleep deprivation, 
withdrawal of alcohol after alcohol abuse, hyponatraemia) 
• 
History of seizures 
• 
Acute cerebrovascular condition 
• 
Acute renal failure or severe renal insufficiency (creatinine clearance 
< 30 ml/min per 1.73 m2) 
• 
Bradycardia < 50/min during clinical examination. 
• 
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) 
• 
Clinically significant laboratory or ECG abnormality that could be a 
safety issue in the study  
• 
Severe somatic or neurological comorbidities 
• 
Smoking including all nicotine containing smoking systems and 
devices (>10 cigarettes/units per day), failure to withstand a test day 
without craving, due to regular consummation pattern  
• 
Pregnancy or breast feeding. Intention to become pregnant during the 
study participation. 
• 
Known or suspected non-compliance  
• 
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 
• 
Enrolment of the investigator, his/her family members, employees 
and other dependent persons 
Measurements and 
procedures 
Assessment of efficacy: Performance in working memory and other tasks after 
repeated administration. The assessment will be performed 3 h after the last 
intake of 10 mg fampridine or placebo at the end of the 7.5-day treatment period 
(visit 3 and 5).  
Assessment of safety:  
• 
the most common side effects of fampridine via VAS by subjects,  
• 
recording Adverse Events. 
Study Product / 
Intervention 
Twice daily oral administration of 10 mg fampridine (Fampyra®) for 7.5 days 
with a wash-out period of at least 6.5 days  
Control 
Intervention 
Twice daily oral administration of placebo for 7.5 days 
Number of 
Participants with 
Rationale 
Total of 38 participants. We expect a drop-out rate of approx. 20%. 
There will be replacement of drop-outs until data for the primary outcome from 
38 participants are completed. The estimation of N=38 is based on a power 
analysis assuming to detect a medium effect size (dz=0.5) of a drug with a 
power of 85% at two-tailed α=0.05 (see also chapter 3.3.4). 
Knowing that the sex-distribution of mild to moderate depression is about 2:1 
(f:m), we aim for at least 13 male participants. 
Study Duration 
Study duration is estimated to be 12-15 months 
Study Schedule 
First-Participant-in (planned): Q2 2025 
Last-Participant-Out (planned): Q2 2026 
 

 
 
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Principal 
Investigator 
Dr. Christiane Gerhards, MD 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8, 4055 Basel  
Phone: +41 61 207 0244 
Email: christiane.gerhards@unibas.ch 
Study Center 
Single-center.  
University of Basel 
Division of Cognitive Neuroscience  
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. In case of significant 
deviation from normality for the dependent variable, appropriate non-
parametric methods will be used (see also chapter 11.4). 
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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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 
BP 
 
Blood Pressure 
Bpm 
 
Beats per minute 
CA 
 
Competent Authority 
CEC 
 
Competent Ethics Committee 
CIPS 
 
Collegium Internationale Psychiatriae Scalarum (Internationale Skalen für Psychiatrie) 
CTCAE  
Common Terminology Criteria for Adverse Events 
ClinO 
Ordinance on Clinical Trials in Human Research  
d’ 2-back 
d’ 2-back as assessed by a letter n-back – a measure of high-load working-memory 
performance 
DIPS 
Diagnostisches Interview bei psychischen Störungen 
DKF 
 
Departement klinische Forschung 
ECG 
Electrocardiography 
EKNZ 
Ethikkommission Nordwest- und Zentralschweiz 
eCRF  
Electronic Case Report Form 
FADP  
Federal Act on Data Protection  
FOPH  
Federal Office of Public Health 
FU 
 
Follow-up 
GCP 
 
Good Clinical Practice 
Gf 
 
Fluid Intelligence 
GGT 
 
Gamma-Glutamyltransferase 
GMP 
 
Good Manufacturing Practice 
GWAS  
Genome-wide association studies 
HAMD   
Hamilton Depression Rating Scale 
Ho 
 
Null hypothesis 
H1 
 
Alternative hypothesis 
HAMD  
Hamilton Depression Rating Scale 
hCG  
 
Human choriongonadotropin 
HR 
 
Heart Rate 
HRA 
 
Federal Act on Research involving Human Beings  
HumRes 
Informationsplattform des BAG zur Humanforschung in der Schweiz, 
www.humanforschung-schweiz.ch 
IC 
 
Informed Consent 
ICH 
 
International Conference on Harmonisation  
IEC 
 
Independent Ethics Committee 
IED 
 
Intra-Extra Dimensional Set Shifting task  
IIT 
 
Investigator-initiated trial 
IMP 
 
Investigational Medicinal Product 

 
 
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IR 
 
Immediate Release 
Kv 
 
Voltage-gated potassium channel 
LabKey® 
Data management software provided by LabKey, https://www.labkey.com 
LDH 
 
Lactatdehydrogenase 
LPLV 
 
Last Patient/Participant Last Visit 
LTP 
 
Long-Term-Potentiation  
MADRS 
Montgomery Asberg Depression Rating Scale  
MDE 
 
Major Depressive Episode 
MRHD  
Maximum Recommended Human Dose 
MS 
 
Multiple Sclerosis 
MTI 
 
Maximum Tolerated Imbalance 
MoCA  
Montreal Cognitive Assessment 
OCT 2  
Organic Cation Transporter 2 
PANAS  
Positive and Negative Affect Schedule 
PI 
 
Principal Investigator 
PR 
 
Prolonged Release 
RWT / S-words  Regensburger Wortflüssigkeits-Test /  
Lexical ability measured by a phonemic verbal fluency test (S-words) 
SADRS 
Serious Adverse Drug Reaction 
SAE 
 
Serious Adverse Event 
SD 
 
Source Data 
SDV 
 
Source Data Verification 
SOP 
 
Standard Operating Procedure 
SPAN  
Adaptiver Arbeitsgedächtnistest, SCHUHFRIED 
SR 
 
Sustained Release 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Studiendatenbank-MCN: Is a local database for study data and is implemented using LabKey®  
TMF 
 
Trial Master File 
VAS 
 
Visual Analog Scale 
VLMT  
Verbaler Lern- und Merkfähigkeits-Test 
15 words 
Verbal episodic memory performance (15 words) measured by immediate and delayed  
word-list recall task.  
WI 
 
Working Instruction 
 
 
 
 
 

 
 
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SUMMARY OF THE REVISION HISTORY IN CASE OF 
AMENDMENTS 
Version 
Nr 
Version 
date 
Chapter 
Description of changes 
Reason for the change 
1.0 
01/03/2022  
 
Initial version 
2.0 
13/01/2025 9.3.1 
9.3.2 
Addition of the responsibilities of the members of the 
study team. 
More detailed description of the diagnosis of 
depression. 
Clarification of the procedure if a patient is diagnosed 
with severe depressive symptoms during screening or 
if a patient develops severe depressive symptoms 
during participation in the study. 
Revision according to the 
conditions of the EKNZ (1st 
directive, 17 December 2024): 
11.2, 3.8 
Clarification of the description of the determination of 
the sample size 
2.1 
16/01/2025 6.2.1, 
6.2.2, 
3.2 
Clarification of the description of the IMP-kits 
New authorization holder for Fampyra® in Switzerland:  
Merz Pharma (Schweiz) AG, Allschwil 
corrections 
3.0 
31/03/2025 
9.3.4 
Safety FU after regular completion of study 
participation or after discontinuation of study 
participation. 
FIR Swissmedic, 31.03.2025 
7.1.1, 9.3.1 
M.I.N.I. adult replaced by Mini-DIPS for depression 
diagnosis. 
a more suitable tool for our 
purposes 
5.2, 9.2.2 
MADRS self-assessment (instead of the external 
assessment version) at visits 2-5. 
Improvement of comparability 
between visits, more practical 
9.2.2, 9.3.1 
References 
Additional references to cognitive tests. 
Additional sources to those 
already mentioned 
4.0 
24/04/2025 4.2, 5.2, 
9.2.2, 12.3.2., 
12.3.3, 
References 
Addition of affective working memory task 
Assess emotion recognition, 
which is not yet included in the 
task battery 
5.0 
14/07/2025 Synopsis 
(outcomes), 
study 
schedule, 
5.2, 9.2.2, 
12.3.2, 
references 
Visits 2 and 4: VAS most common side effects, 
motivation and tiredness new also after completion of 
psychological testing. 
Comparability between the four 
test days (visits 2–5) 
Digit Span Task replaced with an adaptive verbal 
working capacity test (SPAN, SCHUHFRIED, 2024) 
The adaptive design allows for 
a more accurate assessment of 
working memory capacity. 
Precisions concerning descriptions and references of 
some outcomes. 
-- 
6.0 
06/10/2025 Synopsis (in-
/exclusion 
criteria), 
Study 
Schedule, 
3.8, 7.1.1, 
9.3.1 
Increase of inclusion age 
Additional screening for cognitive impairment  
Correction of the MADRS Score from 0 to 1 as an 
exclusion criterion 
Higher recruitment success 
Assessment 
of 
cognitive 
function 
Avoid unnecessary exclusion 
7.0 
17/11/2025 Synopsis (in-
/exclusion 
criteria), 3.8, 
7.1.1, 9.3.1 
Change of inclusion criterion MADRS: 7-19 to 
MADRS: 7-30. 
Higher recruitment success 
 
 
 
 
 

 
 
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STUDY SCHEDULE 
 
Duration 
 
Treatment period 1 
(7.5 days) 
Wash-out 
period 
min. visit 3 +7 and  
max. visit 3 + 28 days 
Treatment period 2 
(7.5 days) 
Safety 
FU 
Visit 
 
Visit 1 
Visit 2  
 
Visit 3 
 
Visit 4 
 
Visit 5 
Visit 6 
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 
FU 
Day 
 
within 28 days 
before Visit 2 
1 
 
8 
 
15-36 
 
22-43 
24-48 
Screening 
• Written IC, assignment of the subject 
number 
• Personal, family and medication history 
• Psychiatric interview Mini-DIPS 
• MADRS external assessment, HAMD, 
PANAS 
• MoCA 
• Subjective working memory deficits 
(VAS), sociodemographics 
• Physical examination, ECG, laboratory 
analysis, drug-drug interaction, vital 
signs 
ca. 2 h 
x 
 
 
 
 
 
 
 
 
Treatment periods 
• Electronic intake diary 
• Electronic AE-diary (VAS headache, 
gastrointestinal discomfort, dizziness) 
7.5 days 
 
 
x 
 
 
 
x 
 
 
Wash-out period 
(min. visit 3 +7 and max. visit 3 + 28 days) 1-4 weeks 
 
 
 
 
x 
 
 
 
 
Test days 
 
 
 
 
 
 
 
 
 
 
Pre-examination test days 
• Pregnancy test (Visits 2 and 4) 
• Sleep duration last 24 hours 
• AE recording, new medications 
• VAS headache, gastrointestinal 
discomfort, dizziness 
• VAS tiredness, motivation 
• MADRS-s  
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 for participants at the study 
centre: 
Visits 2 and 4: 90 min observation time 
after first intake of study medication at the 
beginning of the treatment periods 
Visits 3 and 5: 3 hours until final testing. 
Incl. continental breakfast 30 min after 
intake of study medication  
90 min 
resp. 3 h 
 
90 min 
 
3 h 
 
90 min 
 
3 h 
 
Before start of testing 
• AE recording  
• VAS headache, gastrointestinal 
discomfort, dizziness,  
• VAS tiredness, motivation  
5-15 min 
 
(x)  
(as part of pre-
examination) 
 
x 
 
(x)  
(as part of pre-
examination) 
 
x 
 
Testing Phase – part 1  
(pauses between the tasks: 3-5 min) 
• 
n-back (15 min) 
• 
SPAN (10 min) 
• 
IED (10 min) 
• 
S-words (5 min) 
• 
Word-list learning and IR (5 min) 
45 min 
 
x 
 
x 
 
x 
 
x 
 
Break 
15 min 
 
x 
 
x 
 
x 
 
x 
 
Testing Phase – part 2 
• 
Word List SD (5 Min) 
• 
Tower of London (ToL) (10 min) 
• 
Affective WM Task (15 min) 
30 min 
 
x 
 
x 
 
x 
 
x 
 
After testing phase 
• AE-recording 
• VAS headache, gastrointestinal 
discomfort, dizziness,  
• VAS tiredness, motivation 
5 min 
 
x 
 
(x)  
(as part of final 
examination) 
 
x 
 
(x)  
(as part of final 
examination) 
 
Final Examination  
• AE recording 
• VAS headache, gastrointestinal 
discomfort, dizziness 
• VAS tiredness, motivation 
10 min 
 
x 
 
x 
 
x 
 
x 
 
Follow-up 
• Completion of AE documentation / 
occurrence of new AEs since visit 5? 
• Well-being of the test person 
• Completion of study participation 
5-15 min 
 
 
 
 
 
 
 
 
x 

 
 
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Visit 2/4 (testing day 1/3) 
 
 
Visit 3/5 (testing day 2/4) 
 
pre-
examination
Testing 
phase 1 
(45 min)
break 
(5-15 min)
Testing 
phase 2 
(25 min)
intake study 
medication
Observation 
period 
(90 min)
Check out
pre-
examination, 
intake study 
medication
Waiting 
period 
(30 min)
breakfast + 
further 
waiting 
(150 min)
Testing 
phase 1 
(45 min)
break 
(5-15 min)
Testing 
phase 2 
(25 min)
Check out

 
 
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1 STUDY ADMINISTRATIVE STRUCTURE 
Function 
Address  
Sponsor  
Research Cluster Molecular and Cognitive Neurosciences, University 
of Basel, Birmannsgasse 8, 4055 Basel 
Contact persons: 
Prof. Dominique de Quervain, MD 
University of Basel 
Co-Director Research Cluster 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 
Prof. Andreas Papassotiropoulos, MD 
University of Basel 
Co-Director Research Cluster Molecular and Cognitive Neurosciences 
Director Division of Molecular Neuroscience 
E-Mail: andreas.papas@unibas.ch 
Phone: +41 61 207 05 99 
Prof. Annette Brühl, MD 
Chief physician, Zentrum für Affektive -, Stress- und Schlafstörungen 
& Zentrum für Alterspsychiatrie 
University Psychiatric Clinics Basel 
Wilhelm Klein-Strasse 27, 4002 Basel 
E-Mail: annette.bruehl@upk.ch  
Phone: +41 61 325 50 97 
Principal Investigator 
Dr. Christiane Gerhards, MD 
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 
Trial statistician 
Nathalie Schicktanz, PhD 
Division of Cognitive Neuroscience  
University of Basel 
Birmannsgasse 8 
4055 Basel 
E-Mail: nathalie.schicktanz@unibas.ch 
Phone: +41 61 207 0228 
Psychologist 
Magdalena Ridder, M. Sc. 
Zentrum für Affektive -, Stress- und Schlafstörungen & Zentrum für 
Alterspsychiatrie 
University Psychiatric Clinics Basel 
Wilhelm Klein-Strasse 27 
4002 Basel 

 
 
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Departement Klinische 
Forschung (DKF) 
 
 
 
Contact person monitoring 
 
 
 
Contact person database 
administrator 
 
 
Contact person on site 
management 
Universitätsspital Basel 
Departement klinische Forschung (DKF) 
Schanzenstrasse 55 (BH 3)  
4031 Basel 
 
Klaus Ehrlich 
Phone:  +41 61 556 5261 
E-mail: klaus.ehrlich@usb.ch 
 
David Büchel 
Phone: +41 61 328 59 52 
E-mail: david.buechel@usb.ch 
 
Silke Scarascia 
Phone: +41 61 328 7709 
E-Mail: silke.scarascia@usb.ch 
Pharmacy 
 
 
 
 
 
 
Contact Person 
Spital-Pharmazie 
Universitätsspital Basel 
Qualitätssicherung 
Rossetti-Bau 
Spitalstrasse 26 
4031 Basel 
 
Anne Henn / Katharina Walter 
Apothekerin / Studienkoordinatorin 
Phone:  +41 61 328 74 11 
Fax: 
+41 61 265 32 75 
E-mail: studien.pharmazie@usb.ch 
 

 
 
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2 ETHICAL AND REGULATORY ASPECTS 
The decision of the EKNZ (CEC) and Swissmedic (CA) concerning the conduct of the study will be made 
in writing to the sponsor 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  
Before recruitment starts, the study will be registered in the WHO-recognized primary registry of the U.S. 
National Library of Medicine (https://clinicaltrials.gov). 
In addition, the study will be registered in the Swiss National Clinical Trials Register (HumRes) in German, 
also before the start of the study. 
2.2 
Categorization of study  
This clinical trial comes under Category B as fampridine 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 principal investigator will obtain approval from the Competent Ethics Committee (EKNZ) before the 
start of the clinical trial. 
No changes are made to the protocol without prior principal investigator and EKNZ 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 10.4.  
Amendments are reported according to chapter 2.10 
2.3.1 
Notification and reporting for the first visit and for completion, premature termination, interruption 
and resumption of the clinical trial (ClinO, Art. 38) 
The following notifications have to be made by the principal investigator to the EKNZ. 
• 
The first visit of the first participant (FVFP) in the clinical trial within 30 days. 
• 
The completion of the study within 30 days. Completion of a clinical trial is marked by the last 
participant’s final follow-up visit.  
• 
The discontinuation, interruption or resumption of the clinical trial within 15 days. In the 
notification, the reasons for the discontinuation, interruption or resumption must be stated. An 
interruption lasting for more than two years is considered to be a premature termination. 
• 
The summary final report shall be submitted within one year after completion or premature 
termination of the clinical trial. 
2.3.2 
Notification and reporting on the safety of participants and protective measures (ClinO, Art. 37 and 
43) 
The following notifications and reporting have to be made by the principal investigator to the 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.  
• 
Report containing a list of adverse reactions as specified in Articles 40–41 (SAEs, SUSARs) once 
a year. On this basis, the investigator shall submit a report on their severity and causal relationship 
to the intervention, and on the safety of participants, and shall inform the ethics committee about 
the general progress of the clinical trial (DSUR, see chapter 10.4.5). 
2.4 
Competent Authority (CA) 
The sponsor will obtain approval from Competent Authority (Swissmedic) before the start of the clinical 
trial.  
No changes are made to the protocol without prior sponsor and Swissmedic approval, except where 
necessary to eliminate apparent immediate hazards to study participants. 

 
 
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Serious Adverse Events (SAE) and Suspected Unexpected Serious Adverse Reactions (SUSAR) are 
reported according to chapter 10.4. 
Amendments are reported according to chapter 2.10.  
2.4.1 
Notification and reporting for the first visit and for completion, discontinuation, interruption and 
resumption of the clinical trial (ClinO, Art. 38) 
The following notifications have to be made by the sponsor to Swissmedic: 
• 
The first visit of the first participant (FVFP) in the clinical trial within 30 days. 
• 
the completion of the study within 30 days. Completion of a clinical trial is marked by the last 
participant’s final follow-up visit. 
• 
the discontinuation, interruption or resumption of the clinical trial within 15 days. In the notification, 
the reasons for the discontinuation or interruption must be stated. An interruption lasting for more 
than two years is considered to be a premature termination. 
• 
the summary final report shall be submitted within one year 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 to 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. 
• 
 Report containing a list of adverse reactions as specified in Articles 40–41 (SAEs, SUSARs) 
once a year. On this basis, the investigator shall submit a report on their severity and causal 
relationship to the intervention, and on the safety of participants, and shall inform the ethics 
committee about the general progress of the clinical trial (DSUR, see chapter 10.4.5). 
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 EKNZ and Swissmedic will receive annual 
safety and interim reports and they will be informed about study stop/end in agreement with local 
requirements. The EKNZ will also be informed annually about the general progress of the clinical trial. 
The safety report can be written and submitted in the format of the Development safety update report 
(DSUR). See chapter 10.4.5. 
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 investigator explains to each subject 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 subject will 
be informed that the participation in the study is voluntary and that he/she may withdraw from the study 
at any time. The subjects are informed that they can ask any question, and consult with family members, 
friends, their treating physicians or other experts before deciding about their participation in the study. 
Enough time is given to the subjects. 
The subjects are informed that authorized individuals may examine their medical records. 
All subjects are given a subject information sheet and a consent form describing the study and providing 
sufficient information for the subjects to make an informed decision about their participation in the study.  
The formal consent of a subject, using the approved consent form, must be obtained before the subject 
is submitted to any investigation procedure.   
The subject should read, understand, and voluntarily agree before signing and dating the informed 
consent form, and is given a copy of the signed document. The consent form is signed and dated by the 

 
 
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subject and the PI (or her/his designee). The signed consent form it is retained as part of the investigation 
records. 
For details about the recruitment and inclusion procedure see chapter 7.2. 
Incidental findings during screening procedure (ECG, laboratory analysis) will be reported to the study 
participants. We will recommend further support and organize it if needed. 
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.  
The investigator has appropriate knowledge and skills in the areas of data security and data protection or 
is able to ensure compliance by calling in appropriate expertise (Art. 6, ClinO). 
Individual subject medical information obtained as a result of this study is considered confidential and 
disclosure to third parties is prohibited. Subject confidentiality is ensured by the assignment to each 
subject a unique subject identification number. For the pseudonymization and coding in this project see 
chapter 12.3.1. 
For data verification purposes, authorized representatives of the sponsor, 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. 
2.9 
Premature termination of the study  
The sponsor 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.  
If the study is terminated earlier than planned, the investigator notifies the EKNZ (CEC) and Swissmedic 
(CA) according to the provisions of ClinO Article 38 (see chapters 2.3.1 and 2.4.1).  
2.10 Protocol amendments 
Substantial amendments are only implemented after approval of the EKNZ and Swissmedic 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, the EKNZ and Swissmedic. Such 
deviations shall be documented and reported to the sponsor, the EKNZ and Swissmedic as soon as 
possible.  
All non-substantial amendments are communicated to Swissmedic (CA) as soon as possible and once a 
year to the EKNZ (CEC) with the safety report / general study progress report of the clinical trial. 
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 substantial modifications and have 
to be reported to the EKNZ by the principal investigator (ClinO, Art. 29): 
• 
modifications affecting the participants’ safety and health, or their rights and obligations; 
• 
modifications to the protocol, and in particular modifications based on new scientific findings 
which concern the trial design, the method of investigation, the endpoints or the form of statistical 
analysis; 
• 
a change of trial site, or conducting the clinical trial at an additional site; 
• 
a change of sponsor, coordinating investigator or investigator responsible at a trial site; 
• 
the extension of a deadline in accordance with Articles 23, 23a and 50; in the application to the 
ethics committee, the investigator shall indicate whether the application documents are still up-

 
 
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to-date, particularly with regard to the scientific relevance of the question; if this is not the case, 
the investigator shall submit updated application documents. 
The investigator shall submit to the ethics committee any application documents specified in Annex 3 
(ClinO) which are affected by the modification. At the same time, the investigator shall provide information 
on the reasons for the modification. 
In emergency conditions, deviations from the protocol for the protection of the rights, safety and well-
being of the trial subjects must be documented and reported to the EKNZ within 7 days; without the prior 
approval of the sponsor and the EKNZ. In this report, the safety and protective measures taken and the 
circumstances that made them necessary have to be described. (ClinO, Art. 37) 
Other modifications must be notified to the ethics committee in the annual safety report specified in 
Article 43. (ClinO, Art. 29) 
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 Swissmedic by the sponsor (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 Swissmedic 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. Swissmedic shall reach a decision within 30 days after receipt of the complete application 
documents affected by the change. 
In emergency conditions, deviations from the protocol for the protection of the rights, safety and well-
being of the trial subjects must be documented and reported to Swissmedic within 7 days; without the 
prior approval of the sponsor and Swissmedic. In this report, the safety and protective measures taken 
and the circumstances that made them necessary have to be described. (ClinO, Art. 37) 
Other modifications which affect the documents submitted to Swissmedic must be notified to Swissmedic 
as quickly as possible. (ClinO, Art. 34) 

 
 
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3 BACKGROUND AND RATIONALE 
3.1 
Background and Rationale  
In a recent study we investigated the potential cognitive benefits of fampridine for working memory 
enhancement, leveraging a genome-guided drug repurposing approach (Papassotiropoulos et al., 2024). 
In this double-blind, randomized, placebo-controlled crossover trial with 43 healthy young adults, 
fampridine’s effect on working memory was assessed after 3.5 days of repeated administration. 
Independently of baseline cognitive performance, no significant main effect was observed. However, 
lower baseline performance was associated with higher working memory performance after repeated 
intake of fampridine compared to placebo (ρ=-0.37, P=0.014, n=43). Analysis with the Jonckheere-
Terpstra test confirmed this observation: a significant ordered effect of study medication after repeated 
administration across participants with low (i.e., low tercile), medium (i.e., middle tercile), and high (i.e., 
high tercile) baseline working memory performance was detected (z=-2.24, r=-0.34, P=0.025, n=43). 
Post-hoc tests for each tercile separately revealed a significant main effect of the study medication for the 
low performance group, with fampridine resulting in better working memory performance compared to 
placebo (r=0.54, P=0.035, n=15; Figure 3). No significant main effect of study medication was found in 
the medium (r= 0.17, P=0.59, n=13) or high baseline performance group (r=-0.40, P=0.14, n=15; Figure 
3). 
Figure 1. Analysis of the drug effect on the primary outcome per 
cognitive baseline group, violin plots. Y-axis: individual difference 
(fampridine – placebo) in d’ after repeated administration; values 
above 0 represent improvement under fampridine, values below 0 
represent decrease under fampridine. X-axis: baseline working 
memory performance (d’) stratified in three performance groups (i.e., 
low, medium, high terciles). Gray dots and vertical lines represent 
primary outcome measure means and standard errors of the means, 
respectively. 
 
 
 
 
 
 
Additionally, fampridine significantly lowered (P=0.027) the resting motor threshold (rMT), an indicator of 
cortical excitability, suggesting a neural mechanism linking potassium channel modulation to cognitive 
function. Importantly, lower rMT was associated with higher baseline working memory performance under 
placebo conditions (ρ=-0.38, P=0.019). 
The findings suggest that fampridine enhances working memory in individuals with lower baseline 
performance, highlighting its potential therapeutic value in addressing cognitive deficits in psychiatric 
populations. The study underscores the importance of considering baseline cognitive abilities in 
pharmacological interventions and sets the stage for future trials in clinical populations with psychiatric 
disorders, such as depression. Importantly, working memory deficits are often observed in depression 
(Nikolin et al., 2021) 
3.2 
Investigational Product (treatment) and Indication  
Active study medication consists of a single tablet of fampridine 10mg sustained release (SR) formulated 
for oral administration (Fampyra®). Authorisation holder in Switzerland:   
Merz Pharma (Schweiz) AG 
Hegenheimermattweg 57, 4123 Allschwil 
Handelsregister: Kanton Basel-Landschaft CHE-101.213.674 
Web: https://www.merz.ch/ 
Improved
Worsened
−2
−1
0
1
2
Low
Medium
High
Cognitive Baseline
 
 

 
 
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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). 
Fampridine, whose active ingredient is prolonged release 4-aminopyridine (4-AP), is a broad-spectrum 
voltage-dependent potassium 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 potassium channels; this decreases potassium loss, increases 
action potentials and conduction, and promotes synaptic and neuromuscular transmission of nerve 
signals (Chwieduk and Keating, 2010). Prolonged release (De Giglio, De Luca et al., 2019) 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®1. 
Apparent first-order terminal elimination half-life t1/2 of fampridine is 4.62 h (5.2 to 6.5 h) (Henney, Faust 
et al., 2011). 
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 body 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). 
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 for the treatment of MS is 10 mg twice daily 
(approximately 12 hours apart) without food (see prescribing information Fampyra®). 
 
1 https://www.compendium.ch/it/product/1422958-fampyra-ret-tabl-10-mg 

 
 
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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).  
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. 
Cerebrospinal fluid levels of fampridine peak 30–60 min following peak serum concentration (Donovan, 
Halter ., 2000). 
Previous studies examining long-term use of fampridine reported pro-cognitive effects with 10 mg 
fampridine SR twice daily (see 3.4).  
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 (for pharmaceutical ingredients see chapter 8.1.2.) manufactured 
by  
Losan Pharma GmbH 
Otto-Hahn-Straße 13 
79395 Neuenburg am Rhein 
Germany 
Placebo is chosen here as main comparator. One reason for this choice is that it is scientific standard and 
the best method to control for unspecific potentially confounding effects. The inclusion of a placebo in this 
study design acts as a control measure, aiding in the accurate evaluation of treatment efficacy by creating 
a comparative baseline against which the effects of the investigational drug can be assessed within the 
same individuals. This approach is particularly relevant in within-subject designs, as each participant 
serves as their own control, minimizing variability and enhancing the sensitivity of the study to detect true 
treatment effects. Moreover, employing a placebo in such studies aligns with ethical considerations by 
ensuring rigorous evaluation of the investigational drug's effectiveness while minimizing potential bias. 
The use of a placebo within a within-subject design thus contributes to robust and credible findings by 
allowing for a more precise understanding of the specific effects of the drug being studied in comparison 
to baseline responses observed in the absence of active intervention. 
3.7 
Risks / Benefits 
Although 10 mg fampridine twice a day for a short period is generally well tolerated (Smith, Swan et al., 
2010) (March and Cardi 2009), and a recent study in healthy participants applying fampridine (10 mg) 
twice daily over 3.5 days showed no relevant adverse events (Papassotiropoulos et al., 2024), subjects 
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).  
• 
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 (see chapter 3.5). To assess renal impairment, we will 
perform creatinine and uric acid levels in plasma. 
• 
Fampridine is excreted primarily through the organic cation transporter 2 (OCT 2). OCT 2 inhibitors 
or substrates (e.g. Cimetidine, Carvediol, Propanolol and Metformin) may inhibit elimination of 
fampridine and increase the risk of adverse events. Subjects with concomitant use of OCT 2 – 
inhibitors are excluded from participation. In subjects with concomitant use of OCT 2-substrates the 
potential of drug-drug interaction with fampridine will be checked individually. In case of an confirmed 
increased risk the subject will be 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 
or hyponatraemia (by e.g. drug- induced SIADH).  

 
 
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• 
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.  
• 
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 
within 24 hours of intake 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®). 
• 
For fampridine, no clinical data on exposed pregnancies are available. 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. For additional safety data, refer to the prescribing information 
Fampyra®. 
All sexually active female of childbearing potential are requested to use adequate contraception 
starting 10 days before the first intervention until and including the last visit day, such as oral, 
injectable, or implantable contraceptives or intrauterine devices. No contraception will be required 
from women who are sexually inactive or not heterosexually active. 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 (visits 
2 and 4; start of treatment periods). 
• 
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. 
The benefit of the study lies in the clinical implications with regard to treatment of working memory deficits 
in neuropsychiatric disorders. The benefits are expected to be very relevant for patients with depression 
and could improve quality of life for these patients.  
Therefore, we consider the rather mild and infrequent side effects tolerable in comparison with the 
potential benefits this study might show.    
3.8 
Justification of choice of study population  
We have recently demonstrated that fampridine can enhance working memory in healthy individuals with 
lower baseline performance, suggesting it may hold potential for addressing working memory deficits, 
which are often observed in depression (Nikolin et al., 2021). We will recruit individuals with mild to 
moderate depression, which does not necessitate antidepressant medication to avoid potential interaction 
with such medication.  
As drug effects may vary between sexes, the study will consider sex as a covariate of potential importance 
in the statistical analyses. Given the low prevalence of intersex individuals and those with gender identities 
not congruent with their assigned sex at birth, our study design does not allow consideration of questions 
related to these conditions. 
 

 
 
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4 STUDY OBJECTIVES  
4.1 
Primary Objective 
The primary objective of this study is to evaluate if fampridine improves working memory in mild to 
moderate depression. Additionally, we aim to assess whether baseline working memory performance or 
subjective working memory deficits moderate the drug’s effect. 
4.2 
Secondary Objectives 
The secondary objectives are to assess the influence of fampridine on different working memory functions, 
attention, cognitive flexibility, affective working memory, and mood. 
4.3 
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. 
 
5 STUDY OUTCOMES 
5.1 
Primary Outcome 
High-load working-memory performance: d’ 3-back as assessed by a letter n-back task (Heck et al., 
2022) 
5.2 
Secondary Outcomes 
• 
Reaction time (3-back hits) 
• 
d’ 0-back (Heck et al., 2022) 
• 
Adaptive verbal working memory capacity test (SPAN) backward (SCHUHFRIED, 2024). 
• 
Verbal episodic memory performance (15 words) measured by immediate and delayed word-list 
recall task after acute and repeated intake of study medication. Adapted from a subtest of the 
Verbaler Lern- und Merkfähigkeits-Test (VLMT; Helmstaedter/Lendt/Lux, 2001). 
• 
Accuracy in emotion recognition during the 0-back and 2-back conditions (Affective WM Task) 
• 
Depression (MADRS-s (Svanborg/Åsberg, 1994; Svanborg/Åsberg, 2001), self-rating version).  
• 
Tower of London (ToL; Phillips et al., 2001; Shallice, 1982). 
• 
Intra-Extra Dimensional Set Shift (IED; Fray, Robbins & Sahakian, 1996). Adapted version for 
this study from GitHub (Sochat, V., 2016–2017). 
• 
Lexical ability measured by a phonemic verbal fluency task (S-words). Adapted from a subtest of 
the Regensburger Wortflüssigkeits-Test (RWT; Aschenbrenner/Tucha/Lange, 2001). 
5.3 
Safety Outcomes 
• 
The most common side effects of fampridine (headache, dizziness and gastrointestinal 
complaints) are recorded by the participants during the treatment phases at home and at the 
study centre at the visits using VAS. (see chapter 10.1.1) 
• 
AE-recording 
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 7.5. days of 10 mg fampridine (oral 
administration) twice daily on cognitive processes, in particular working memory, in 38 patients with mild 
to moderate depression using the following design: 
• 
randomized 
• 
double-blind (participant, study team) 
• 
placebo-controlled  
• 
cross-over 
• 
counter-balanced 
The total duration of the study, from the first participant to the last participant’s completion, will be 
approximately 12-15 months. The duration for each individual participant will range from 4 to 9 weeks, 
depending on the length of the wash-out phase, the latter being at least 6.5 days (i.e., exceeding 25 half-
lives of the active moiety fampridine (t½ = 6 hours)) and up to 27 days. After the screening visit (visit 1), 
participants will return to the clinic for four test days. Two test days will be conducted during each study 
period to assess performance in cognitive tasks (see Figure 2). 
Figure 2. Study design overview. Illustration of the study's double-blind, placebo-controlled, randomized, crossover 
design. After the 4visit (Visit 1), eligible participants will be randomly assigned to receive either fampridine or placebo 
as their initial treatment. Following a washout period of at least 6.5 days, participants will switch to the alternate 
treatment (fampridine or placebo) for the second phase. Baseline assessments of working memory performance will 
be conducted at visits 2 and 4, before the first dose of either fampridine or placebo. At visits 3 and 5, working memory 
performance will be reassessed after 7 days of treatment with the respective intervention. 
 
During the screening visit (visit 1), the investigator will explain the study’s aims, procedures, the drug 
being investigated, and potential risks to the participant. Written informed consent will be obtained from 
all participants, with no time constraints for signing. Participants who are potential candidates for 
enrolment will be assessed for eligibility based on the inclusion and exclusion criteria during the screening 
visit. The screening visit will occur within 4 weeks prior to the first test visit (visit 2). 
Eligible participants will be randomized on test day 1 (visit 2) to receive either placebo or fampridine first, 
following a cross-over design. Baseline cognitive testings will be conducted before the first tablet is taken 
at visits 2 and 4. After completing the test battery, participants will take the first tablet in the study centre 
and remain under observation for 90 min to monitor for acute side effects. They will then be discharged 
with 13 tablets to take at home, 2 tablets per day (one in the morning and one in the evening), starting the 
day of test days 1 and 3 (visits 2 and 4). Participants will have to document every study drug intake via 
an online tool. Participants will return to the clinic on day 8 for test days 2 and 4 (visits 3 and 5), where 
they receive the last tablet. At the end of test days 1 and 3 (visits 2 and 4), participants will be interviewed 
regarding their current well-being. If no complaints or symptoms are reported, they will be allowed to 
leave. In cases of minor health issues, participants will stay at the clinic under medical supervision until 
recovery. 
Of note, we selected a 7.5-day treatment period based on our previous findings in healthy subjects, where 
no effect was observed after acute administration, but a significant effect emerged after 3.5 days. 
Extending the treatment to 7.5 days may further enhance efficacy. A longer treatment period was avoided 
in this proof-of-concept study to minimize dropout risk and ensure feasibility. 
Fampridine
Placebo
Fampridine
Placebo
Visit 2
Visit 3
Visit 4
Visit 5
Washout period
Randomization 
of included 
patients
Visit 1

 
 
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6.2 
Methods of minimizing bias  
To minimize bias, participants will be randomly allocated to treatment groups (i.e. starting with fampridine 
or placebo) and study medication will be double-blinded. 
6.2.1 
Randomization  
After pre-examination on visit 2, each eligible participant will be assigned 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® which contains the randomization list. The randomization list is 
generated with a clinical trial randomization tool2 of the National Institute of Health (NIH), USA, by the 
data manager of the DKF (secuTrial®). This procedure ensures that participants will be randomly allocated 
to the two groups, while accounting for sex as a covariate of potential importance. 
Replacement of dropouts will be carried out after the assignment of the first 38 randomisation numbers. 
The replacement of all drop-outs will be carried out after assignment of all 38 medication kits is completed. 
There will be replacement of drop-outs until data for the primary outcome of 38 participants are completed. 
Knowing that the sex-distribution of mild to moderate depression is about 2:1 (f:m), we aim for at least 13 
male participants. 
6.2.2 
Blinding procedures  
The IMP and the placebo are identically looking tablets to ensure double-blind conditions.  
The pharmacy will prepare two kits of study mediation per participant (one per intervention period). Each 
kit will consist of two intransparent plastic containers, one containing either 14 tablets of blistered 
fampridine and a drying agent or unblistered placebo and a drying agent (visits 2 and 4 and treatment 
phase at home) and one containing either one tablet of blistered fampridine and a drying agent or 
unblistered placebo and a drying agent (visits 3 and 5). 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 
for seven days in a closed container while adding a drying agent (professional / prescribing information 
Germany Fampyra® SR).  
Each kit (and all parts of it) 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 and visit in a separate room (visits 2-5). If Verum is inside she/he will 
unblister the tablets, if Placebo is inside nothing has to be done. Afterwards he/she hands over the 
container to the responsible staff member for the participant. On visits 2 and 4 the container will be handed 
over to the subject for the first intake in the study center and the intake of the study medication at home. 
During each intervention period a tablet must be taken approximately every 12 hours for 13 times at home. 
The last (15th) intake of the study medication will be again in the study center (second container for the 
treatment phase).  
The IMP and the placebo are identically looking tablets to ensure double-blind conditions.  
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. All study team members will be blinded to 
ensure that those assessing the outcomes will be blind to group assignment. Testing will take place at the 
same location at the premises of the Division of Cognitive Neuroscience, University of Basel for each 
participant and during the same time window 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 principal 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®. 
 
2 https://ctrandomization.cancer.gov/ 

 
 
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The principal investigator or a representative will report to the sponsor within 24 hours 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  
7.1.1 
Inclusion criteria 
Participants fulfilling all of the following inclusion criteria are eligible for the study: 
• 
Male or female  
• 
Major depressive episode confirmed by the Mini-DIPS Open Access Interview (Margraf et al., 
2017) 
• 
Currently mild to modrate (MADRS external assessment: 7-30). See section 9.3.1 for details 
• 
Normotensive (BP: 90/60mmHg - 140/90mmHg). Sufficiently treated hypertensive subjects will 
be included. 
• 
BMI: 19 - 34,9 kg/m2 
• 
Age: 18 - 55 years 
• 
Fluent in German  
• 
IC as documented by signature 
7.1.2 
Exclusion criteria 
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 
• 
Treatment with OCT 2 inhibitors and -substrates (e.g. cimetidine, propranolol) 
• 
Treatment with antidepressants or antipsychotics within the last 3 months and throughout the 
study period 
• 
Current intake of psychoactive drugs (e.g. benzodiazepines, antidepressants, neuroleptics).  
• 
Other acute or chronic psychiatric disorder (e.g. psychosis, somatoform disorder, alcohol or drug 
abuse disorder)  
• 
Cognitive impairment (MoCA< 25) 
• 
MADRS item 10 > 1 (suicidal tendency) 
• 
Risk of lowered seizure threshold (due to e.g. sleep deprivation, withdrawal of alcohol after 
alcohol abuse, hyponatraemia) 
• 
History of seizures 
• 
Acute cerebrovascular condition 
• 
Acute renal failure or severe renal insufficiency (creatinine clearance < 30 ml/min per 1.73 m2) 
• 
Bradycardia < 50/min during clinical examination. 
• 
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) 
• 
Clinically significant laboratory or ECG abnormality that could be a safety issue in the study  
• 
Severe somatic or neurological comorbidities 
• 
Smoking including all nicotine containing smoking systems and devices (>10 cigarettes/units 
per day), failure to withstand a test day without craving, due to regular consummation pattern 
• 
Pregnancy or breast feeding. Intention to become pregnant during the study participation. 
• 
Known or suspected non-compliance  
• 
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 
• 
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7.2 
Recruitment and pre-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 will also advertise the study in print and online media 
(including social media) and in public transportation and via flyers. 
After contacting us, the interested person will be sent the “Subject information sheet and informed consent 
form” together with some administrative information. If the subject is still interested in participating, a study 
team member will call the subject to inform him/her about the study and answer his/her questions. 
Afterwards, a pre-screening (phone call) with a check of the main in- and exclusion criteria will be 
performed. If the subject meets all inclusion criteria and none of the exclusion criteria and is interested in 
participating the screening visit will be fixed.  
The pre-screening documents of subjects eligible for a study participation will be filed as part of the Source 
Data (SD) in the participant’s dossier.  
The pre-screening documents of subjects NOT eligible for a study participation will be kept in an 
pseudonymous form until LPLV. Then they will be shredded.  
For screening procedures see chapter 9.3.1. 
A study compensation of CHF 450 including travel expenses will be paid at the end of the second test 
visit. Screening Failures and Drop-Outs receive a pro rata temporis compensation.  
After obtaining informed consent, each participant will be assigned a participant number. At visit 2, eligible 
participants are randomly assigned to treatment group (i.e. either fampridine or placebo first) following the 
order of the randomization list imported into secuTrial®. For detailed procedure see chapter 6.2.1 
(randomization) and 12.2 (coding). 
7.3 
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 
• 
Intake of psychoactive substances within 3 days before test days (e.g. benzodiazepines, 
neuroleptics, cannabis) 
• 
Start of a treatment with antidepressants during the study 
• 
Sleep deprivation (24 hours without sleep) 
 
• 
Positive pregnancy test (test day 1 or test day 3)  
• 
More than 2 tablets were not taken in one of the two treatment periods (according to the online 
diary and/or the number of tablets returned) at visit 3/5. 
• 
Non-Compliance  
• 
Administrative troubles 
• 
Severe protocol violations 
 
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. 
7.4 
Contraception and pregnancy 
All female participants of childbearing potential are requested to use adequate contraception starting 10 
days before the first intervention period until the final visit, such as oral, injectable, or implantable 
contraceptives or intrauterine devices. Women who declare that they remain sexually inactive 10 days 
before the first intervention period until the last visit and confirm this by signing a declaration are exempt 
from the requirement to use contraception. 
To minimize the risk of exposure to IMP we will perform a pregnancy test before administration of the 
study drug on test day 1 and 3.  

 
 
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If despite all contraceptive measures a pregnancy occurs 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 within 24 hours.  
For documentation and reporting and handling of pregnancies see chapters 10.3 and 10.4.4. 

 
 
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8 STUDY INTERVENTION 
8.1 
Identity of Investigational Products  
8.1.1 
Experimental Intervention  
Active study medication consists of 15 tablets (7.5 days) of fampridine 10 mg formulated for oral 
administration taken in the morning and evening approximately 12 h apart without food. Tablets must be 
administered as a whole: do not divide, crush, chew, or dissolve Fampyra® tablets. 
There will be a washout period of at least 6.5 days equalling over 40 half-lives of the active substance 
fampridine (t½ = 4.62 h) between experimental and control intervention.  
The permitted time window for the start of the second treatment phase is as follows: 
• 
Visit 3 plus at least 7 days AND 
• 
Visit 3 plus max. 28 days 
8.1.2 
Control Intervention  
One identically looking placebo tablet formulated for oral administration consisting of 
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 at a maximum of 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.  
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 directly after intake. A study team member will send a note if entry is missing to 
remind the subject of intake of the investigational product. 

 
 
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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 chapters 6.2.1 and 6.2.2., 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. Nonsteroidal and anti-inflammatory medication is allowed and has to be recorded as 
concomitant medication. 
8.7 
Concomitant Interventions (treatments)  
Treatments with OCT 2 inhibitors (e.g. cimetidine, trimethoprim, propranolol, carvedilol, metformin) 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 University Hospital Basel (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 13) 
9.2 
Assessments of outcomes  
9.2.1 
Assessment of primary outcome  
• 
High-load working memory performance after repeated (i.e., 7.5 days) intake of study medications 
(visit 3 and 5) 
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 
Performance in other working memory-related tasks and other n-back outcomes will be measured as 
follows: 
• 
Reaction time (for correct 3-back responses). 
Performance in a 0-back task (d’) as a measure of attention. We will use parallel versions 
(different sequences) for the test days. 
• 
Verbal working memory capacity will be assessed with an adaptive working memory test (SPAN) 
(SCHUHFRIED, 2024). The SPAN is a computer-based, adaptively administered test based on 
item response theory (Rasch model; Rasch, 1980). In the study, test form S2 (backward digit 
span) is used, which captures both storage capacity and executive functions (Baddeley, 2010). 
Adaptive administration allows for precise, efficient, and individually tailored assessment while 
minimizing floor and ceiling effects. 
Test scoring is based on the estimation of a continuous person parameter (θ) using weighted 
maximum likelihood (Warm, 1989). This parameter reflects the individual's latent working memory 
ability and is additionally converted into a digit span score with decimal precision, allowing for 
nuanced interpretation (Gignac & Weiss, 2015). 
• 
Verbal episodic memory performance measured by immediate and delayed word-list recall task 
after acute and repeated intake of study medication. In this test a list of 15 selected words will be 
presented to the participants with a rate of one word per two seconds and the participant should 
recall the words immediately in writing (immediate recall). Around 15 minutes later the participants 
are asked to recall the words again (short delay). Number of correct words recalled in each stage 
is considered as the participant’s immediate and delayed recall score respectively. We use the 
four 15-words wordlists A-D out of the following Test: Verbaler Lern-und Merkfähigkeitstest, VLMT 
(Helmstaedter/Lendt/Lux, 2001). 
• 
Lexical ability measured by phonemic verbal fluency test (S-words) after acute and repeated 
intake of study medication; adapted from a subtest of the Regensburger Wortflüssigkeits-Test 
(RWT; Aschenbrenner/Tucha/Lange, 2001). In this task participants should name orally as many 
words as possible initiating with a special letter in one minute (e.g. Mary, Milk, Mouse, etc. for the 
letter M). The number of unique meaningful words will be considered as the participant’s score. 
For each test day we will use a different letter (B, K, P, M). 
• 
Planning and Problem solving, key aspects of executive functioning, will be measured with 
the “Tower of London” (ToL) test (Freiburger Version, Kaller, C.P. et al., Schuhfried GmbH). In 
this test, participants will be tasked to rearrange colour balls to match a target arrangement in as 
few moves as possible (ToL; Shallice, 1982). The raw score for planning ability (number of 
correctly solved trials with the minimum number of ball placements) is considered as the 
participants score. Parallel versions will be used for the four test days. 
• 
Cognitive Flexibility will be assessed through the “Intra-Extra Dimensional Set Shifting 
(IED)” task. Participants are asked to use the given feedback to work out a rule that determines 
which stimulus (shapes and lines in different combinations) is correct. After six correct responses, 
the stimuli and/or rule changes. The shifts in rule are initially intra-dimensional and then later 

 
 
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extra-dimensional. (IED; Fray, Robbins, & Sahakian, 1996). The highest reached level is 
considered as the participant’s score. Parallel version will be used for the four test days.  
• 
Processing of emotional information (0-back) and its alteration through reduced affective working 
memory capacity (2-back) will be assessed using a newly developed affective working memory 
task. The task follows a classic N-back paradigm with two conditions: 0-back and 2-back. 
Emotional faces (happy, sad, neutral; male/female) from the Karolinska Directed Emotional Faces 
set (Lundqvist et al., 1998) are presented for 1500 ms with a 1350 ms inter-stimulus interval. 
Participants indicate whether each stimulus is a "hit" or "non-hit," based on the current stimulus 
(0-back) or compared to the stimulus two trials prior (2-back). The severity of depressive 
symptoms will be assessed using MADRS-s (Svanborg/Åsberg, 1994; Svanborg/Åsberg, 2001), 
self-rating version. For visits 2-5, this refers to the previous week. The MADRS-s consists of 9 
items assessing subjects' mood, inner tension, sleep, appetite, ability to concentrate, initiative, 
emotional involvement, pessimism and zest for life. Each item is scored between 0 and 6. The 
total score is calculated by summing the answers of the ten items, ranging between 0 and 54 
(higher scores indicate increased severity). 
9.2.3 
Assessment of potential confounders 
• 
Tiredness and motivation will be rated by the participant using visual analogue scales.  
9.2.4 
Assessment of safety outcomes 
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.  
The following very common AEs, which are already described in the prescribing information for Fampyra® 
(version January 2022), are excluded from recording, but will be measured as a possible confounding 
factor using VAS during the treatment periods (morning/evening) and also at all four visits in the study 
centre: 
• 
headache,  
• 
gastrointestinal complaints such as dyspepsia, abdominal pain, constipation and nausea, 
• 
dizziness. 
All other clinically relevant AEs will be fully recorded. See chapter 10.3 for documentation of Adverse 
Events. 
SAEs will 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.  
Laboratory parameters: No laboratory parameters will be assessed after completed screening. 
Vital signs (BP, HR) will be taken as described in screening procedures.  
9.3 
Procedures at each visit 
9.3.1 
Screening visit (visit 1)  
During the screening visit the investigator explains to the subject 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. Subjects 
who are candidates for enrolment into the study will be evaluated for eligibility during the screening visit 
by an 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  
• 
Assessment of medication history 
• 
Physical examination (including body weight and height) 
• 
VAS subjective working memory problems (ranging from not impaired to heavily impaired) 
• 
Sociodemographic self-assessment questionnaire   
The following questionnaires will be used to assess psychiatric disorders:  

 
 
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• 
Mini-DIPS Open Access (Margraf et al., 2017). We will use a shortened version to avoid 
redundancy and focus on relevant inclusion and exclusion criteria.  
• 
Clinician rating of depression severity: MADRS external assessment (Schmidtke et al.,1988 
(German version), HAMD (Hamilton 1960, German version CIPS 1977) 
• 
Affect will be measured using the PANAS (Breyer et al., 2016) 
• 
Montreal cognitive assessment test (MoCA) for detection of cognitive impairment (Nasreddine et 
al., 2005). We will use a shortened version scoring between 0 and 29. A score of 25 or over is 
considered to be normal.  
• 
Assessment of clinical properties for characterizing patient’s disorder: duration of illness, duration 
of current episode, characteristics of current episode (melancholic vs. nonmelancholic) 
HAMD and PANAS are not used to diagnose depression in this study; instead, they are employed to 
further characterize the patient population. Affect will be measured using the PANAS (Positive and 
Negative Affect Schedule) questionnaire. It is self-report questionnaire that measures the intensity of 
positive and negative emotional states over a specific period. (Krone et al., 1996). To evaluate the 
intensity of depression the HAMD (Hamilton Depression Rating Scale) will be used. It includes a series 
of questions related to mood, behaviour, and physical symptoms that will be asked by an clinical trained 
personnel. (Schmitt et al., 2012). 
Diagnosis of major depression: Mental disorders will be assessed using the Mini-DIPS (Margraf et al., 
2017). The Mini-DIPS is a brief diagnostic interview for mental disorders. It offers a quick yet reliable 
diagnostic assessment of mental disorders according to DSM-5 and ICD-10. The Mini-DIPS provides an 
overview of the general burden of the persons examined and enables the documentation of important 
anamnestic information for practice and research. In addition to the interview guide, the short interview 
provides supplementary information and diagnostic checklists based on the DSM-5 criteria for all listed 
mental disorders. It will be used to confirm the clinical diagnosis of a major depressive episode and 
assess the severity of suicidality, and to exclude other relevant mental disorders such as bipolar disorder, 
schizophrenia, drug and alcohol dependency and others. The duration is about 20 minutes in a shortened 
version. To diagnose a current Major Depressive Episode (MDE) using Mini-DIPS, the individual must 
have experienced a consistently depressed mood or a marked loss of interest or pleasure in most 
activities for at least two weeks. Additionally, at least five symptoms must be present during this period, 
including significant changes in appetite or weight, sleep disturbances (insomnia or hypersomnia), 
psychomotor agitation or retardation observable by others, fatigue or loss of energy, feelings of 
worthlessness or excessive guilt, diminished ability to concentrate or make decisions, or recurrent 
thoughts of death, suicidal ideation, or a suicide plan. These symptoms must cause clinically significant 
distress or impairment in social, occupational, or other important areas of functioning, and cannot be 
attributed to the physiological effects of a substance or another medical condition. The Mini-DIPS uses 
structured questions to systematically assess these criteria and ensure a reliable diagnosis. 
The severity of the depressive symptoms will be assessed by the diagnostic interview MADRS 
(Schmidtke et al.,1988 (German version)). The MADRS consists of 10 items assessing subjects' apparent 
and reported sadness, inner tension, sleep, appetite, ability to concentrate, initiative, emotional 
involvement, pessimism and zest for life. Each item is scored between 0 and 6. The total score is 
calculated by summing the answers of the ten items, ranging between 0 and 60 (higher scores indicate 
increased severity). A score of 7 or higher indicates a mild depressive episode (score 7-19). A score of 
20 or higher indicated moderate depression and a score of 34 or higher severe depression. Only subjects 
with a clinically confirmed depression and a mild or lower moderate severity will be included. In case of 
suicidal thoughts (MADRS Item 10 > 1) or a MADRS score > 30, the subject is excluded and advised to 
consult a psychologist/psychiatrist.  
In cases of severe depressive symptoms, with or without suicidality, a timely clinical appointment will be 
arranged at the Acute Outpatient Clinic or the Central Admissions of the Psychiatric University Hospital 
Basel. If patients feel unable to cope with their situation until their scheduled appointment at the hospital, 
they are encouraged to contact us directly or to seek an earlier consultation at the UPK. 
For patients with mild to moderate, but clinically relevant, depressive symptoms, those who are not 
currently undergoing psychological treatment will be advised to consult a psychologist or psychiatrist. 
Patients with moderate symptoms will be advised to do so as soon as possible, while patients with mild 
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Addresses of recommended professionals will be provided. Furthermore, it will be documented if 
participants begin psychological treatment during their study participation.  
A trained psychologist experienced in diagnosing psychiatric conditions carries out the diagnostic 
interview. The final decision on inclusion/exclusion is the responsibility of the investigator.  
Screening for cognitive impairment: To ensure internal validity when assessing working memory in 
individuals with mild to moderate depressive disorder, global cognitive screening with the Montreal 
Cognitive Assessment (MoCA) will be performed, in order to detect subtle cognitive impairments (such as 
mild cognitive impairments other etiologies or dementia syndromes), that might confound the 
measurements. The MoCA was chosen because it is a brief, well-validated screening instrument with 
superior sensitivity for detecting mild and subtle cognitive deficits relative to other brief screens. (Tsoi et 
al., 2015). Screening with the MoCA at enrolment will allow prespecified exclusion or stratification of 
participants whose global cognitive deficits could confound interpretation of working-memory outcomes 
related to depression, and permit adjustment for baseline global cognition in statistical models to reduce 
residual confounding. Participants with MoCA results below 25 points, suggesting possible mild 
neurocognitive disorder, will be excluded and be recommended to get a comprehensive 
neuropsychological evaluation.  
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 “Ambulantes 
Studienzentrum” (ASZ), University Hospital Basel (USB) 
• 
Venous blood samples (2.7 ml and 4.7 ml) will be taken at “Ambulantes Studienzentrum” (ASZ), 
University Hospital Basel (USB), to measure:  
o 
Blood count (incl. platelets) / hemoglobine / 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-reak. Protein, creatine kinase. 
o 
To further investigate abnormal laboratory findings during the screening, the investigator 
has the possibility to measure other blood values in order to clarify certain findings 
relevant for in- or exclusion.  
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. 
If a test or exam result suggest that further medical evaluation or treatment may be necessary, the 
participant will be notified and advised to see their care provider for further evaluation or treatment. 
The investigator decides, whether there are contraindications for the administration of study medication.  
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 investigator or the sponsor notifies the EKNZ and the Swissmedic of the first study participant, in 
accordance to Art 23a ClinO. If the first participating person is not included in the trial within two years 
following the issuance of the last authorization, the trial is considered interrupted. The clinical trial may 
not be commenced until an application for an extension of the time limit has been approved. The 
application for the extension is submitted to the EKNZ, and to Swissmedic. (see also chapter 2.3.1 and 
2.4.1).  
9.3.2 
Test days (visits 2 - 5)  
At the beginning of the visits 2 and 4, all female participants will perform a pregnancy test. Pregnancy test 
will be performed in a urine sample. A one-step hCG (monoclonale anti-hCG antibodies) urine pregnancy 

 
 
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test will be used for qualitative (visual) determination of hCG in urine specimen for early detection of 
pregnancy.  
Women who declare that they remain sexually inactive 10 days before the first intervention period until 
the last visit and confirm this by signing a declaration are exempt from the requirement to use 
contraception. 
There will be a short examination consisting of assessment of concomitant medication and intake / 
consumption of psychoactive substances, sleep duration last 24 hours, and adverse events.  
On test days 1 and 3 (visits 2 and 4), subjects should take breakfast at home no later than 2 hours before 
the planned intake of the first tablet at our study center. After a brief examination, baseline cognitive 
performance is measured before taking the study medication. After taking the first tablet at the start of 
both study phases, the subjects remain at the study centre for observation for at least 90 minutes to 
monitor possible acute side effects. Intake of study medication will take place at approx. the same time 
point for each subject at test day 2 and 4 (visits 3 and 5). We will provide a continental breakfast to be 
eaten 30 min after intake of study medication. Testing will take place at approx. the same time for each 
subject to minimize the influence of diurnal differences in cognitive test performance. After intake of study 
medication on test days 2 and 4 (visits 3 and 5), there will be a 3-h waiting period before 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 14). 
At the end of each test day, participants will be asked about their current 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. 
At the last visit (visit 5 - last regular visit / 6 -safety follow-up), or at the time point of dropping out of the 
study: For patients who developed severe depressive symptoms, with or without suicidality, a timely 
clinical appointment will be arranged at the Acute Outpatient Clinic or the Central Admissions of the 
Psychiatric University Hospital Basel. If patients feel unable to cope with their situation until their 
scheduled appointment at the hospital, they are encouraged to contact us directly or to seek an earlier 
consultation at the UPK.  
For patients with mild to moderate, but clinically relevant, depressive symptoms, patients will be advised 
to consult a psychologist or psychiatrist if their symptoms do not improve within the next few weeks. 
Addresses of recommended professionals will be provided. 
 
All visits of the study are conducted in the Division of Cognitive Neuroscience of the University of Basel. 
 
Study staff involved: The cognitive tests on the test days (visits 2-5) will be conducted by a psychologist 
or trained study staff. The preparation of the study medication (deblistering) at the beginning of the 
treatment phases is carried out by a member of the study team who is not further involved in the conduct 
of the study. The tablets are dispensed by the psychologists, the investigator or trained study staff (see 
also chapter 6.2.2, randomization and blinding). The study coordinator is responsible for maintaining the 
study's drug accountability log.  
9.3.3 
Treatment periods 
During the visits 2 and 4 (test days 1 and 3) every subject will be supplied with a plastic container 
containing 14 tablets of IP to be taken twice per day during the following 7 days, the first tablet on site 
after baseline cognitive performance testing and the second in the evenings of visits 2 and 4 (test days 1 
and 3) and the last tablet in the evenings before visits 3 and 5 (test days 2 and 4). Each subject receives 
a total of 15 verum tablets and 15 placebo tablets. The last tablets on visits 3 and 5 will be given to the 
participants by a staff member in the study center. 
During the treatment days, the participants document the intake of the tablets twice a day 
(morning/evening) and the most common side effects via visual analog scales via a separate personal 

 
 
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login directly in secuTrial® (s. chapter 8.4 - Compliance with study intervention, and chapter 9.2.4 – 
assessment of safety outcomes).   
9.3.4 
Safety follow-up  
After the washout period for fampridine of at least 5 half-lives (approximately 30 hours) after Visit 5, we 
will perform a safety check. Within 2 to 7 days after completion of the second treatment phase (Visit 5), 
an investigator will contact each subject by telephone to inquire about adverse events that have occurred 
since visit 5 and/or about the outcome of open adverse events and to ensure that subjects are doing well. 
A safety follow-up will also take place after an early study termination if the first treatment phase has 
already started (from Visit 2).  
 

 
 
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10 SAFETY 
The Sponsor’s SOPs provide more detail on safety reporting. 
During the entire duration of the study, all adverse events (AE) and all serious adverse events (SAEs) are 
collected, fully investigated and documented in source documents and case report forms (CRF). Study 
duration encompassed the time from when the participant signs the informed consent until the last 
protocol-specific procedure has been completed. 
For the assessment and documentation of (serious) adverse events see the chapters 10.2 and 10.3. 
For the reporting of (serious) adverse events see chapter 10.4. 
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.  
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 jeopardise 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 evaluates the 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 case of double-blinded studies, unblinding may be needed to determine a SUSAR. The sponsor should 
not disclose the treatment allocation to the investigator, nor to the study staff, in order not to make the 
subject ineligible. 
 

 
 
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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 make a causality assessment of the event to the study investigational 
medicine product, 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 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 
(according to CTCAE, NIH 2021). 
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.  
In addition, we document the study phase in which an AE occurred and the visit. 
For assessment of safety outcomes see chapters 9.2.3. 
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 principal investigator of 
the study. The principal 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 EKNZ via BASEC by the principal investigator and to Swissmedic 
via sponsor within 7 days, if the event is life-threatening or fatal, or within 15 days (all other events). 

 
 
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IMPORTANT: The reporting obligations of SUSAR also apply if the principal investigator or the sponsor 
becomes aware of a suspected case that has arisen in Switzerland after termination of the clinical trial, or 
if the investigator or the sponsor only becomes aware of such a suspected case after termination of the 
clinical trial.  
10.4.3 
Reporting of immediate safety and protective measures 
All suspected new risks and relevant new aspects of known adverse reactions that require immediate 
safety-related measures, must be reported to the sponsor-investigator within 24 hours. The sponsor-
investigator must report these measures within 7 days to the EKNZ via BASEC and to 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 
documented and reported to the sponsor within 24 hours.  
The course and outcome of the pregnancy should be followed up carefully, and any abnormal outcome 
regarding the mother or the child should be documented and reported. 
10.4.5 
Periodic reporting of safety and general progress of the clinical trial 
Once a year, the principal-investigator submits to the EKNZ a list of the safety events including the severity 
of the events, their causality to the intervention and the safety of the study participants. The start date for 
the safety report is the sponsor’s first authorisation to conduct a clinical trial in any country worldwide. 
The principal-investigator also informs the EKNZ about the general progress of the clinical trial.  
The safety report / general study progress report is submitted once a year to the EKNZ via principal-
investigator and to Swissmedic via sponsor-investigator.  
The safety report / general study progress report is submitted throughout the duration of the clinical trial, 
and the last submission of the safety report will cover the Last Patient Last Visit (LPLV). 
The safety report can be written and submitted in the format of the Development safety update report 
(DSUR) in compliance to ICH Harmonised Guideline E2F for commercial and non-commercial sponsor.  
The safety report and the general study progress report can be merged in one single report. If a pregnancy 
occurs during the course of the study, we will submit the study information and informed consent form for 
pregnant participants (based on the Swissethics template) to the EKNZ for evaluation." 
10.4.6 
Follow-up of (Serious) Adverse Events (AE) 
Occurrence during a visit to the study centre 
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. 
The investigator is responsible for assessing the severity of the health problems. 
Information about the outcome in all above-mentioned cases will be collected until full recovery and stored 
in the participants dossier and in the eCRF.  
Occurrence during treatment periods 
Will be assessed using daily online ratings by participants. The Investigator will contact patients if extends 
and frequency exceeds a SOP defined level. 
 

 
 
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11 STATISTICAL METHODS 
11.1 Hypothesis 
a) Fampridine improves working memory functions in patients with mild to moderate depression. 
b) Patients’ baseline working memory performance or subjective working memory problems moderate 
the effect of fampridine on working memory functions. Specifically, we expect that patients with lower 
baseline working memory performance or more profound subjective working memory problems will 
exhibit a greater improvement in working memory functions when treated with fampridine. 
11.2 Determination of Sample Size  
In our recent cross-over study (Papassotiropoulos, Freytag et al., 2024) investigating the effect of 
fampridine on working memory performance in healthy subjects, we observed a large effect size (dz = 
0.82) for drug-related improvements in individuals with low baseline working memory performance (i.e., 
lowest tercile). This effect size (dz = 0.82) accounts for within-person correlation and standard deviations 
observed in the published study. However, for the proposed study in a clinical population, we do not 
expect to replicate such a large effect size due to the increased variability and noise typically present in 
clinical samples. Consequently, we have adopted a more conservative approach, estimating a moderate 
effect size of dz = 0.5 (assuming similar within-person correlation and standard deviations as in the 
published paper). Based on this effect size and assuming a power of 85% at two-tailed α=0.05, the 
estimated sample size is N=38 (software: G-power 3.1). Considering an expected drop-out rate of 10–
20%, we plan to recruit a sample of 45–50 participants. There will be replacement of drop-outs until data 
for the primary outcome from 38 participants are completed.  
While the estimated sample size of 38 participants is justified as detailed above, unknown factors might 
influence the expected effect size. Although an interim analysis could provide a better estimate of the 
effect size, it carries the risk of introducing unintentional downstream biases due to unblinding, which may 
affect the integrity of the study moving forward. For this reason, we would prefer to refrain from conducting 
an interim analysis in this case. 
11.3 Statistical criteria of termination of trial  
Statistical criteria of termination of trial: As soon as at least 38 participants will have complete data for the 
primary outcome. 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), with treatment, period, and sequence as fixed effects and subject IDs as the random effect of the 
mixed model. Sex, age and baseline cognition 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 possible confounders, we will also consider, tiredness, motivation, headache, 
gastrointestinal discomfort, dizziness, mood as assessed by MADRS-s (self-rating version), potassium 
blood concentration at screening, body weight and duration of washout period as covariates (each 
covariate entering the statistical analysis separately). In case of a significant interaction between 
independent variables of interest and covariates, post-hoc analysis will be applied to describe the 
interaction effect.  
In case of significant deviation from normality for the dependent variable, appropriate non-parametric 
methods will be used. 
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 have complete data for primary outcome. Before 
unblinding, the logfiles of the n-back task will be reviewed for completeness and compliance. There will 
be replacement of Drop-Outs until primary outcome data of 38 participants are completed. Drop-Outs will 
be thoroughly described to assess the reason(s) for dropping out.  

 
 
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We will recruit up to 4 subjects more towards the end of the trial to prevent under-recruitment due to Drop-
Outs. If more than 38 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. d’ 3-back after repeated (i.e., 7 days) administration 
of study medication). The independent variable of interest is the experimental condition (placebo or 
verum). We will also conduct correlation analyses between the delta (i.e. verum primary outcome – 
placebo primary outcome) and a) baseline working memory performance, defined as the mean d’ score 
from the 3-back task assessed during visits 2 and 4 prior to drug administration, and b) subjective working 
memory problems as defined by the respective visual analog scale during the screening visit. If a 
significant correlation is observed, we will perform post-hoc analyses to evaluate the effect of the study 
medication following repeated administration, stratifying participants into respective sub groups. 
11.4.3 
Analyses for secondary outcomes  
Secondary outcome measures will be treated statistically the same way as the primary outcome measure. 
These analyses will be considered exploratory, i.e. no Bonferroni correction for multiple comparisons will 
be applied. 
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. In 
addition, should in the meantime other studies report important effects or confounding effects related to 
our study, we will include these 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 is responsible for implementing and maintaining quality assurance and quality control 
systems with written SOPs and Working Instructions. The PI is responsible for training of all involved 
study personnel. 
12.2 Pseudonymization and Coding 
After obtaining informed consent, the participant number will be assigned. Each subject will be assigned 
to a numeric code (3 digits) starting with 101. Additionally, the year of birth is used for the laboratory and 
ECG in the context of the screening. 
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 age of the interested person. The 
telephone screening form does not contain any other identifying information. For subjects signing the 
informed consent, the telephone screening form becomes part of the participant dossier. For individuals 
who do not sign the consent form, the telephone screening form is sorted in coded form and shredded 
after LPLV.  
The participant number of subjects who have signed the informed consent are listed in the electronic 
combined Screening, Enrolment and Identification Log (Subject Master List, SML). Subjects not having 
signed the informed consent, will not be entered in the SML. The SML will be kept under lock and key. 
Access to the participant identification list will have only authorized study team members.  
Data will not be anonymised after statistical analysis. They will be stored coded. After the study has been 
completed, only the people authorised by the sponsor for the archiving in the Divisions of Molecular and 
Cognitive Neuroscience, University of Basel, will have access to the key list. 
12.3 Data handling and record keeping / archiving 
12.3.1 
Case Report Forms (CRF) 
Study data is recorded with electronic Case Report Forms (eCRF). secuTrial® will be used for the eCRF. 
For each enrolled study participant an 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. We will use a coded identification consisting of 
a participant number (see chapter 12.2.2).  
Authorized for eCRF entries is mainly the investigator, the psychologist, the study coordinator, and other 
staff members involved in the conduct of the study. Some questionnaires can be completed by study 
participants themselves. There are separate logins for the participants. The DMP for secuTrial® contains 
a detailed authorisation matrix. secuTrial® has a detailed audit trail so that every relevant change is 
traceable and assignable to the person who made it. 
(see contract with “Departement Klinische Forschung” (DKF), University Hospital Basel) 

 
 
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12.3.2 
Logfiles psychological testing 
The following tasks are not entered into the eCRF (secuTrial®) but are collected directly using (web-based) 
software. The psychological tests will take place at the study centre. The following overview shows the 
affected tests, the software used, type of collected data, server location and if a study-specific contract, 
(which also regulates data protection in detail and ensures equivalence to Swiss data protection law) has 
to be concluded.  
Test 
Software 
Categories 
of data * 
Server location  
study-specific 
contract needed 
for Software 
3-Back 
Affective WM-Task 
Presentation® 
Neurobehavioral Systems (NBS)3, 
Inc., USA 
coded 
 University of Basel 
(local execution of the 
software, local storage 
of log files, no data 
transfer)  
No 
 (licence per 
device on which 
the software is 
running) 
Adaptive working 
memory capacity test 
(SPAN) 
WTS market place,  
SCHUHFRIED GmbH4, Österreich 
coded 
SCHUHFRIED GmbH, 
Österreich 
Yes 
15 Words 
SoSci-Survey5 
coded 
sciCORE6, Unibas, CH 
No 
Tower of London (ToL) 
WTS market place,  
SCHUHFRIED GmbH7, Österreich 
coded 
SCHUHFRIED GmbH, 
Österreich 
Yes 
Intra-Extradimensional-
Dimension (IED) 
In-house development by a research 
group at the UPK Basel with 
JavaScript-Framework „jspsych“. 
coded 
University of Basel, 
CH 
Yes, the MIT 
license (GitHub)8 
* All of the tools listed generate log files that do NOT contain any information that identifies the subjects. The following 
information required to assign the log files to the individual test subjects is entered for all tools: code, visit, version of 
the test for parallel versions, in some cases a study identifier. In addition, the log files are provided with a date and 
time stamp. 
The logfiles will be transferred to a secure electronical archive (Studiendatenbank-MCN) regularly to 
guarantee originality and to prepare the data for data analysis.  
During the data collection phase, data collected with soSci-Survey (sciSCORE), Presentation and WTS 
the data are backed-up and cannot be changed by the study team. The originality is thus ensured.  
We transfer the data continuously to the secure electronical archive (Studiendatenbank-MCN). The data 
on the servers will be deleted after LPLV at the latest. 
12.3.3 
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. labor analysis, ECG and pre-screening documentation) 
• 
AE-documentation, concomitant medication 
• 
Mini-DIPS interview documentation 
• 
MADRS and HAMD during screening (both external rating) 
• 
MoCA 
• 
S-Words task 
• 
Administrative documents: visit checklists, individual visit overview, etc. 
Direct data entry with secuTrial® by staff members 
 
3 https://www.neurobs.com/index_html 
4 https://marketplace.schuhfried.com/de/TOL   //   https://marketplace.schuhfried.com/de   
5 www.soscisurvey.de 
6 Center for Scientific Computing at the University of Basel (sciCORE) 
7 https://marketplace.schuhfried.com/de/TOL   //   https://marketplace.schuhfried.com/de   
8 The utilized IED Test is a modified version of a publicly available test dataset obtained from GitHub repository. The repository is 
licensed under the MIT license, which permits its use in this context. 

 
 
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• 
Checklist in-/exclusion criteria (investigator) 
• 
Pre-examination visits 2-5 (pregnancy test on visits 2 and 4, etc,) 
• 
Study completion form  
Direct data entry with secuTrial® by participants: 
• 
Questionnaires: VAS subjective working memory deficits, sociodemographic data, MADRS-s 
(self-rating version) (visits 2-5) 
• 
IMP-intake and VAS during treatment periods 
• 
PANAS  
Direct data entry with Presentation® by participants: 
• 
n-back  
• 
Affective WM-Task 
Direct data entry with SoSci-Survey by participants 
• 
15 Words 
Direct data entry by participants (SCHUFRIED GmbH, Mödling, Österreich) 
• 
Tower of London (ToL) 
• 
Adaptive verbal working memory capacity test (SPAN) backward  
Direct data entry by participants (University of Basel) 
• 
Intra-Extra Dimensional Set Shift (IED) 
12.3.4 
Record keeping / Archiving  
The sponsor retains all data relating to the clinical trial until the expiry date of the last delivered batch of 
the medicinal product under investigation, but for at least twenty years after completion or premature 
termination of the clinical trial. The principal investigator retains all documents necessary for the 
identification and follow-up of the trial participants and all other original data for at least twenty years after 
completion or discontinuation of the clinical trial. 
All study related data will be archived in the archives of the Division of Cognitive and Molecular 
Neuroscience, University of Basel, and in case of the eCRF additionally in the electronic archive-system 
of the University Hospital Basel.  
All electronically captured psychological test data (see 12.3.2) will be archived in a read only status in 
Studiendatenbank-MCN for at least twenty years (for further information on Studiendatenbank-
MCN/LabKey® see chapter 12.3.4).  
12.4 Data management  
12.4.1 
Data management systems 
SecuTrial® (eCRF) runs on a server maintained by the IT-department of the University Hospital Basel. 
The data management group at the Department of Clinical Research (DKF) of the University Hospital 
Basel implements the eCRF. The user administration and user training is performed by a data manager 
of the DKF 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. 
Studiendatenbank-MCN  
Studiendatenbank-MCN is a local database for study data and is implemented using LabKey®. LabKey® 
Server is a software suite for integrating and analyzing biomedical research data. It provides a secure 
data repository and access via a web browser. Studiendatenbank-MCN extends the LabKey® server 
platform with scripts and workflows for archiving and tracking study data and related logfiles as well as 
performing the data transformation to provide data files in the format for statistical analysis as detailed in 
the statistical methods section. 
Studiendatenbank MCN and SoSci-Survey run 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 basis. An additional text-file-based 

 
 
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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 all electronically captured psychological test logfiles, see 12.3.2) will be stored 
on a Linux or Macintosh file-system with restricted user access (main file-system). The meta-information 
of the source 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. 
For source data, we do not 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®. 
12.4.2 
Data security, access and back-up 
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, and in 
all other used electronic systems, participants are only identified by a unique participant number and the 
age in years. 
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. Software running on servers of the University 
of Basel, especially Studiendatenbank-MCN, SoSci-Survey and the electronic SML (encrypted) are 
additionally protected via the VPN (2-factor authentification) of the university. 
12.4.3 
Analysis and Archiving 
The eCRF (secuTrial®) will be locked after all data was monitored and all raised queries have been 
resolved. Data is exported and transferred to the principal investigator by the data manager of the DKF 
according to internally defined processes. The exported data will be archived by the data manager MCN 
in the Studiendatenbank-MCN and printed version from the CRFs by the study coordinator (see 12.3.4). 
The electronic data collected by direct data by the participants during the psychological assessments are 
stored and archived as original data in the Studiendatenbank-MCN in a read-only folder on the university 
file system.  
The data analysis will be performed with R. 
12.4.4 
Electronic and central data validation  
secuTrial®: Data entered into the eCRF can be validated for completeness and discrepancies 
automatically as defined during setup of the data base. 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). 
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.  
An independent monitor from the DKF 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. 
For source data (including all electronically captured psychological test 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. 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-

 
 
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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.  
12.5 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 principal 
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 DKF Basel (see contract). Monitoring will be performed according to 
the separate monitoring plan.  
The Principal Investigator will permit study related monitoring visits, audits, EC reviews, and regulatory 
inspections, and provide direct access to all source data.  
12.6 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. 
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. 
12.7 Confidentiality and Data Protection  
Participant’s confidentiality will be maintained at all times. Personnel from the sponsor, the principal 
investigator, DKF Basel, 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 Ms. Magdalena Ridder, Prof. Dominique de Quervain, Prof. 
Andreas Papassotiropoulos, Prof. Annette Brühl, Dr. Nathalie Schicktanz and Dr. Christiane Gerhards.  
No publication or communication involving the results of the study is authorized without prior written 
consent from the Prof. de Quervain, Prof. Andreas Papassotiropoulos and Prof. Annette Brühl.  
 
14 FUNDING AND SUPPORT 
Funding of the trial: Getrud Thalman Fond and intramural funds of the Research Cluster Molecular and 
Cognitive Neurosciences, University of Basel. 
 
15 INSURANCE 
The sponsor 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. A copy of the certificate is filed in the investigator 
site file and in the trial master file. 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 
1. Declaration of Helsinki, Version October 2013, 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/ 
2. Federal Act on Research involving Human Beings (Human Research Act, HRA) of 30 September 
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3. Federal Act on Data Protection (FADP) of 25 September 2020 (Status as of 7 July 2025). 
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6. Common Terminology Criteria for Adverse Events (CTCAE) 
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7. 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/WC5000027
49.pdf 
8. International Conference on Harmonization (ICH, 1997) E8 Guideline: General Considerations for 
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http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guid
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