A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicentre Study of the Efficacy and Safety of Nicotinamide in Patients With Friedreich Ataxia
Phase: PHASE2
Conditions: Friedreich Ataxia
Sponsor: RWTH Aachen University

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 1 of 63 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, MULTICENTRE STUDY OF THE EFFICACY AND 
SAFETY OF NICOTINAMIDE IN PATIENTS WITH FRIEDREICH´S ATAXIA 
(NICOFA) 
 
Sponsor 
RWTH Aachen University 
represented by the Rector, himself 
represented by the Center for Translational & Clinical 
Research Aachen (CTC-A) 
Sponsor’s 
Representative 
Dr. med. Susanne Isfort   
Managing Director CTC-A 
Pauwelsstraße 30, 52074 Aachen, Germany 
T 
+49 241 80 80092 
F 
+49 241 80 33 80092 
E-Mail sisfort@ukaachen.de 
Sponsor`s Study Code 
15-138 
EudraCT- Number 
2017-002163-17 
Investigational Product 
Nicotinamide 
Investigator (PI) 
Univ.-Prof. Dr. med. Jörg Schulz 
Head of Department of Neurology 
RWTH Aachen University Hospital, Germany 
Biostatistician 
Prof. Dr. Ralf-Dieter Hilgers 
Department of Medical Statistics 
RWTH Aachen University Hospital, Germany 
Central Organization/ 
Project Management 
Jennifer Kistermann  
T 
+49 241 80 35768  
F         +49 241 80 33 80092 
Monitoring 
Name 
T 
+49 241 80   
F         +49 241 80 33 80092 
Status, Version, Date  
V03.4, 05.12.2018 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 2 of 63 
 
Sponsor, Investigators and Administrative Structure 
Sponsor 
RWTH Aachen University for the Medical Faculty, represented by Center for 
Translational & Clinical Research Aachen (CTC-A) 
Pauwelsstraße 30, 52074 Aachen, Germany 
Sponsor’s Representative:  
Dr. med. Susanne Isfort, Managing Director CTC-A 
T 
+49 241 80 80092 
F 
+49 241 80 33 35849 
E-Mail sisfort@ukaachen.de 
Coordinating Investigator  
Univ.-Prof. Dr. med. Jörg Schulz 
Head of Department 
Department of Neurology – University Hospital Aachen  
Pauwelsstr. 30, D-52074 Aachen, Germany 
T 
+49 241 80 89600 
F 
+49 241 80 82582 
E-Mail jschulz@ukaachen.de 
Investigator`s Representative 
Univ.-Prof. Dr. med. Kathrin Reetz  
Senior Physician 
Department of Neurology – University Hospital Aachen 
Pauwelsstraße 30, D-52074 Aachen, Germany 
T 
+49 241 80 85522 
F 
+49 241 80 82582 
E-Mail  kreetz@ukaachen.de 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 3 of 63 
 
Biostatistician 
Univ.-Prof. Dr. rer. nat. Ralf-Dieter Hilgers 
Department of Medical Statistics 
Pauwelsstr. 19, D-52074 Aachen, Germany 
T 
+49 241 80 89358 
F 
+49 241 80 82501 
E-Mail rhilgers@ukaachen.de 
Ethics Committee 
Ethics Committee at the Medical Faculty of the RWTH Aachen University 
Chairman: Univ.-Prof. Dr. med. G. Schmalzing 
Pauwelsstraße 30, D-52074 Aachen, Germany 
T 
+49 241 80 89963  
F 
+ 49 241 80 82012  
E-Mail ekaachen@ukaachen.de 
Competent Authority of Germany 
Federal Institute for Drugs and Medical Devices 
Kurt-Georg-Kiesinger-Allee 3 
53175 Bonn, Germany 
T 
+49 228 207 4318 
F 
+49 228 207 4355 
E-Mail klinpruefung@bfarm.de 
Central Organization / Project Management 
Center for Translational & Clinical Research Aachen (CTC-A)  
Jennifer Kistermann, Project Manager 
RWTH Aachen University  
Pauwelsstraße 30 
52074 Aachen  
T  
+49 241 80 35768 
F 
+49 241 80 33 80092 
E-Mail jkistermann@ukaachen.de 
 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 4 of 63 
 
Table of Contents 
SPONSOR, INVESTIGATORS AND ADMINISTRATIVE STRUCTURE ...................... 2 
1 
STUDY FLOW CHART .......................................................................... 14 
1.1 
Abbreviations ............................................................................................ 17 
2 
STUDY RATIONALE AND CLINICAL RELEVANCE ..................................... 19 
2.1 
Description of evidence and medical need ............................................... 19 
2.2 
Rationale and Clinical Evidence ............................................................... 20 
3 
AIM OF STUDY ................................................................................... 22 
3.1 
Primary objectives .................................................................................... 22 
3.2 
Secondary objective ................................................................................. 22 
3.3 
Tertiary objectives ..................................................................................... 22 
4 
INVESTIGATIONAL DRUG AND COMPARATOR ......................................... 23 
4.1 
Investigational Drug .................................................................................. 23 
4.1.1 Packaging, Labelling and re-supply of Investigational Product (IP) 23 
4.1.2 Management of IMP ....................................................................... 23 
4.1.3 Administration of IMP...................................................................... 23 
4.1.4 Advice for using the IMP ................................................................. 23 
4.2 
Placebo ..................................................................................................... 24 
4.3 
Preclinical data of Nicotinamide ................................................................ 24 
4.4 
Benefit Risk Assessment .......................................................................... 24 
4.5 
Known adverse events for Nicotinamide ................................................... 25 
4.5.1 Dose-Response Assessment ......................................................... 25 
5 
STUDY DESIGN AND DURATION ........................................................... 28 
5.1 
Study Design ............................................................................................ 28 
5.2 
Study Duration .......................................................................................... 28 
5.3 
Stratification .............................................................................................. 28 
5.4 
Allocation Ratio ......................................................................................... 28 
6 
STUDY POPULATION .......................................................................... 29 
6.1 
Number of Patients ................................................................................... 29 
6.2 
Inclusion Criteria ....................................................................................... 29 
6.3 
Exclusion Criteria ...................................................................................... 29 
6.4 
Subjects of Reproductive Potential ........................................................... 30 
7 
STUDY PROCEDURES ......................................................................... 31 
7.1 
Informed Consent ..................................................................................... 31 
7.2 
Overview Study Treatment ....................................................................... 31 
7.3 
Blinding ..................................................................................................... 33 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 5 of 63 
 
7.4 
Unblinding Procedures ............................................................................. 34 
7.5 
Package and Labelling of IMP and Placebo ............................................. 35 
7.6 
Compliance ............................................................................................... 36 
8 
TREATMENT DETAILS ......................................................................... 37 
8.1 
Variables ................................................................................................... 37 
8.1.1 Efficacy ........................................................................................... 37 
8.1.1.1 Primary endpoints: ...................................................................... 37 
8.1.1.2 Secondary endpoints: ................................................................. 37 
8.1.1.3 Tertiary endpoints: ...................................................................... 37 
8.2 
Methods .................................................................................................... 38 
8.2.1 Blood Collection for serum chemistry and biomarkers .................... 38 
8.2.2 Transthoracic echocardiography (ECHO) ....................................... 39 
8.2.3 Pregnancy Test .............................................................................. 39 
8.2.4 Vital signs and physical exam ......................................................... 39 
8.2.5 Clinical measures and rating scales ............................................... 39 
8.2.6 Electrocardiogram (ECG) ............................................................... 40 
8.2.7 MRI ................................................................................................. 41 
8.2.8 AEs ................................................................................................. 41 
9 
SAFETY DATA COLLECTION, RECORDING AND REPORTING .................... 42 
9.1 
Definition of Adverse Events (AEs) ........................................................... 42 
9.1.1 Instructions for completing adverse event case report forms .......... 42 
9.2 
Definition of Serious Adverse Events (SAEs) ........................................... 43 
9.3 
Reporting Procedures of SAEs ................................................................. 44 
9.4 
Pregnancy................................................................................................. 44 
10 ADJUSTMENT OF STUDY MEDICATION AND STUDY TERMINATION ............ 45 
11 STATISTICS ....................................................................................... 48 
11.1 Statistical analysis .................................................................................... 48 
11.2 Interim analyses ........................................................................................ 48 
11.3 Data analyses ........................................................................................... 48 
11.4 Power calculation ...................................................................................... 49 
11.5 Bias protection .......................................................................................... 49 
12 ETHICAL AND LEGAL ASPECTS ........................................................... 50 
12.1 Independent Ethics Committees ............................................................... 50 
12.2 Authorization of the Competent Authority ................................................. 50 
12.3 Notification Requirements ......................................................................... 50 
12.4 Informed Consent ..................................................................................... 50 
12.4.1 Subject card .................................................................................... 51 
12.4.2 Post-study treatment ...................................................................... 51 
12.4.3 Subject privacy ............................................................................... 51 
12.4.4 Contact point .................................................................................. 51 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
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12.5 Duties of the Investigator .......................................................................... 52 
12.6 Delegation of Investigator’s Duties ........................................................... 52 
12.7 Protocol Changes ..................................................................................... 52 
12.8 Data Protection ......................................................................................... 52 
13 DATA QUALITY ASSURANCE ............................................................... 53 
13.1 Quality control ........................................................................................... 53 
13.2 Source documentation requirements ........................................................ 53 
13.3 Data management .................................................................................... 54 
13.4 Direct Access to Source Data ................................................................... 54 
13.5 Monitoring ................................................................................................. 54 
13.6 Auditing ..................................................................................................... 55 
14 DATA HANDLING AND RECORD KEEPING .............................................. 56 
14.1 Conclusion of Documentation ................................................................... 56 
14.2 Corrections to data ................................................................................... 56 
14.3 Record keeping ......................................................................................... 56 
14.4 Archiving of Documents ............................................................................ 57 
14.5 Destruction of study documents ................................................................ 57 
15 OVERSIGHT COMMITTEE ..................................................................... 57 
15.1 Data Monitoring Committee ...................................................................... 57 
16 PUBLICATION POLICY ......................................................................... 58 
17 FINANCE AND INSURANCE ................................................................... 58 
17.1 Financing .................................................................................................. 58 
17.2 Insurance .................................................................................................. 58 
18 STATEMENT OF COMPLIANCE .............................................................. 59 
19 SIGNATURES ..................................................................................... 60 
20 REFERENCES .................................................................................... 61 
 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 7 of 63 
 
SYNOPSIS 
Item 
Description 
Study Title 
A randomized, double-blind, placebo-controlled, parallel-group, 
multicentre study of the efficacy and safety of nicotinamide in 
patients with Friedreich ataxia 
Study Short 
Name 
NICOFA 
Study Number 
15-138 
EudraCT-Number 
2017-002163-17 
Phase 
IIb/III 
Protocol version 
V03.4, 05.12.2018 
Registration with 
ClinicalTrials.gov 
NCT03761511 
Regulations 
In accordance to the Declaration of Helsinki, ICH E6 Guideline for 
Good Clinical Practice (GCP), German Medicine Act (AMG), Good 
Clinical Practice Act (GCP- V), Local Rules, regulations and applicable 
requirements. 
Sponsor 
 
RWTH Aachen University for the Medical Faculty, represented by 
Center for Translational & Clinical Research Aachen (CTC-A) 
Pauwelsstraße 30, 52074 Aachen, Germany 
Sponsor’s Representative:  
Dr. med. Susanne Isfort, Managing Director CTC-A 
Phone: +49 241 80 80092 
Fax 
+49 241 80 33 35849 
E-Mail sisfort@ukaachen.de 
Investigator  
Univ. Prof. Dr. med. Jörg Schulz 
Department of Neurology 
RWTH Aachen University Hospital 
Pauwelsstraße 30,  
52074 Aachen, Germany 
Phone: +49 241 80 89600 
Fax: 
+49 241 80 82582 
E-Mail: jschulz@ukaachen.de 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 8 of 63 
 
Item 
Description 
Financing 
This is an investigator-initiated trial.  
The trial will be financed by research funding of the clinic (E-rare/DFG). 
 
Insurance 
A patient's insurance in accordance to § 40 (1) and (3) No.8 AMG will 
be completed by the sponsor (the insurance policy number will be filed 
subsequently).  
Risk Benefit 
Assessment 
Nicotinamide is a classical class III HDAC inhibitor (Vaquero et al., 
2007), has a good bioavailability, rapidly penetrates all tissues, and 
readily crosses the blood brain barrier (Hoane et al., 2006; Spector 
and Kelley, 1979). Nicotinamide has over the past forty years been 
given at high doses for a variety of therapeutic applications. A review 
on safety of high-dose nicotinamide has revealed that the therapeutic 
index of nicotinamide is wide but at very high doses reversible 
hepatotoxicity has been reported in animals and humans (Knip et al., 
2000). Minor abnormalities of liver enzymes can infrequently occur at 
the high or mega doses. There is no evidence of teratogenicity from 
animal studies and nicotinamide is not in itself oncogenic; at very high 
doses it does however potentiate islet tumor formation in rats treated 
with streptozotocin or alloxan. There is no evidence of oncogenicity in 
man. Growth inhibition can occur in rats but growth in children is 
unaffected. High-dose nicotinamide should still, however, be 
considered as a drug with toxic potential at adult doses in excess of 3 
g/day and only applied under supervision. To our knowledge 
nicotinamide has been applied in Friedreich´s ataxia in such high 
doses (> 3 g) only in the exploratory, open-label, dose-escalation study 
in Friedreich´s ataxia in the UK (ClinicalTrials.gov, number 
NCT01589809) (Libri et al., 2014). Nicotinamide has been given safely 
for 5 years at about 3 g (1.2 g/m2) per day to more than 250 individuals 
including children from 3 years and above, adolescents and adults in 
an attempt to prevent diabetes in an at-risk population (Gale et al., 
2004). No serious adverse effects were observed. In a recent 
exploratory, open-label and dose-escalation study on ten patients with 
Friedreich ataxia, nicotinamide was given in single doses, 2-8 g per 
day oral nicotinamide for 5 days and 8 weeks (Libri et al., 2014). 
Nicotinamide was generally well tolerated with nausea being the most 
frequent dose-related adverse event in this study; this was readily 
controlled with the use of antiemetics and by modification of the dose. 
Here, nicotinamide was rapidly absorbed after oral administration and 
generally well tolerated in Friedreich´s ataxia patients after repeated 
daily dosing for 8 weeks. 
Key Words 
Rare disease, ZSEA, Nicotinamide, Friedreich ataxia 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 9 of 63 
 
Item 
Description 
Study Drug INN 
Nicotinamide 
Dose: 0.5 g per capsule 
Mode of administration: oral 
Adult: 4 g per os per day (8 capsules) 
 
Comparator 
Drug(s) INN if 
applicable 
(International 
Nonproprietary 
Name) 
Matching Placebo 
Indication 
Friedreich ataxia 
Medical Study 
Rationale 
Friedreich ataxia is the most frequent early-onset autosomal recessive 
hereditary ataxia. It is caused by a pathological expansion of a GAA 
repeat in the first intron of the frataxin gene (FXN) and results in 
decreased levels of FXN protein. FXN deficiency results in a 
relentlessly progressive neurodegenerative condition which frequently 
presents around puberty. Patients gradually lose coordination, 
become dysarthric and are frequently wheel-chair bound as 
adolescents. There is no disease modifying therapy and many patients 
die prematurely of cardiomyopathy. It was subsequently found that the 
FXN gene is silenced at the chromatin level by the formation of 
heterochromatin and that this heterochromatin formation can be 
antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 
2013). A recent proof-of-concept clinical study on ten patients with 
Friedreich ataxia demonstrated that FXN levels can be restored to 
those seen in asymptomatic carriers using the class III HDACi 
nicotinamide at a dose that is well tolerated by patients (Libri et al., 
2014). Since carriers are asymptomatic, this degree of restoration of 
FXN expression might be expected to halt disease progression. 
Nicotinamide readily crosses the blood brain barrier and has 
previously been given at high doses for long periods to normal 
individuals without serious adverse effects (Gale et al., 2004; Knip et 
al., 2000). This study will be the first to provide clinical evidence for the 
efficacy and safety of nicotinamide in patients with Friedreich´s ataxia. 
Primary 
Objectives 
To evaluate the efficacy of daily doses of nicotinamide in slowing 
disease progression as measured by changes in the Scale for the 
Assessment and Rating of Ataxia (SARA) as compared with placebo 
in patients with Friedreich´s ataxia. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 10 of 63 
 
Item 
Description 
Secondary 
Objectives 
 
To determine the change of secondary endpoints such as quality of 
life, functional motor and cognitive measures, clinician’s and patient’s 
global impression-change scales as well as frataxin protein level, 
safety reasons and survival/death under treatment of daily doses of 
nicotinamide as compared with placebo in patients with Friedreich´s 
ataxia. 
Tertiary 
Objectives 
To evaluate cognition, cardiac and spinal cord/brain measures.  
Evaluation 
Criteria 
Primary endpoints: 
 
Change in the Scale for the Assessment and Rating of Ataxia 
(SARA). 
Secondary endpoint:  
 
Quality of life (EQ5D, ADL), functional (SCAFI, CCFS), 
modified Friedreich Ataxia Ratings Scale (mFARS) and 
cognitive measures (MoCA), clinician’s and patient’s global 
impression-change scale (CGI-C, PGI-C), frataxin protein 
level, safety reasons and survival/death. 
Study Design 
Phase A (weeks 1-4): Open-label dose adjustment wash-in period 
with nicotinamide immediately followed by  
Phase B (weeks 5-104): Multicentre, prospective, controlled, double-
blind, randomized, two arm parallel, placebo-controlled, phase IIb/III 
study, with a 2:1 allocation ratio. 
Study Duration 
24 months per patient, in total 36 months including evaluation and 
clinical study report. The recruitment period will last 12 months, and 
data cleaning, processing, analysis and reporting about 3 months. 
Patients Number  
In total 225 patients (75 patients control arm and 150 patients 
treatment arm).  
Screening is expected to be necessary in 360 patients.  

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 11 of 63 
 
Item 
Description 
Inclusion Criteria 
1. Patients must have a molecular genetic diagnosis of Friedreich 
ataxia with a GAA-repeat expansion on both alleles of the FXN 
gene and a SARA Score >7 and <28. 
2. Patients must be ≥18 and <50 years old and have a weight of at 
least 50kg.  
3. Written informed consent prior to study participation. 
4. A female subject is eligible to participate if she is of: Non-
childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal 
defined as 12 months of spontaneous amenorrhea or of 
childbearing potential and agrees to use of highly effective birth 
control methods (Pearl Index < 1).  
Exclusion 
Criteria 
1. Patients with any medical condition or illness that, in the 
opinion of the investigator would interfere with study 
compliance and/or impair the patient´s ability to participate or 
complete the study. 
2. Any uncontrolled medical or neurological/neurodegenerative 
condition (other than Friedreich ataxia).  
3. Clinically significant psychiatric illness (e.g., uncontrolled major 
depression, schizophrenia, bipolar affective disorder) within 6 
months prior to screening. 
4. Patients with significant clinical dysphagia. 
5. Hypersensitivity to nicotinamide. 
6. Patients known to be positive for human immunodeficiency 
virus (HIV). 
7. Patients with a significant history of substance abuse (e.g. 
alcohol or drug abuse) within the previous six months before 
enrolment. 
8. Patients with a history of severe allergies to medications.  
9. Indication of impaired liver function as shown by an abnormal 
liver function profile at screening (e.g., repeated values of 
aspartate aminotransferase [AST], alanine aminotransferase 
[ALT] and bilirubin ≥3 × the upper limit of normal). 
10. History of malignancy or carcinoma. The following exceptions 
may be made after discussion with the Sponsor: 
• Subjects with cancers in remission more than 5 years prior to 
screening. 
• Subjects with a history of excised or treated basal cell or 
squamous carcinoma. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 12 of 63 
 
Item 
Description 
• Subjects with prostate cancer in situ. 
11. History or evidence of an autoimmune disorder considered 
clinically significant by the Investigator or requiring chronic use 
of systemic corticosteroids or other immunosuppressants. 
12. History of clinically significant cardiac disease (ejection fraction 
< 40% [normal range 50-70%], cardiac insufficiency defined as 
New York Heart Association [NYHA] Class >2; clinically 
significant 
congenital 
or 
acquired 
valvular 
disease; 
symptomatic coronary disease such as prior myocardial 
infarction or angina, B-type natriuretic peptide (BNP) level 
increase more than 2 x of the normal age- and gender 
dependent range; history of unstable arrhythmias, history of 
atrial fibrillation). 
13. The subject received an investigational drug within 30 days 
prior to inclusion into this study. 
14. Patients taking sodium valproate, tranylcypromine or any other 
known histone deacetylase inhibitor. 
15. Use of vitamin B1 (thiamine), withdrawal should be at least 3 
months prior screening or 5 half-lives, whichever is longer. 
16. Use of vitamin B3 (nicotinamide), withdrawal should be at least 
3 months prior screening. 
17. If patients are taking idebenone or coenzyme Q10 (CoQ), this 
should be stable over the last three months and not changed 
during the study. 
18. The subject is unwilling or unable to provide written informed 
consent and to follow the procedures outlined in the protocol. 
19. For subjects who will undergo an MRI: Any contraindications to 
MRI such as, but not limited to cardiac pacemaker, implanted 
cardiac defibrillator, aneurysm clips, carotid artery vascular 
clamp, neurostimulator, implanted drug infusion devices, metal 
fragments or foreign objects in the eyes, skin or body, bone 
growth/fusion stimulator, cochlear, otologic implant, severe 
claustrophobia or any condition that would counterindicate an 
MRI scan.  
20. Patients participating at start or have been within 30 days 
before start of study in another pharmacological and non-
pharmacological clinical trial, excluding natural history / 
observational studies.  
21. The subject is mentally or legally incapacitated. 
22. Pregnant females as determined by positive [serum or urine] 
hCG test at Screening or prior to dosing. Participants of child-

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 13 of 63 
 
Item 
Description 
bearing age should use adequate contraception as defined in 
the study protocol. 
23. Lactating females. 
Treatment and 
Visits 
Treatment:  
Phase A (weeks 1-4): Open-label dose adjustment wash-in period with 
nicotinamide: All patients will be slowly titrated with an increase of 0.5 
g nicotinamide every three days up to a dose of 4 g/day Thus, the 
titration period will be three weeks, patients should then be stable on 
4g/d or the highest tolerated dose for one week. Phase A 
is immediately followed by a 2:1 randomization.  
Phase B (weeks 5-104): Multicentre, prospective, controlled, double-
blind, randomized, two arm parallel, placebo-controlled, phase IIb/III 
study, with a 2:1 allocation ratio. 
Adult patients will receive nicotinamide 4 g p.d. or placebo for a period 
of 24 months (minimum dose: 2 g p.d.).  
The blood chemistry will be evaluated at screening, baseline as well 
as 1, 4, 8, 12, 18 and 24 months after initiation of the therapy. 
If a patient is eligible to participate in the study according to the in- and 
exclusion criteria the patient will randomly be assigned to one of the 
two treatment arms. The randomisation of eligible patients will take 
place after all screening examinations are completed and prior to the 
treatment phase. A randomisation code will be assigned for each 
randomised patient. This code will be used to label all information that 
are gathered for each patient (e.g. blood samples and case report 
forms (CRFs) and to label the study medication. 
The Randomisation list will be prepared by Department of Medical 
Statistics of the RWTH Aachen University Hospital, using randomizeR. 
The lists will be sent to the pharmacy for packaging the treatments to 
be applied and maintain concealment and double blinded treatment 
allocation. 
Sample size and 
Statistics 
Power calculation 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 14 of 63 
 
1  Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 15 of 63 
 
 
Visit Schedule 
Study Period 
Screening 
Phase A 
1 month 
Phase B 
23 months 
Visit No. 
 
1 
2 
3 
4 
5 
6 
7 
Activity 
 
 
 
Baseline 
Randomization 
 
1 
month 
 
 
 
4 
month 
 
 
8 
month 
 
 
12 
month 
 
 
18 
month 
EOS (End of Study) 
 
24 
month 
Visit window 
+/- calendar 
days 
 
 
±3 days 
±1 week 
±1 week 
±1 week 
±1 week 
±1 week 
Informed 
consent  
X 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
criteria1 
X 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
Pregnancy 
test 
X 
X 
X 
X 
X 
X 
X 
X 
Demography 
 
X 
 
 
 
 
 
 
 
Vital signs2, 
respiratory 
rate, resting 
pulse, height 
and weight 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
pressure2 
X 
X 
X 
X 
X 
X 
X 
X 
Body 
temperature 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination  
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardio
gram (ECG) 
 
X 
X 
X 
X 
X 
X 
X 
Echocardiogr
am (ECHO) 
 
X 
 
 
 
 
X 
 
X 
Quest. about 
exercise 
(QPE) 
 
X 
X 
X 
X 
X 
X 
X 
Clinical 
measures3 
SCAFI, 
CCFS, 
mFARS, 
ADL, EQ5D, 
MoCA, CGI-
C, PGI-C 
 
X 
X 
 
 
X 
X 
X 
X 
X 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 16 of 63 
 
Study Period 
Screening 
Phase A 
1 month 
Phase B 
23 months 
Visit No. 
 
1 
2 
3 
4 
5 
6 
7 
Activity 
 
 
 
Baseline 
Randomization 
 
1 
month 
 
 
 
4 
month 
 
 
8 
month 
 
 
12 
month 
 
 
18 
month 
EOS (End of Study) 
 
24 
month 
Visit window 
+/- calendar 
days 
 
 
±3 days 
±1 week 
±1 week 
±1 week 
±1 week 
±1 week 
Scale for the 
Assessment 
and Rating 
Ataxia 
(SARA) 
X 
X 
X 
X 
X 
X 
X 
X 
Standard 
laboratory 
evaluation4 
X 
X 
X 
X 
X 
X 
X 
X 
Up-regulation 
of Frataxin 
(FXN) protein 
level 
 
X 
X 
 
 
 
X 
 
X 
Gene 
expression of 
Frataxin 
(FXN) gene 
 
X 
 
 
 
 
X 
 
X 
RNA-
Sequencing 
of Frataxin 
gene 
 
X 
 
 
 
 
X 
 
X 
PK sampling  
(nicotinamide 
level) 
X 
X 
X 
X 
 
X 
 
X 
MRI (brain 
and spine) 
 
X 
 
 
 
 
X 
 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse 
events 
evaluation 
 
X 
X 
X 
X 
X 
X 
X 
 
1 might include genetic testing, if participants are not included in the EFACTS registry 
2 after at least 15 minutes of resting 
3 ADL, Activity of Daily Living; CCFS, Composite Cerebellar Functional severity; CGI-C, Clinician’s Global Impression-Change Scale; 
EQ5D, EuroQol five dimensions questionnaire; INAS, Inventory of Non-Ataxia Signs; MoCA, Montreal Cognitive Assessment; PGI-C, 
Patient’s Global Impression-Change Scale; SCAFI, Spinocerebellar Ataxia Functional Index   
4 Hematology (total and differential blood count) and blood chemistry  

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 17 of 63 
 
1.1 Abbreviations 
AAV 
Adeno-associated Virus 
ADL 
Activity of Daily Living 
AE 
Adverse Event 
BfArM 
Federal Institute for Drugs and Medical Devices 
BNP 
 
Brain Natriuretic Peptide  
CCFS 
Composite Cerebellar Functional Severity 
CGI-C 
Clinicians’s Global Impression-Change Scale 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTC-A 
Center for Translational & Clinical Research Aachen 
DNA 
Deoxyribonucleic Acid 
DRG 
Dorsal Root Ganglion 
EBV 
Epstein - Barr Virus 
EC 
Ethics Committee 
ECG 
Electrocardiogramm 
eCRF 
Electronic Case Report Form 
EFACTS 
European Friedreich´s Ataxia Consortium for Translational Studies 
EOS 
End of Study 
FARS 
Friedreich´s Ataxia Rating Scale 
FAS 
Full Analysis Set 
FRDA 
Friedreich´s Ataxia 
FU 
Follow up visits 
FXN 
Frataxin 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HDACi 
Histone Deacetylase Inhibitors 
ICH 
Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 18 of 63 
 
INAS 
Inventory of Non-Ataxia Signs 
IP 
Investigational Product 
IRB 
Institutional Review Board 
LMEM 
Linear Mixed Effect Model 
LV 
Left ventricular 
MMRM 
Mixed effect Model Repeat Measurement 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
Nrf2 
Nuclear factor (erythroid-derived 2) – like 2 
PBMC 
Peripheral Blood Mononuclear Cell 
PGI-C 
Patient’s Global Impression-Change Scale 
PEV 
Position Effect Variegation 
RNA 
Ribonucleic Acid 
RWTH 
Rheinische Westfälische Technische Hochschule 
SAE 
Serious Adverse Event 
SAER 
Serious Adverse Event Report 
SARA 
Scale for the Assessment and Rating Ataxia 
SCA 
Spinocerebellar Ataxia 
SCAFI 
Spinocerebellar Ataxia Functional Index 
SD 
Standard deviation 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operation Procedure 
QPE 
Questionnaire about physical exercise 
WOCBP 
Women of Childbearing Potential 
ZSEA 
Zentrum für Seltene Erkrankungen Aachen 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 19 of 63 
 
2 Study Rationale and Clinical Relevance 
Friedreich ataxia is the most frequent early-onset autosomal recessive hereditary ataxia. It is 
caused by a pathological expansion of a GAA repeat in the first intron of the frataxin gene 
(FXN) and results in decreased levels of FXN protein. FXN deficiency results in a relentlessly 
progressive neurodegenerative condition which frequently presents around puberty. Patients 
gradually lose coordination, become dysarthric and are frequently wheel-chair bound as 
adolescents. There is no disease-modifying therapy and many patients die prematurely of 
cardiomyopathy. It was subsequently found that the FXN gene is silenced at the chromatin 
level by the formation of heterochromatin and that this heterochromatin formation can be 
antagonized by histone deacetylase inhibitors (HDACi) (Chan et al., 2013). A recent proof-of-
concept clinical study on ten patients with Friedreich´s ataxia demonstrated that FXN levels 
can be restored to those seen in asymptomatic carriers using the class III HDACi nicotinamide 
at a dose that is well tolerated by patients (Libri et al., 2014). Since carriers are asymptomatic, 
this degree of restoration of FXN expression might be expected to halt disease progression.  
Nicotinamide readily crosses the blood brain barrier and has previously been given at high 
doses for long periods to normal individuals without serious adverse effects (Gale et al., 2004; 
Knip et al., 2000). This study will be the first to provide clinical evidence for the efficacy and 
safety of nicotinamide in patients with Friedreich ataxia. 
2.1 Description of evidence and medical need 
Friedreich ataxia (FRDA) is an autosomal recessive inherited ataxia. This devastating and 
incurable neurodegenerative disease often manifests in childhood and in many cases leads to 
severe disability by early adulthood. Although FRDA is the most common hereditary ataxia in 
caucasian populations, however, with an estimated prevalence of about 2–4/100,000 people, 
it remains a rare disease (Schulz et al., 2009) In 1996, the genetic mutation that underlies most 
Friedreich ataxia cases (Campuzano et al., 1996) was discovered as a homozygous 
pathological expansion of GAA triplet repeats in the first intron of the frataxin (FXN) gene, 
which encodes for the mitochondrial protein frataxin. FXN deficiency results in spinocerebellar 
ataxia, dysarthria, proximal weakness, sensory loss and cardiomyopathy, and leads to 
dependence on a wheelchair and reduced life expectancy with a mean of 20 years after 
disease onset. Many Friedreich ataxia patients die from cardiomyopathy. To date, there is no 
disease-modifying therapy for this disabling progressive disease. 
Before a phase IIa trial (Libri et al., 2014) with nicotinamide was initiated in patients, careful 
preclinical studies were performed. First, nicotinamide was tested on EBV-transformed 
lymphoblastoid cell lines (Chan et al., 2013). Modest up-regulation of FXN mRNA levels was 
obtained in patient-derived cell lines with relatively little effect on FXN expression in the normal 
control cell line. Second, to assess the effect of nicotinamide under more physiological 
conditions, fresh primary lymphocytes derived from Friedreich ataxia-affected or normal 
healthy individuals were treated. A small effect (2-fold increase) in FXN mRNA level was 
produced for healthy primary cells after nicotinamide treatment suggesting that minor 
chromatin effects might occur at the healthy FXN locus. Notably, the increase in FXN mRNA 
level in Friedreich ataxia individuals was much larger (4.5-fold). Third, in Friedreich ataxia 
transgenic mice (Al-Mahdawi et al., 2006) treated with nicotinamide for 6 days with a dose of 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 20 of 63 
 
750 mg/kg increases of FXN mRNA expression were found in all Friedreich´s ataxia – relevant 
tissues and the most substantial increases, in terms of fold up-regulation, were observed in 
spinal cord and cerebellum with 1.8-fold up-regulation of frataxin (Chan et al., 2013). Taken 
together, these results strongly suggest that nicotinamide can reactivate the silenced FXN 
gene in both human Friedreich ataxia cells and in vivo transgenic Friedreich´s ataxia models. 
Also, mechanistic preclinical investigations were performed. Treating primary lymphocytes 
from Friedreich ataxia patients with nicotinamide strongly reduced the disease-associated 
increase in histone H3K9 and H3K27 trimethylations and increased the histone acetylation at 
the FXN gene. Furthermore, the DNase I accessibility at the FXN gene was increased in 
Friedreich ataxia patient cells. High-throughput RNA sequencing on libraries generated from 
untreated and nicotinamide-treated Friedreich ataxia primary lymphocytes revealed that 67% 
of the genes known to be dysregulated in Friedreich´s ataxia was ameliorated by the treatment. 
Thus, it was demonstrated that expanded GAA-triplet repeats can induce gene silencing in 
vivo leading to the archetypal epigenetic gene silencing phenomenon of position effect 
variegation (PEV) (Saveliev et al., 2003). This GAA-repeat silencing was exquisitely sensitive 
to the gene dosage of PEV modifiers which encode enzymes that modify chromatin. Moreover, 
it was demonstrated that the FXN gene is silenced at the chromatin level by the formation of 
heterochromatin. This heterochromatin formation can be antagonized by histone deacetylase 
inhibitors (HDACi) (Chan et al., 2013). Nicotinamide is a classical class III HDACi.   
2.2 Rationale and Clinical Evidence 
Friedreich ataxia is an autosomal-recessive inherited disorder due to a gene mutation resulting 
in expansion of a repeating DNA sequence (GAA) which partially switches off the frataxin gene. 
The deficiency of frataxin causes the disease. A recent exploratory, open-label and dose-
escalation study on ten patients with Friedreich´s ataxia demonstrated that frataxin levels can 
be restored towards asymptomatic carrier levels using nicotinamide (Libri et al., 2014). 
Friedreich ataxia patients were given single doses, as well as repeated daily doses of 2-8 g 
oral nicotinamide for 5 days and 8 weeks. Nicotinamide was generally well tolerated with 
nausea being the most frequent dose-related adverse event in this study. In addition 
nicotinamide has a good bioavailability and rapidly penetrates all tissues, readily crosses the 
blood brain barrier, and has previously been given at high doses from 1.2 g/m2 up to 3 g/d for 
long periods (up to 5 years) to normal individuals including children from 3 years and above, 
adolescents and adults without serious adverse effects (Gale et al., 2004). Moreover, a 
sensitive clinical rating measure to assess disease progression, the Scale for the Assessment 
and Rating of Ataxia (SARA) is now available, which was proved most suitable to measure 
clinical disease progression within the registry of the European Friedreich´s Ataxia Consortium 
for Translational Studies (EFACTS, www.e-facts.eu) framework. Other current clinical trials in 
Friedreich ataxia (based on www.clinicaltrials.gov) stratified by their mechanism of action are: 
I. 
Antioxidants and mitochondrial enhancers: Two phase 3 trials using idebenone as a 
mitochondrial enhancer and antioxidant showed a negative outcome (Lynch et al., 
2010) despite a very positive phase 2 trial (Di Prospero et al., 2007). The antioxidant 
α-tocopheryl quinone (A0001) was tested in a randomized placebo-controlled phase 2 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 21 of 63 
 
trial for 28 days and resulted in a neurological improvement. There is no registered 
follow-up trial. The approach to scavenge mitochondrial iron overload with deferiprone 
resulted in a negative outcome in a randomized, placebo-controlled phase 2 trial. There 
is an ongoing phase 2 trial using the Nrf-2 activator RTA-408 to improve mitochondrial 
function (NCT02255435). 
II. 
Frataxin stabilizers, enhancers and replacement: Erythropoietin has been shown to 
increase 
frataxin 
protein 
concentration 
by 
posttranscriptional/-translational 
mechanisms (Mariotti et al., 2013). However, a long term study of 48 weeks did not 
show any neurological improvement and did not replicate the findings of frataxin up-
regulation in PBMCs (Sacca et al., 2016). Furthermore, frataxin up-regulation was not 
replicated in a phase 2 trial with carbamylated erythropoietin (Boesch et al., 2014).  
III. 
Increase of frataxin gene expression by epigenetic mechanisms: In addition to the 
strategy of using nicotinamide as a HDAC inhibitor, a specific HDAC class 1 inhibitor, 
RG 2833 (or HDACi 109), was developed and similarly to nicotinamide showed an 
increase in frataxin mRNA and protein expression in the blood of patients with 
Friedreich ataxia in a phase 2 trial (Soragni et al., 2014). However, the development of 
this drug was discontinued due to side-effects and poor penetration of the blood brain 
barrier. An effect of resveratrol to increase frataxin expression in PBMCs could not be 
demonstrated in a phase 2 trial (Yiu et al., 2015). In a non-blinded twelve-week phase 
2 trial subcutaneous injection of interferon γ-1b led to a small but significant increase 
in frataxin levels in red blood cells, platelets and PBMCs (Seyer et al., 2015). A phase 
3 trial on interferon γ-1b in the US was initiated (NCT02415127) but had a negative 
outcome (press release).  
IV. 
Increase of frataxin gene expression by virus-mediated gene transfer: In animal 
models, very promising results have been published to treat manifest cardiomyopathy 
with AAV-mediated gene (Perdomini et al., 2014). Similar results using viral gene 
transfer with tropism to DRG neurons do not exist so far.  
Although our knowledge about the pathophysiological processes and clinical progression has 
increased substantially over the last years, all vigorous international attempts to establish a 
disease-modifying therapy for Friedreich ataxia have failed to show any beneficial effect. Thus, 
many patients are severely disabled by adulthood or die prematurely of cardiomyopathy. 
Previous clinical trials have all focussed on attempts to ameliorate the downstream effects of 
FXN deficiency (Perlman, 2012). They all lacked statistical significance, indicating that more 
specific and potent candidate drugs, as well as more sensitive clinical measures and better-
powered clinical trial designs are needed. Recent research now provides both, 
(1) a novel and radical therapeutic cost-effective approach to restore FXN expression, 
and  
(2) sensitive clinical measures. 
If successful, this therapeutic approach could be applied to the growing number of diseases 
which have been shown to be caused by a similar mechanism. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 22 of 63 
 
3 Aim of Study 
The aim of the study will have a direct impact on health care – in terms of the first treatment 
for the chronic and devastating neurodegenerative disease Friedreich ataxia. To date, there is 
no cure or treatment that can slow down the disease which frequently results in severe 
disability by early adulthood. Patients become progressively more dependent on carers and 
frequently die prematurely of heart disease. This multinational study NICOFA will investigate 
whether nicotinamide is an effective treatment for Friedreich´s ataxia.    
3.1 Primary objectives 
The primary objective of the study is to evaluate the efficacy of daily doses of nicotinamide in 
slowing disease progression as measured by changes in the Scale for the Assessment and 
Rating of Ataxia (SARA) as compared with placebo in patients with Friedreich ataxia.  
3.2 Secondary objective 
Secondary objectives are to determine the change of secondary endpoints such as quality of 
life, functional motor and cognitive measures, clinician’s and patient’s global impression-
change scales as well as the up-regulation of the frataxin protein level, safety and 
survival/death. 
3.3 Tertiary objectives 
Tertiary objectives are mainly neuroimaging measures of the central nervous system (spinal 
cord and brain). 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 23 of 63 
 
4 Investigational Drug and Comparator 
4.1 Investigational Drug 
The investigational study drug nicotinamide (3-Pyridinecarboxamide), licensed in the EU, will 
be obtained from Euro OTC Pharma GmbH (Edisonstraße 6, 59199 Bönen) and will be 
produced according Good Manufacturing Practice (GMP) regulations by an approved 
manufacturer pharmacists at the University of Mainz in Germany.  
4.1.1 
Packaging, Labelling and re-supply of Investigational Product (IP) 
The Randomization list prepared by Department of Medical Statistics of the RWTH Aachen 
University Hospital, Aachen in Germany using randomizeR is stratified by center. The lists will 
be sent to the pharmacy before packaging the treatments. The packaging will be done at the 
pharmacy of the University in Mainz, Germany. The pharmacy will send out the packages 
(placebo or drug) that are labelled according to the randomization list. 
4.1.2 
Management of IMP 
Administration of IMP to patients will be delegated to the responsible study nurse by the 
investigator. The study nurse will document charge number, expire date and randomization 
number and will maintain the drug accountability log (including return of IMP by patients). 
4.1.3 
Administration of IMP 
Subjects will receive an oral dose of 4 g/d nicotinamide (pyridine-3-carboxylic amide, [formula 
C6H6N2O]) or a dose of placebo once a day for the time period of two years. 
4.1.4 
 Advice for using the IMP 
Subjects will be instructed to take the study medication once a day (4g/d or placebo, 8 
capsules) in the morning after breakfast at approximately the same time a day throughout the 
study. Subjects will swallow the study medication whole, and will not manipulate or chew the 
medication prior to swallowing. 
Daily dosing of 3.5-6 g has been shown to upregulate frataxin expression. However, treatment 
above 4 g/d (such as 6-8 g/d) is associated with nausea. Our experience is that if nicotinamide 
is introduced gradually nausea is frequently transient and resolves over a few days.  
To maintain blinding, there will be a Phase A (weeks 1-4): All patients will be slowly titrated 
with an increase of 0.5 g nicotinamide every three days up to a dose of 4 g/day [titration would 
be: 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0 g per day]. Thus, the titration period will be three weeks, 
patients should then be stable on 4g per day or the highest tolerated dose for one week. If 
nausea or vomiting occur it is at the discretion of the investigator to flexible reduce the dosing 
and then reach the highest possible dose. Domperidone as first choice medication (1-3 x 10 
mg/day) and/or metoclopramide as second choice (1-3 x 10 mg/day) may be used individually 
as rescue treatments. 
Phase B (week 5 - 104): Phase A is immediately followed by a 2:1 randomization. 
Randomization includes safety visit. ⅓ of the FRDA patients will be withdrawn from active 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 24 of 63 
 
treatment and switched to placebo. ⅔ of the FRDA patients will stay on active treatment with 
4 g nicotinamide per day or the highest tolerated dose of phase A. The switch from phase A to 
phase B will be done without discontinuation of treatment to prevent a second titration period.  
Again, in the event of nausea, the dose will be adjusted and the patient will be maintained on 
the maximum tolerated dose (MTD). A telephone safety assessment following each dose 
increment will allow dose-adjustment if necessary. The minimal dose would be 2 g/d. Dose 
escalation will be adjusted or stopped on the basis of tolerability and anti-nausea treatments 
will be given when needed. 
Drug will be dispensed to the subject at each clinic visit. 
Between clinic visits, subjects will be responsible for establishing a process for reliable 
outpatient dosing to ensure dosing compliance. To facilitate compliance assessment, a dosing 
diary will be supplied to the subject, who will be instructed to record the time for each daily 
doses of study medication. Subjects will be instructed to bring the completed diary to the clinic 
at the time of each visit, along the used and in-use packs to assess compliance. 
If a subject misses a scheduled dose, that dose should be taken as soon as possible, but not 
later than 12 hours beyond the scheduled time of administration. If it is greater than 12 hours 
beyond the scheduled dose, the subject should be instructed to skip that dose and resume 
dosing at the next regularly scheduled time. Missed doses and reasons for missed doses 
should be recorded on the dosing diary. 
 
Storage conditions:  
Receipt, usage and return must be documented on the respective forms for Drug Accountability 
of the Center for Translational & Clinical Research Aachen. Account will be given for any 
discrepancy. See instruction of use (SmPC). 
4.2 Placebo 
The approved manufacturer pharmacists at the University of Mainz in Germany will further 
provide an oral dose of placebo with identical appearance. 
4.3 Preclinical data of Nicotinamide 
See Summary of Product Characteristics (SmPC). 
4.4 Benefit Risk Assessment 
Nicotinamide is a classical class III HDAC inhibitor (Vaquero et al., 2007), has a good 
bioavailability and rapidly penetrates all tissues, readily crosses the blood brain barrier (Hoane 
et al., 2006; Spector and Kelley, 1979). Nicotinamide has over the past forty years been given 
at high doses for a variety of therapeutic applications. A review on safety of high-dose 
nicotinamide has revealed that the therapeutic index of nicotinamide is wide but at very high 
doses reversible hepatotoxicity has been reported in animals and humans (Knip et al., 2000). 
Minor abnormalities of liver enzymes can infrequently occur at the high or mega doses. There 
is no evidence of teratogenicity from animal studies and nicotinamide is not in itself oncogenic; 
at very high doses it does however potentiate islet tumor formation in rats treated with 
streptozotocin or alloxan. There is no evidence of oncogenicity in man. Growth inhibition can 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 25 of 63 
 
occur in rats but growth in children is unaffected. High-dose nicotinamide should still, however, 
be considered as a drug with toxic potential at adult doses in excess of 3 g/day and only applied 
under supervision. To our knowledge nicotinamide has been applied in Friedreich ataxia in 
such high doses (> 3 g) only in the exploratory, open-label, dose-escalation study in 
Friedreich´s ataxia in the UK (ClinicalTrials.gov, number NCT01589809) (Libri et al., 2014). 
Nicotinamide having been given safely for 5 years at about 3 g (1.2 g/m2) per day to more than 
250 individuals including children from 3 years and above, adolescents and adults in an 
attempt to prevent diabetes in an at-risk population (Gale et al., 2004). No serious adverse 
effects were observed. In a recent exploratory, open-label and dose-escalation study on ten 
patients with Friedreich ataxia (Libri et al., 2014), nicotinamide was given single doses, 
repeated daily doses of 2-8 g oral nicotinamide for 5 days and 8 weeks. Nicotinamide was 
generally well tolerated with nausea being the most frequent dose-related adverse event in 
this study; this was readily controlled with the use of antiemetic’s and by modification of the 
dose. Here, nicotinamide was rapidly absorbed after oral administration and generally well 
tolerated in Friedreich ataxia patients after repeated daily dosing for 8 weeks. 
4.5 Known adverse events for Nicotinamide 
The following most common adverse events have been described in the exploratory, open-
label, dose-escalation study by (Libri et al., 2014): Nausea, headache, lightheadedness, 
vomiting, hypersomnia, fatigue, diarrhea, raised AST and ALT, falls, anorexia, migraine, 
dizziness, sore throat, retching, cold, fever, infections, cough, anemia, flu-like symptoms. 
4.5.1 
Dose-Response Assessment 
The following section accords the Opinion of the Scientific Committee on Food on the tolerable 
upper intake levels of Nicotinamide, European Commission, Brussels, Belgium 17-April-2002:  
 
Vasodilatory effects (flushing) 
The flushing reported with nicotinic acid does not occur following nicotinamide, either given as 
an intravenous injection (Bean and Spies, 1940) or when it is given orally at high-doses to 
patients with diabetes (Knip et al., 2000). 
 
Gastrointestinal effects 
Gastrointestinal effects are rare following high-dose treatment with nicotinamide (Knip et al., 
2000). Nausea was reported in a single subject who had taken nicotinamide 3 g daily followed 
by 9 g per day for several days (Winter and Boyer, 1973). 
 
Hepatotoxicity 
Only one patient has been reported to have developed hepatitis after nicotinamide alone, and 
this subject had been given 3 g daily followed by 9 g per day for several days (Winter and 
Boyer, 1973); other subjects who developed liver disease after nicotinamide had also received 
prolonged treatment with nicotinic acid (Rader et al., 1992). 
Increased serum transaminase levels were reported for 17 out of 41 children with attention 
deficit disorders treated for 12 weeks with daily doses of 3 g nicotinamide, in combination with 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 26 of 63 
 
1.2 g pantothenic acid, 3 g ascorbic acid and 0.6 g pyridoxine (Haslam et al., 1984). 
Whether this hepatotoxic effect was related to the high dose of nicotinamide, or to the 
combination with the high doses of pantothenic acid, vitamin C and pyridoxine, cannot be 
concluded from this study, and therefore, this study cannot be used in risk assessment of 
nicotinamide. 
The supplementation trials on the use of nicotinamide to prevent or delay the development of 
diabetes mellitus have not reported hepatitis as an adverse effect (Knip et al., 2000); however 
these have involved smaller number of subjects, have been of shorter duration and at lower 
doses than the trials on the use of nicotinic acid for the treatment of hypercholesterolaemia. 
Ten newly diagnosed Type 1 diabetic patients were given 1 g/day for 45 days (Mendola et al., 
1989), and compared over the following year with a group who were treated with placebo; the 
authors reported that no adverse effects were observed when physical, biochemical and 
haematological parameters were considered (no details of the tests were given and the main 
aim of the paper was to study efficacy). A group of 35 patients, aged 6 to 18 years, were given 
either placebo (n=17), or up to 1.5 g/day of slow-release nicotinamide (n=18) for 12 months 
(Chase et al., 1990); various tests, including measurement of serum transaminases, alkaline 
phosphatase and bilirubin, were performed after 4 and 12 months, and remained normal in all 
subjects. No adverse effects were reported in a group of nine Type 1 diabetic patients with 
ketosis given 3 g of nicotinamide per day, three of whom were treated for up to 12 months, 
compared to 7 similar patients given placebo (Vague et al., 1987). 
Major long-term studies in patients with Type 1 diabetes mellitus, at dosages of 2-3 g of 
nicotinamide per day, have been undertaken recently [ENDIT - (Pociot et al., 1993); IMDIAB 
III - (Pozzilli et al., 1995); DENIS - (Lampeter et al., 1998)]. The ENDIT (European Nicotinamide 
Diabetes Intervention Trial) has reviewed the safety data on nicotinamide before starting the 
clinical phase, but no results of the trial have yet been published (Knip et al., 2000; Pociot et 
al., 1993). The IMDIAB III study involved a double-blind trial in which 28 newly diagnosed 
patients with Type 1 diabetes mellitus were given 25 mg/kg bw of nicotinamide daily for 12 
months, and a similar number treated with placebo; no adverse effects were reported and 
biochemical parameters including liver and kidney function were normal during follow-up (the 
publication describes the measurement of bilirubin). The DENIS trial (Deutsche Nicotinamide 
Intervention Study) was a study in young children (average age 3 years) at high risk of 
developing Type 1 diabetes mellitus in which 25 subjects were randomized to receive 
nicotinamide (1.2 g per m2 per day), and 30 to receive placebo; the trial continued for 3 years 
and during this period all biochemical markers (including alanine aminotransferase, aspartate 
aminotransferase and bilirubin) were in the normal range. 
 
Cardiac Events 
In more than 40% of patients with FRDA the heart is affected as well. Hypertrophic 
cardiomyopathy is a recognized cause of premature death in Friedreich Ataxia, by arrhythmia 
or cardiac failure, reducing life expectancy to 29 to 38 years. Thus, we expect ongoing cardiac 
events during the study and the cardiac situation needs and will be controlled upon a regular 
basis (see study design). 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 27 of 63 
 
Glucose intolerance 
Nicotinamide has been studied in relation to reducing the risk of the development of diabetes 
mellitus; none of the studies (see above) has reported a worsening of symptoms in the treated 
groups. 
 
Other effects and overall dose-response relationships 
There have been no other adverse effects reported following the administration of nicotinamide 
in trials in patients with diabetes. Determination of the NOAEL from the intervention trials is 
difficult, because of the different dosage regimens employed. Studies have used fixed doses 
of 1 g/day (Mendola et al., 1989), 1.5 g/day (Chase et al., 1990), 3 g/day (Vague et al., 1987), 
25 mg/kg bw/day (IMDIAB III trial) and 1.2 g/m2/day (DENIS trial). These different doses can 
be calculated on a body weight basis using the data on body weights or ages in the different 
publications; the doses approximate to 17 mg/kg bw/day [(Mendola et al., 1989); average age 
18.3 years), 37 mg/kg bw/day (Chase et al., 1990); average age 12.5 years), 43 mg/kg bw/day 
adults (Vague et al., 1987), 25 mg/kg bw/day (IMDIAB III trial; ages in the range 5-35 years) 
and 50-40 mg/kg bw/day (DENIS trial; ages 3-12 years]. The lowest of these values (25 mg/kg 
bw/day) was from one of the largest published studies, and this has been used as the NOAEL 
for nicotinamide. 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 28 of 63 
 
5 Study Design and Duration 
5.1 Study Design 
This clinical trial contains two phases: 
Phase A (weeks 1-4): Open-label dose adjustment wash-in period with nicotinamide: All 
patients will be slowly titrated with an increase of 0.5 g nicotinamide every three days up to a 
dose of 4 g/day [titration would be: 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0 g per day]. Thus, the 
titration period will be three weeks, patients should then be stable on 4g/d or the highest 
tolerated dose for one week. Phase A is immediately followed by a 2:1 randomization.  
Phase B (weeks 5-104): Multicentre, prospective, controlled, double-blind, randomized, two 
arm parallel, placebo-controlled, phase IIb/III study, with a 2:1 allocation ratio. 
Nicotinamide Group (2/3): Nicotinamide 4 g (capsules) or highest tolerated dose with a 
minimum of 2 g/d per os once daily  
Placebo Group (1/3): 
Matching Placebo (capsules) once daily 
5.2 Study Duration 
The recruitment of patients for the inclusion of the study will start 2019. The expected duration 
of study inclusion will be 12 months; the study will be 24 months per patient and in total 36 
months including evaluation and clinical study report. 
5.3 Stratification 
The study will be stratified according to center. There are ten centers to be included in the trial: 
Aachen, Bonn, Tübingen, Munich (all in Germany), Innsbruck (Austria), Milan (Italy), Paris 
(France), 2x London (ICL & UCL, UK) and Madrid (Spain). 
Accordingly, the randomization list prepared by Department of Medical Statistics of the RWTH 
Aachen University Hospital, using randomizeR is stratified by center. The packaging following 
the randomization list will be done in Mainz, Germany, labelled and A or B. The allocation of 
the nicotinamide or placebo group to A or B will be balanced by study site. This will maintain 
concealment and double blinded treatment allocation.  
5.4 Allocation Ratio 
Patients will be allocated to treatment groups by randomization stratified by center. The 
Randomisation list will be prepared by Department of Medical Statistics of the RWTH Aachen 
University Hospital, using randomizeR. A 2:1 allocation ratio favouring the active treatment is 
intended. To make the trial more attractive to FRDA patients, we will use a 2:1 randomisation, 
in which the probability that a patient is assigned to the experimental treatment arm is 2/3. The 
best practice randomization procedure to minimize the impact of selection and time trend bias 
on the type one error will be selected via a simulation study (ERDO).  
 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 29 of 63 
 
6 Study Population 
6.1 Number of Patients 
N=225 (n=75 control arm; N=150 treatment arm). Screening is expected to be necessary in 
360 patients. Patients will be recruited via EFACTS, ataxia outpatient centers and patient 
advocacies. 
6.2 Inclusion Criteria 
Subjects, fulfilling the following inclusion criteria are suitable for participation in the study: 
1. Patients must have a molecular genetic diagnosis of Friedreich ataxia with a GAA-repeat 
expansion on both alleles of the FXN gene and a SARA Score >7 and <28. 
2.  Patients must be >18 and <50 years old and have a weight of at least 50kg.  
3. Written informed consent prior to study participation 
4. A female subject is eligible to participate if she is of: Non-childbearing potential defined as 
pre-menopausal females with a documented tubal ligation or hysterectomy; or 
postmenopausal defined as 12 months of spontaneous amenorrhea or of childbearing 
potential and agrees to use of highly effective birth control methods (Pearl Index < 1). 
6.3 Exclusion Criteria 
Subjects, fulfilling one or more of the following exclusion criteria will not be included in the 
study: 
1. Patients with any medical condition or illness that, in the opinion of the investigator would 
interfere with study compliance and/or impair the patient´s ability to participate or complete 
the study. 
2. Any uncontrolled medical or neurological/neurodegenerative condition (other than 
Friedreich ataxia).  
3. Clinically significant psychiatric illness (e.g., uncontrolled major depression, schizophrenia, 
bipolar affective disorder) within 6 months prior to screening. 
4. Patients with significant clinical dysphagia that will be screened with dysphagia screening 
questionnaire. 
5. Hypersensitivity to nicotinamide. 
6. Patients known to be positive for human immunodeficiency virus (HIV). 
7. Patients with a significant history of substance abuse (e.g. alcohol or drug abuse) within 
the previous six months before enrolment. Substance abuse refers to the harmful or 
hazardous use of psychoactive substances, including alcohol and illicit drugs.  
8. Patients with a history of severe allergies. 
9. Indication of impaired liver function as shown by an abnormal liver function profile at 
Screening (e.g., repeated values of aspartate aminotransferase [AST], alanine 
aminotransferase [ALT] and bilirubin ≥3 × the upper limit of normal). 
10. History of malignancy or carcinoma. The following exceptions may be made after 
discussion with the Sponsor: 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 30 of 63 
 
• Subjects with cancers in remission more than 5 years prior to screening. 
• Subjects with a history of excised or treated basal cell or squamous carcinoma. 
• Subjects with prostate cancer in situ. 
11. History or evidence of an autoimmune disorder considered clinically significant by the 
Investigator 
or 
requiring 
chronic 
use 
of 
systemic 
corticosteroids 
or 
other 
immunosuppressants. 
12. History of clinically significant cardiac disease (ejection fraction < 40% [normal range 50-
70%], cardiac insufficiency defined as New York Heart Association [NYHA] Class >2; 
clinically significant congenital or acquired valvular disease; symptomatic coronary disease 
such as prior myocardial infarction or angina, B-type natriuretic peptide (BNP) level 
increase more than 2 x of the normal age- and gender dependent range; history of unstable 
arrhythmias, history of atrial fibrillation). 
13. The subject received an investigational drug within 30 days prior to inclusion into this study. 
14. Patients taking sodium valproate, tranylcypromine (monoamine oxidase inhibitor [MAOI]) 
or any other known histone deacetylase inhibitor. 
15. Use of vitamin B1 (thiamine), withdrawal should be at least 3 months prior screening or 5 
half-lives, whichever is longer. 
16. Use of vitamin B3 (nicotinamide), withdrawal should be at least 3 months prior screening. 
17. If patients are taking idebenone or coenzyme Q10 (CoQ), this should be stable over the last 
three months and not changed during the study. 
18. The subject is unwilling or unable to provide written informed consent and to follow the 
procedures outlined in the protocol. 
19. For subjects who will undergo an MRI: Any contraindications to MRI such as, but not limited 
to cardiac pacemaker, implanted cardiac defibrillator, aneurysm clips, carotid artery 
vascular clamp, neurostimulator, implanted drug infusion devices, metal fragments or 
foreign objects in the eyes, skin or body, bone growth/fusion stimulator, cochlear, otologic 
implant, sever claustrophobia or any condition that would counterindicate an MRI scan.  
20. Patients participating at start or have been within 30 days before start of study in another 
interventional clinical trial. 
21. The subject is mentally or legally incapacitated. 
22. Pregnant females as determined by positive [serum or urine] hCG test at Screening or prior 
to dosing. Participants of child-bearing age should use adequate contraception as defined 
in the study protocol. 
23. Lactating females. 
6.4 Subjects of Reproductive Potential  
Women during pregnancy and lactation must not be included in the study. Before entering the 
study and at every visit a pregnancy test has to be conducted to exclude pregnancy. 
Female patients capable of bearing children should inform their sexual partner of their 
participation in this clinical study and use highly effective methods of birth control such as 
abstinence, sterilization, birth control pills, Depo-Provera injections, or contraceptive implants 
during treatment and for an additional 1 month after the end of treatment. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 31 of 63 
 
Male patients should inform their sexual partner of their participation in this clinical study and 
use highly effective methods of birth control such as abstinence, vasectomy, or condom in 
combination with hormonal birth control or barrier methods used by women during treatment 
and for an additional 3 months after the end of treatment.  
Vasectomised partner is a highly effective birth control method provided that the partner is the 
sole sexual partner of the WOCBP trial participant and that the vasectomised partner has 
received medical assessment of the surgical success. 
7 Study Procedures 
7.1 Informed Consent 
The patient must personally sign and date the latest approved version of the informed consent 
form before any study specific procedures are performed. The Patient information leaflet and 
Informed Consent Form to be used must be revised by the sponsor and approved by the Ethics 
committee of the study site. Each patient’s chart will have his or her signed ICF and/or assent 
form for study participation attached to it. It must also be available for any required inspection. 
Written and verbal versions of the Patient Information Sheet and Informed Consent will be 
presented to the patients detailing all pertinent aspects of the study procedures to be taken no 
less than: the exact nature of the study; the implications and constraints of the protocol; the 
known side effects and any risks involved in taking part. It will be clearly stated that the patient 
is free to withdraw from the study at any time for any reason without prejudice to future care, 
and with no obligation to give the reason for withdrawal. The patient will be allowed as much 
time as wished to consider the information, and the opportunity to ask any question at any time 
to the Investigator, whether he/she will participate in the study. Written Informed Consent will 
be given voluntarily by the patients and obtained by means of a patient‘s dated signature and 
dated signature of the study principal investigator who presented and obtained the informed 
consent. Other physician investigator / study personnel who obtained the consent must be 
suitably qualified and experienced, and have been authorized to do so by Principal 
Investigator. A copy of the signed Informed Consent will be given to the patient. The original 
signed form will be retained at the study site (in the study file). 
7.2 Overview Study Treatment 
 
7.2.1 Screening and eligibility assessment 
 
Patients are pre-screened by the study nurse of the centre to select those patients who meet 
the inclusion and exclusion criteria. Every patient fulfilling the inclusion criteria will be proposed 
by the investigator to participate to this trial. The subjects will voluntarily confirm their 
willingness after complete information about their disease, options of treatment, potential 
outcomes, risk and benefits of several therapies, and trial process, including number of visits, 
clinical and laboratory determinations, and time of follow-up. The informed consent of all 
aspects of the trial that are relevant to the subject's decision to participate has to be in writing 
and verbally by the investigator. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 32 of 63 
 
In detail, the screening procedures will be realized with the following information and 
determinations:  
 
Demographics 
The major demographic factors such as date of birth, gender, race, weight, height, smoking 
and drinking habits, and type of anticonception when applicable will be recorded on CRFs (see 
also Data Management and Validation Plan [DMVP]).  
 
Medical History 
Details of any history of disease, medical history, or clinical relevant surgical interventions. 
 
Concomitant Medication  
All over-the-counter or prescription medication, vitamins, and/or herbal supplements will be 
recorded on CRFs.   
 
Physical Examination / Vital signs 
Height, weight and body temperature will be recorded on CRFs. 
Resting pulse, blood pressure (BP) and respiratory rate measurements will be measured after 
the participant has sat for at least five minutes. 
 
Questionnaire about physical exercise (QPE) 
At each visit, physical exercise performance of the study participants will be obtained (average 
duration in minutes per week, frequency, kind of exercise (e.g. aerobic, strength), change in 
contrast to exercise performance before). We will further request not to change their typical 
physical exercise performance during the study.  
 
Laboratory tests 
The following routinely used laboratory tests will be necessarily determined at baseline in all 
potential participants: 
 
Hemoglobin levels, white blood cell count (total and differential blood count), creatinine, 
glomerular filtration rate, bilirubin levels, blood urea, aspartate aminotransferase [AST] and 
alanine aminotransferase [ALT], blood glucose, HbA1c, PTT, Quick/INR, CRP and BNP 
(should be measured in the morning, fasten and at rest [not after any exercise]). All laboratory 
results will be reviewed and the reports signed by the investigator who will record in the CRF 
whether they are normal, abnormal but not clinically significant, or abnormal and clinically 
significant. In the latter case the eligibility of the participants will be reviewed.  
 
As the following are of particular interest in terms of safety, we apply the following definitions: 
 
Liver function tests such as aspartate aminotransferase [AST] and alanine aminotransferase 
[ALT]: According to previous definitions used in the phase II study for nicotinamide in Friedreich 
ataxia, we define mild increase as 3-5x upper normal limit (Grade 1), moderate as >5-20x 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 33 of 63 
 
upper the normal limit (Grade 2) and severe raised LFT as >20x upper the normal limit  (Grade 
3) (Libri et al., 2014). 
 
Bilirubin: mild increase (Grade 1): < 1.5 x normal limit; moderate increase (Grade 2): >1.5 – 3 
x upper normal limit; sever increase (Grade 3): > 3 – 10 x upper normal limit. 
 
B-type natriuretic peptide (BNP) level: in general, a cut-off of > 200 pg/ml is used, however as 
these results are age- and gender-dependent, we extend this to values that are 2 times upper 
the normal level. 
 
7.2.2 Subsequent assessment 
For each visit, we will consider inclusion of: 
1. 
Eligibility check.  
2. 
Assessment of endpoints/outcome measures. 
3. 
Assessments 
of 
safety 
including 
general 
(e.g. 
physical 
examination; 
electrocardiogram), specific safety assessments (e.g. specific laboratory tests 
according to the applicable product information and/or population, clinical assessments 
(e.g. specific questionnaires) and adverse event collection. 
4. 
Dispensing of study drugs. 
5. 
Assessment of compliance with study drugs.  
6. 
Recording of concomitant medications. 
 
7. 
Lab test to evaluate treatment response as defined in the schedule. 
 
7.2.3 End of trial assessment 
The end of trial will be the date of the last scheduled visit of the last participant. The end of trial 
study (EOT) visit form should include: 
1. 
Assessment of endpoints/outcome measures. 
2. 
Assessments of safety including general (e.g. physical examination; echocardiography; 
echocardiogram), specific safety assessments (e.g. specific laboratory tests according 
to the applicable product information and/or population; MRI), clinical assessments 
(e.g. specific questionnaires) and adverse event collection. 
3. 
Assessment of compliance with study medication.  
4. 
Recording of concomitant medications. 
7.3 Blinding 
This trial is double-blinded. After randomization neither the patients nor the investigator or 
sponsor will be aware of the treatment allocation. Patients assigned to one of the double- 
blinded treatment will take Nicotinamide capsules or matching placebo. The capsules will be 
identical in appearance. The involved staff of the Department of Medical Statistics of the RWTH 
Aachen University Hospital as well as the involved staff of the pharmacy are aware about the 
randomized treatment allocation sequence but keep the list and information concealed till 
closure of the database. Neither the Department of Medical Statistics of the RWTH Aachen 
University Hospital nor the pharmacy are involved in patient recruitment. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 34 of 63 
 
7.4 Unblinding Procedures 
In the event of medical emergency which requires identification of an individual patient’s 
treatment, investigators will be able to access information via decoding envelopes, which can 
be found along the packages, but not given to the patients and can be collected at the monitor 
visits. The randomization centre should be contacted before unblinding and the reason for 
unblinding should be documented in the medical records. 
The responsible biostatistician from the Department for Medical Statistics at the RWTH Aachen 
University ensures best data quality and that no unblinded data will be given to the participating 
centers. Information provided to investigators, patients and raters will be limited as possible.  

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 35 of 63 
 
7.5 Package and Labelling of IMP and Placebo 
Master Label for Primary and Secondary Packaging (German & English Version): 
 
 
 
Hersteller:  Apotheke der Universitätsmedizin, Langenbeckstr. 1, D-55131 Mainz, 
Tel. 06131-17-5359 
Sponsor:  Center for Translational & Clinical Research (CTC-A), Uniklinik RWTH 
Aachen, Pauwelsstr. 30, 52074 Aachen; Tel.: 0241 80 80092 
NICOFA 
Protocol No.: 15-138 
EudraCT-Nr.: 2017-002163-17 
 
Kruke enthält XXX Kapseln Nicotinamid oder Placebo zur oralen 
Einnahme 
1 Kapsel enthält 500 mg Nicotinamid oder Placebo 
Dosierung: ______ Kapseln pro Tag (vom Prüfarzt einzutragen)  
Gruppe: ______ (A oder B) 
Patientennummer: ________  (vom Prüfarzt einzutragen) 
 
Medikationsnummer: ____________ 
 
Verwendbar bis: DD.MM.JJJJ 
 
         Ch.-B.: SJJJJ/XXX/XXX 
 
Die Kapseln sind vor Licht geschützt und nicht über 25°C und für Kinder 
unzugänglich aufzubewahren!  
Zur klinischen Prüfung bestimmt! 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 36 of 63 
 
 
7.6 Compliance 
Patients will be asked to bring all trial medication to each trial visit. Capsules will be counted 
by the corresponding study nurse and compliance will be calculated in a worksheet which must 
be kept as a source document.  
 
 
Producer:  Apotheke der Universitätsmedizin, Langenbeckstr. 1, D-55131 Mainz, 
Tel. 06131-17-5359 
Sponsor:  Center for Translational & Clinical Research (CTC-A), Uniklinik RWTH 
Aachen, Pauwelsstr. 30, 52074 Aachen; Tel.: 0241 80 80092 
NICOFA 
Protocol No.: 15-138 
EudraCT-No.: 2017-002163-17 
 
Pot contains XXX capsules Nicotinamid or Placebo for oral intake 
1 capsule contains 500 mg Nicotinamid or Placebo 
Dose: ______ capsules per Day (entered by investigator)  
Group: ______ (A or B) 
Patient No.: ________  (entered by investigator) 
 
Medication No.: ____________ 
 
Useable till: DD.MM.YYYY 
         Ch.-B.: SJJJJ/XXX/XXX 
 
The capsules are to be stored in the packaging carton, protected from sunlight, not 
above 25°C and out of the reach of children. Destined for clinical trial! 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 37 of 63 
 
8 Treatment Details  
8.1 Variables  
8.1.1 
Efficacy 
To prove efficacy with respect to the primary and secondary endpoints, a linear mixed effects 
model (LMEM) will be used with the fixed effects of treatment, treatment-by-time interaction, 
center, baseline score and age as well as the random intercept and time. The primary as well 
as the secondary efficacy endpoints will be evaluated over the Full Analysis Set (FAS), which 
is the set of subjects who have been randomized and have taken at least one dose of 
nicotinamide or placebo. 
 
8.1.1.1 
Primary endpoints: 
The primary endpoint is SARA, validated for Friedreich ataxia and shown to be the most 
suitable measure of disease progression in Friedreich ataxia (Burk et al., 2013; Reetz et al., 
2015; Reetz et al., 2016). 
8.1.1.2 
Secondary endpoints:  
Secondary endpoints will include: 
1) Progression of quality of life measures such as the `Activity of Daily Living´ (ADL) 
scores, part of the `Friedreich ataxia rating scale´ (FARS), and the EuroQol five 
dimensions questionnaire (EQ-5D) 
2) Modified Friedreich Ataxia Rating Scale (mFARS) (Subramony et al., 2005). Modified 
FARS scores are defined as the sum of scores for bulbar function, upper limb 
coordination, lower limb coordination, and upright stability (or the total FARS score 
minus the PNS score) 
3) Progression of `Spinocerebellar Ataxia Functional Index´ (SCAFI) (Schmitz-Hubsch et 
al., 2008) 
4) Progression of `Composite Cerebellar Functional Severity´ (CCFS), which has been 
validated in children and adults with Friedreich ataxia (Filipovic Pierucci et al., 2015) 
5) Up-regulation of frataxin protein level 
6) Clinician’s Global Impression-Change Scale (CGI-C) including comparison of change 
to the last visit 
7) Patient’s Global Impression-Change Scale (PGI-C) including comparison of change to 
the last visit 
8) Safety  
9) Survival/ death 
8.1.1.3 
Tertiary endpoints:  
Tertiary endpoints will include:  
1) Progression of the `Montreal Cognitive Assessment´ (MoCA)  
2) Active modification of the FXN locus, as measured by chromatin immunoprecipitation 
and chromosome confirmation capture sequencing  
3) Percentual change in left ventricular mass index as measured by echocardiogram 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 38 of 63 
 
4) Structural and functional changes of the brain and spinal cord, measured by magnetic 
resonance imaging (MRI) 
All recruiting centers will be asked to perform spinal/brain tertiary measures, however they will 
be optional, as they are of explorative nature and partly depending on existing infrastructure 
(e.g. MRI scanner). 
8.2 Methods 
8.2.1 
Blood Collection for serum chemistry and biomarkers 
At V1, V5, V7 approx. 50 ml; V3, V4 and V6 approx. 30 ml and at V2 approx. 20 ml blood 
sampling will be performed as shown below: 
Visit 
Parameter 
Material collected [mL] 
V1, V2, V3, V4, V5, V6 and V7 
 
Central Lab 
 
20 or 30 
V1, V5 and V7 
Research Lab 
 
20 
Total amount / visit 
 
20-50 mL  
Total amount / study 
 
260 mL 
 
Measurements for serum chemistry and haematology are performed by the central labs at the 
sites. The liver enzymes need to be monitored by a medical team member. When abnormal 
liver enzymes are recognized, medication will be adjusted or even terminated (as described in 
section 10).  
 
All patients that are included in the EFACTS registry (www. e-facts.eu) will have genetic testing 
performed at the Laboratory of Experimental Neurology at the Université Libre de Bruxelles in 
Brussels, Belgium. In the case of participating only in the NICOFA clinical trial but not in 
EFACTS, we will require blood samples evaluating genetic analyses. This should be send to 
Prof. Dr. Massimo Pandolfo, Laboratoire de neurologie expérimentale [Laboratory of 
Experimental Neurology], Campus Erasme, Hopital Erasme et bâtiment C, niveaux 2 et 3, 
campus 
universitaire 
Erasme, 
Bruxelles, 
Belgium 
(phone: 
+32-2-
555.39.92/ 41.15/ 42.17/ 41.16/ 64.08, 
fax +32-2-555.39.42, 
email: 
massimo.pandolfo@ulb.ac.be).  
 
Blood samples for evaluating nicotinamide level, RNA-Sequencing of Frataxin gene or gene 
expression of Frataxin (FXN) gene are send to Prof. Dr. Jörg B. Schulz at the Department of 
Neurology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany (phone: +49 
241 808900, E-mail: jschulz@ukaachen.de). Nicotinamide level will be measured by the 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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Institute for Occupational and Social Medicine at the RWTH Aachen University Hospital (Prof. 
Thomas Kraus).  
 
Blood samples for evaluating frataxin level are send to Prof. Dr. Richard Festenstein at the 
Department of Medicine, Imperial College London, Room 2003, MRC Building, Hammersmith 
Campus, Du Cane Road, London, W12 ONN, United Kingdom (phone: +44 20 3313 8310, E-
mail: r.festenstein@imperial.ac.uk). 
 
8.2.2 
Transthoracic echocardiography (ECHO) 
For systolic function: Left ventricular ejection fraction (EF), LV end-systolic volume and LV end-
diastolic volume will be determined by manual tracing of end-systolic and end-diastolic 
endocardial borders using apical 4-chamber and 2-chamber views, employing biplane 
Simpson’s Method. Left atrial volume will be determined by manual tracing of end-systolic 
endocardial borders using apical 4-chamber and 2-chamber views with LA volume being 
calculated by (0.85 x A1 (LA area 4-chamber view) x A2 (LA are 2-chamber view))/ L (length 
of the left atrium in 4-chamber view). Endsystole will be marked as aortic valve closure in apical 
long axis views. For regional wall motion LV segments were defined according to the 
standardized myocardial segmentation model of the American Heart Association.  
For diastolic function: Peak E: early diastolic mitral inflow velocity, LA volume and LV annular 
flow (e') by tissue doppler technique, E/e' ratio and 2D and novel 3D parameter global Strain 
Rate E by myocardial deformation imaging.   
8.2.3 
Pregnancy Test 
For all females of child-bearing potential, pregnancy testing (urine β-hCG pregnancy) will be 
performed at each visit. 
8.2.4 
Vital signs and physical exam 
Will include resting systolic and diastolic blood pressure and pulse including respiratory rates 
at a supine position after at least 5 minutes resting and will be measured at every visit. The 
physical exam includes a basic medical including cardiological, pulmonal and gastro-intestinal, 
and neurological clinical examination. 
8.2.5 
Clinical measures and rating scales 
Modified Friedreich Ataxia Rating Scale (mFARS) 
The modified Friedreich Ataxia Rating Scale (mFARS) scores are defined as the sum of scores 
for bulbar function, upper limb coordination, lower limb coordination, and upright stability or the 
total FARS score minus the PNS score (Subramony et al., 2005).  
 
Activity of Daily Living (ADL) 
Activities of Daily Living (ADLs) are tasks related to personal care. The ADL score looks at four 
of these tasks: transfer, bed mobility, toileting and eating. For functional staging we will use 
the ADL assessment that is incorporated into the Friedreich ataxia rating scale (FARS). 
 
EuroQol five dimensions questionnaire (EQ-5D) 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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Applicable to a wide range of health conditions and treatments, the EQ-5D health questionnaire 
provides a simple descriptive profile and a single index value for health status. 
 
Spinocerebellar Ataxia Functional Index (SCAFI) 
Quantitative performance measures or timed tests are used to supplement the results of 
clinical rating scales. Presumed advantages include high interrater and retest reliabilities. The 
SCAFI is composed of a timed 8m walk at maximum speed (8MW), the 9-hole peg test (9HPT), 
and the PATA rate, a measure of speech performance. SCAFI was validated in a large multi-
center cohort of SCA patients. 
 
Composite Cerebellar Functional Severity (CCFS) 
The CCFS is a simple and validated method for assessing cerebellar ataxia over a wide range 
of severity. The pegboard and click tests are easy to perform and accurately reflect the severity 
of the disease. 
 
Montreal Cognitive Assessment (MoCA) 
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument 
for mild cognitive dysfunction. It assesses different cognitive domains: attention and 
concentration, executive functions, memory, language, visual constructional skills, conceptual 
thinking, calculations, and orientation. 
 
Scale for the Assessment and Rating Ataxia (SARA)  
SARA is a clinical scale that is based on a semi quantitative assessment of cerebellar ataxia 
on an impairment level. SARA has 8 items that are related to gait, stance, sitting, speech, 
finger-chase test, nose-finger test, fast alternating movements and heel-shin test. Although the 
cerebellum is directly involved in the coordination of eye movements, oculomotor functions are 
not considered, as the validation trials indicated that they are determined by other factors than 
appendicular and midline ataxia. SARA underwent a rigorous validation procedure involving 
three large multi-center trials in SCA and non-SCA ataxia patients, as well as controls.  
 
Global Impression-Change Scale (CGI-C and PGI-C) 
The Clinical Global Impressions-Change (CGI-C) Scale is used for the clinician to quantify and 
track patient progress and treatment response over time. The self-report Patient Global 
Impressions-Change (PGI-C) Scale is used for the patient to quantify and track patient 
progress and treatment response over time. 
 
8.2.6 
Electrocardiogram (ECG)  
The 12-lead ECG records the electrical activity of your heart at rest. It provides information 
about your heart rate and rhythm, and shows if there is enlargement of the heart due to high 
blood pressure (hypertension) or evidence of a previous heart attack (myocardial infarction). 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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8.2.7 
MRI  
For subjects who consent to an MRI scan, contraindications to having a brain MRI (e.g., 
pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign 
body; claustrophobia) need to be checked. The spinal and brain MRI scan will contain 
structural (anatomical, T1, T2) and functional (resting-state, brain only) MRI measurements. 
Subjects will lie on a kind of couch, which slides for the measurements into the MR scanner. 
Subjects are asked to move as little as possible and will receive headphones and earplugs to 
protect the ears from the MR noise. The whole procedure takes about 45 minutes. 
 
8.2.8 
AEs  
AEs may be volunteered spontaneously by the patient, or discovered as a result of general 
non-directed questioning by the study personnel or by physical examination. All AEs will be 
followed until the event resolves or stabilizes at a level acceptable to the investigator. 
For further detailed description see section 10.  

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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9 Safety Data Collection, Recording and Reporting 
Safety assessments will consist of monitoring and recording all adverse events and serious 
adverse events, the regular monitoring of haematology, blood chemistry and urine values, 
regular measurement of vital signs and the performance of physical examinations. 
The investigator will be provided with AE and SAE reporting forms by CTC-A, receive training 
for AE/SAE definition, documentation and reporting. AE and SAE documentation and reporting 
will be monitored on site.  
9.1 Definition of Adverse Events (AEs) 
An adverse event (AE) is defined in the International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) as “any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.” (ICH E6:1.2) 
9.1.1 
Instructions for completing adverse event case report forms 
Each adverse event is to be reported on an Adverse Event Case Report Form. As far as 
possible, each adverse event must also be described by: 
 
1. its duration (start and end dates), 
 
2. its severity grade (mild, moderate, severe) 
 
3. its relationship to the study drug (suspected / not suspected) 
 
4. treatment required and action taken with trial drug 
 
5. outcome 
 
6. seriousness 
 
Examples of the severity grade, relationship to study treatment and actions taken, as 
presented in the case report form, are provided below. 
The severity grade of an adverse event provides a qualitative assessment of the extent or 
intensity of an adverse event, as determined by the investigator or as reported by the subject. 
The severity grade does not reflect the clinical seriousness of the event, only the degree 
or extent of the affliction or occurrence (e.g. severe nausea = nausea including vomiting, 
mild seizure), and does not reflect the relationship to study drug. 
 
 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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Severity grade for an adverse event 
The intensity of the AE should be judged based on the following 
 
1 = Mild 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
2 = Moderate 
Enough discomfort to cause interference with usual activity  
3 = Severe 
Incapacitating or causing inability to work or to perform usual activities  
 
Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship must be recorded for each adverse event. 
 
Causality will be reported as either “Yes” or “No”. 
 
 
Yes: 
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No: 
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Examples for clinically notable laboratory abnormalities 
Blood glucose:  
fasting glucose > 240 mg/dl or randomly determined glucose level of 
> 400 mg/dl and confirmed by a second measurement  
(not the same day). 
Liver parameters:  serum AST, ALT, y-GT, AP and bilirubin, please see page 35 
Renal parameters:  change of estimated GFR (abbreviated MDRD formula) < 7 0% , serum 
potassium above normal range 
Hematological 
Abnormal blood cell counts 
parameters:  
 
9.2 Definition of Serious Adverse Events (SAEs) 
A serious adverse event (SAE) is defined as an adverse event that 
 
results in death (fatal); 
 
is immediately life-threatening; 
 
results in persistent or significant disability/incapacity; 
 
requires or prolongs patient hospitalization;  
 
is a congenital anomaly/birth defect;  

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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or 
 
based upon appropriate medical judgment, may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the afore listed outcomes from 
occurring (e.g. intensive treatment in an emergency room without hospitalization).  
 
A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a health care facility. Any adverse 
event that does not meet one of the definitions of serious (eg, emergency room visit, outpatient 
surgery, or requires urgent investigation) may be considered by the investigator to meet the 
“other significant medical hazard” criterion for classification as a serious adverse event.  
An event does not need to be reported as a SAE if it represents only a relapse or an expected 
change or progression of the condition that was the cause of treatment without any other 
symptoms and signs than those present before treatment. This type of event needs only to be 
reported as an AE. 
9.3 Reporting Procedures of SAEs  
All serious adverse events (SAEs) will be reported by the principle investigator to the sponsor 
(CTC-A) within 24 hours of discovery or notification of the event. The sponsor will forward all 
SAE reports to the BfArM within 24 hours after receipt.  
More information on filling in the SAE form is provided in the “General Instructions for 
Completion of SAE Form” you find in the investigator site file. 
9.4 Pregnancy 
If a subject becomes pregnant or fathers a child during the study or within one month after 
treatment, the investigator should report to the sponsor within 1 working day and use the 
provided pregnancy notification form. The sponsor will inform BfArM and provide respective 
initial and follow-up information in cooperation with the investigator. 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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10 Adjustment of Study Medication and Study Termination 
Adjustment of Study Medication 
 
The main well-known adverse event when taking nicotinamide is nausea. This can be 
treated with usage of antinausea drugs and/ or dose reduction. If nausea or vomiting 
occurs it is at the discretion of the investigator and/or a medical team member to flexible 
reduce the dosing and then reach the highest possible dose. Domperidone as first 
choice medication (1-3 x 10 mg/day) and/or metoclopramide as second choice (1-3 x 
10 mg/day) may be used individually as rescue treatments. 
 
Mild to moderate increases in abnormal results from liver function tests. Study 
medication should be reduced and liver function controlled, until normal levels are 
reached.  
 
The dose should be 4g/d p.o.. If side effects or any other situation requires a dose 
reduction, this will be allowed up to the smallest unit of 2 g/d p.o..  
 
Study medication will be stopped immediately in patients with severe nausea including 
vomiting and/or severe increased liver enzymes (Grade 3, see chapter 7.2.1). If this 
occurs during phase A, we will wait for clinical recovery and normalization of liver 
function tests (serum AST, ALT, y-GT, AP and bilirubin), and ask the patient for a 
second attempt to take the study medication. This requires a new begin of phase A with 
the above mentioned titration procedure. If this occurs in phase B, the participant needs 
to drop out of the study.   
 
Termination 
The study will be prematurely terminated for an individual subject, if one of the following criteria 
is fulfilled: 
 
The subject experiences severe and nausea including vomiting, that cannot be 
sufficiently treated with antinausea drugs (prokinetica such as metoclopramide and 
domperidone) and/ or dose reduction. 
 
Severe increases in abnormal results from liver function tests (serum AST, ALT, y-GT, 
AP and bilirubin Grade 3, see chapter 7.2.1). 
 
Severe progression and/or unstable cardiac situation (cardiomyopathy, unstable 
arrhythmias). 
 
The subject experiences an AE that does not resolve or requires continued treatment 
that meets exclusion criteria. 
 
Pregnancy (to be reported to Sponsor on Pregnancy Notification Form) 
 
Non-compliance. 
 
Subject withdraws informed consent. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 46 of 63 
 
 
Severe and unforeseen administrative problems that impact the study design and 
procedures. 
 
Occurrence of a contraindication or a serious adverse reaction of the study medication, 
e.g. severe infection. 
 
Appearance of an illness that interferes with study assessments. 
 
Death of patient. 
 
Subjects may exit the study at any time and for any reason.  
 
The investigator can temporarily or permanently withdraw a subject from the study for 
any safety reason or if it is in the subject's best interests. 
 
Subject lost to follow-up: the subject cannot be located. The investigator must make 
every effort to reconnect with the subject (and record his attempts in the source file), at 
least to determine whether the subject is alive or dead. 
 
If a subject exits the trial prematurely or withdraws consent, any data collected prior to 
the date of premature exit may still be used. 
Reason, time point, and specific reason for premature study termination of each subject will 
be documented. The investigator should determine a primary reason for premature study 
termination of each subject. All relevant safety data until subject’s study termination will be 
collected and reported. 
 
This study may be prematurely terminated if there is sufficient reasonable cause related to the 
benefit risk assessment of participating in the study or for regulatory or medical reasons. 
Reasons for terminating the study may include, but are not limited to, the following: 
 
Determination of unexpected, significant, or unacceptable risk to participants 
 
The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients 
 
Recommendation of DMC for safety issue 
 
Determination of futility (endpoint cannot be reached given the trial design and number 
of enrolled participants) 
 
Non-compliance with the International Council for Harmonization (ICH) guideline for 
Good Clinical Practice and the Declaration of Helsinki  
 
Insufficient compliance to protocol requirements 
The study will entirely be terminated in case the risk-benefit-ratio changes in such way, that 
premature study termination is indicated in order to protect subject’s health. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
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If the study is prematurely terminated, the sponsor will notify the principal investigator, the 
involved ethics committees as well as the competent authorities (BfArM) and will provide the 
reason(s) for the termination. 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
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11 Statistics 
11.1  Statistical analysis 
Analysis will be performed within the Full Analysis Set (FAS), which is the set of subjects who 
have been randomized and have taken at least one dose of the trial medication. No other 
exclusion is eligible. 95% confidence intervals based on the contrast of the treatment 
progression derived from the above mentions linear mixed effects model will be used taking 
into account the sequential nature of the trial, i.e. a linear mixed effects model (LMEM) with 
the fixed effects of treatment, treatment-by-time interaction, center, SARA baseline score and 
age as well as the random intercept and time. Similar models will be used to test the treatment 
effects for FARS, SCAFI, CCFS, EQ-5D and ADL. 
Details of the statistical analysis (in particular for the secondary endpoints), including statistical 
design aspects, primary hypotheses, statistical model, risk of error probabilities, definition of 
analysis set, statistical software and reporting (e.g. MOC tables and graphs) will be included 
the trial statistical analysis plan (TSAP). Connected to this document is the data management 
and validation plan (DMVP).   
By slope (progression) analysis we assume a progression of 1.18/year increase in control 
patients with a SARA score between 8 and 28 at baseline. We estimate a reduction of this 
progression by 50% i.e. 0.59/year in the treatment group, giving a mean difference after 2 
years of 1.19. A SARA score of 1 has been used in former studies as a meaningful difference 
between placebo and vehicle treatment (Romano et al., 2015).  
Within the range of observed SARA measurements, it has been shown, that SARA progression 
is perfectly linear over time (Reetz et al., 2015; Reetz et al., 2016). Due to the specific type of 
disease and health care a strong physician-patient-relationship ensures a low withdrawal rate. 
Thus, with respect to withdrawals and intercurrent events, we assume that our linear mixed 
effects model the bias, i.e. overestimation of the treatment effect is negligible. Taking into 
account the concept paper on an addendum to ICH E9, we will further model estimands by an 
advanced sensitivity analysis, i.e. fitting a MMRM model to the data (Mallinckrodt et al., 2001).  
We not intend to perform futility stops, taken into account, that nicotinamide has no major side 
effects and that patient’s perspective is expressed by deriving a convincing level of evidence 
data from a convincing sized study. Due to potential biased effects and with regard to the 
above-mentioned uncertainty of the effect estimands, results in the suggestion to conduct the 
trial without interim analyses.  
11.2 Interim analyses 
No interim analysis will be applied. 
11.3 Data analyses 
Efficacy of nicotinamide versus placebo is tested by the linear contrast of the time by treatment 
interaction applied to the linear mixed effects model (LMEM, assumed variance – covariance 
error structure = unstructured) with treatment, treatment-by-time interaction, center, SARA 
baseline score and age as fixed effect and random intercept and time. Test of the primary 
hypothesis will be tested by the linear contrast on the treatment by time interaction at the 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
Page 49 of 63 
 
overall 5% significance level. Analysis will be performed within the Full Analysis Set (FAS), 
which is the set of subjects who have been randomized and have taken at least one dose of 
the trial medication. No other exclusion is eligible. 95% confidence intervals based on the 
contrast of the treatment progression will be used taking into account the sequential nature of 
the trial. Equal models will be used to test the treatment effects for INAS, SCAFI, CCFS, EQ5D 
and ADL. In a sensitivity analysis a mixed effects repeated measures model (MMRM) using 
the method described in Mallinckrodt (2001) with the fixed effects treatment, time and 
treatment by time interaction as well as the covariates baseline SARA score and the baseline-
by-visit interaction age of onset, age will be fitted to the data. 
11.4 Power calculation 
Within the EFACTS register (Reetz et al, 2015 and 2016), inclusion of patients with a SARA < 
28 and an age < 50 years the slope is 1.19 with a treatment effect after 2 years of 2.38. With 
an intended 2:1 allocation ratio, a sample size of 150 + 75 = 225 is required (90% power). An 
overall type one error rate by 5% (two-sided) is used to test the primary hypothesis at a power 
of 90%. A reduction of 0.5 is assumed for the treatment effect after 2 years.  
11.5 Bias protection 
To minimize selection bias and chronological bias the treatment allocation will use the 
appropriate randomization procedure and randomization is stratified by center. The selection 
of the randomization procedure will be based on an evaluation of the risks of bias prior to the 
generation of the randomization list. Details will be given in a randomization report by the 
Institute for Medical Statistics at the RWTH Aachen University, which will be kept concealed 
until closure of the database. Performance bias will be minimized by definition of the eligible 
co-treatments in the protocol and monitoring during the trial. Compliance will be documented 
in patient diaries and visits. Attrition bias will be reduced by strict follow-up of the patients, 
which are closely linked to the treating physician, as is usual for patients with rare diseases. 
Ascertainment and concealment bias will be kept as low as possible, by double-blinding, 
although the investigators are aware of the effect of unblinding due to observed side effects. 
With a sensitivity analysis, a statistical model including the selection bias and chronological 
bias effect will be fitted to the data. Details are given in the TSAP. 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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12 Ethical and Legal Aspects 
12.1 Independent Ethics Committees 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki. 
In accordance with the Declaration of Helsinki, the German Medicines Act (Deutsches 
Arzneimittelgesetz (AMG)) as well as the Good clinical practice (GCP)-guideline the study will 
be presented to the competent Ethics Committee for RWTH Aachen University and its 
endorsement will be obtained prior to inclusion of any subject into the study. 
In accordance with local legal requirements, study documents also have to be submitted to the 
respective regulatory authority(ies) for separate approval. 
Any change in the study protocol and/or informed consent form will be presented to the named 
Ethics Committee. They have to be approved by the Ethics Committee before implementation 
(except for changes in logistics and administration or when necessary to eliminate immediate 
hazards). 
12.2 Authorization of the Competent Authority 
The sponsor will request approval from the respective competent authority (Federal Institute 
for Drugs and Medical Devices (BfArM), Germany). The trial will only start after the competent 
authority has approved it. The sponsor will provide copies of the approval documentation to 
the principle investigator for his files. Any change in the study protocol will be presented to the 
named Competent Authority. They have to be approved by the Competent Authority before 
implementation (except for changes in logistics and administration or when necessary to 
eliminate immediate hazards). 
12.3 Notification Requirements 
The notification of the clinical trial according to § 67 German Medical Act to the local 
supervising authority before trial start and in case of any amendments as well as after the end 
of the study will with consent of investigator be performed by the sponsor according to SOP. 
The sponsor will provide a copy of the notification to the principle investigator for his files.  
12.4 Informed Consent 
According to AMG and GCP-guideline, informed consent must be obtained from subjects prior 
to participation in the trial.  
The subjects will voluntarily confirm their willingness to participate in the trial, after having been 
informed by a physician in writing and verbally of all aspects of the trial that are relevant to the 
subject's decision to participate. They will be informed about requirements concerning data 
protection and have to agree to the direct access to their individual data. 
The subjects will sign an informed consent form for study participation as well as disclosure of 
individual data.  
The informed consent form has to be signed and personally dated by the subject and one of 
the sub-investigators. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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Before informed consent is obtained, the investigator has to provide the subject ample time 
and opportunity to inquire about details of the trial and to decide whether or not to participate 
in the trial. All questions about the trial have to be answered to the satisfaction of the subject. 
Copies of the informed consent forms will be given to the volunteers. The subject information 
and informed consent form will be prepared and informed consent will be obtained from the 
subject according to sponsors SOPs.  
The subject will be informed by a physician in a timely manner if new information becomes 
available that may be relevant to the subject's willingness to continue participation in the trial. 
The communication of this information will be documented. The subject will receive a copy of 
any amendments to the written information and a copy of the signed and dated consent form 
updates. 
Subjects will be informed that they are free to withdraw from the study at any time at their own 
discretion without necessarily giving reasons. 
The participation in the clinical trial must be documented on the patient’s health records. 
12.4.1 Subject card 
A subject card will be given to the subjects who will be instructed to keep it in their possession 
at all times. The subject card will contain the following printed information: 
 
The name, address and telephone number of the investigator or institution, as the 
main contact for product information. 
 
The name, address, and telephone number of the sponsor 
 
A 24-hour hotline number for emergencies. 
12.4.2 Post-study treatment 
No specific post-study arrangements are made and no specific post-study care will be 
performed after this study. All subjects will return to their standard medical care after the study, 
as needed. This also applies to subjects who withdraw their consent during the course of the 
study. 
12.4.3 Subject privacy 
Patients will be informed about data protection and that data will be pseudonymized and 
handed to third party anonymized. Access to encoded data or source documents will only be 
given to authorized bodies or persons (sponsor, authorized staff, auditors, competent 
authorities or ethics commission) for validation of data. Also in case of publication 
confidentiality of collected data will be warranted.  
12.4.4 Contact point 
All subjects will be provided in the informed consent form with a contact address where they 
may obtain further information regarding clinical studies. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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12.5 Duties of the Investigator 
The responsibilities of investigator are stated in a separate agreement, which will be prepared 
by the sponsor, CTC-A; according SOP CTC01 and will be signed by all parties. 
12.6 Delegation of Investigator’s Duties 
The investigator will ensure, that all assisting study personnel will be adequately qualified and 
informed about the study protocol, any amendments, the study medication and their study 
related responsibilities and functions. 
The investigator will maintain a study staff authorization log according to the coordination to 
SOP, on which all persons he delegated which responsibilities to are listed.   
12.7 Protocol Changes 
The authorization of relevant competent authority and approval of the ethics committee for any 
amendments, which will become necessary during the study, will be applied by the sponsor, 
CTC-A, according to SOPs. 
Reportable amendments are changes which may affect following aspects: 
 
Safety of subjects 
 
Integrity and credibility of data 
 
Protocol amendment 
 
Changes in risk evaluation of drugs consisting/ including genetically modified 
organisms 
Every amendment of the protocol has to be signed by the coordinating investigator, the 
sponsor and the biostatistician. 
12.8 Data Protection 
All subjects will be identified by a unique randomization number. Each investigator holds a 
subject identification list according to the Sponsors SOP which will allow the identification of 
the subjects by holding information about the subject’s personal data and randomization 
number. This list will be safely filed by the investigator in the investigator’s file and a 
room/locker with limited access. 
The subject’s informed consent, which bears subject’s printed name and signature will 
accordingly filed separately in the investigators file.  
Monitors, auditors or the competent ethics committee will have access to personal data, but 
under no circumstances may copy the subject identification list or an informed consent. 
Where required, personal data, and health data in particular, may be: 
 
hold for inspection by the competent ethics committee for monitoring the orderly 
performance of the study, 
 
to be passed on to the investigators or an authorized party for analysis in an 
pseudonymized manner.  
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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13 Data Quality Assurance 
Inspections by regulatory authority representatives and IECs/IRBs are possible at any time, 
even after the end of study. The investigator is to notify the sponsor immediately of any such 
inspection. The investigator and institution will permit study-related monitoring, audits, reviews 
by the IEC/IRB and/or regulatory authorities, and will allow direct access to source data and 
source documents for such monitoring, audits, and reviews. 
13.1 Quality control 
Standardization procedures will be implemented to ensure accurate, consistent, complete, and 
reliable data, including methods to ensure standardization among sites (e.g., training, 
newsletters, investigator meetings, monitoring, central laboratories, centralized evaluations, 
and validation methods). 
The monitors will be trained during a monitoring kick-off meeting. To prepare the investigators 
and to standardize performance a training will be held during an investigators’ meeting before 
study start. 
This study will be monitored regularly by a qualified monitor from the CTC-A according to GCP 
guidelines and the respective SOPs (see Section Monitoring). 
13.2 Source documentation requirements 
All data collected from a subject during the course of a clinical study should be entered and/or 
filed in the respective subject file. This includes a copy of the letter sent to the subject’s primary 
physician about the subject’s participation in the study (provided the subject has a primary 
physician and has agreed to the primary physician being informed). 
The subject file must also contain a descriptive statement on the informed consent procedure 
(see Section “Informed consent”). 
All entries have to be entered first in the subject file (CRF-Case Report Forms). The subject’s 
participation in this study must be appropriately documented in the subject file with study 
number, subject number, date of subject information, date of informed consent, date of each 
visit, and date of each telephone contact. 
If a study site is using an electronic system for documenting source data, a member of the site 
staff must print out the source data after each visit. The paper print-outs must be overlapping, 
if possible (i.e., must contain at least the last row of data from the subject’s previous visit). If it 
is not possible to obtain overlapping paper print-outs, the completeness of source data must 
be ensured by other suitable means. The print-out must be signed and dated by a member of 
the site staff who can confirm the accuracy and completeness of data in the paper print-out. 
The monitor should also sign and date after verifying the source data. The paper print-out 
should be stored in the ISF. If source data information is entered retrospectively, this must be 
done directly on the paper print-out and should be initiated and dated. The same applies to 
any corrections of initial data. 
If the site is using a validated computer system including audit trail with a separate access for 
the monitor (i.e., the monitor can only access the data of the study subjects), then no such 
paper print-outs are required. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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If corrections are necessary, the subject should be instructed to make a correction by drawing 
only a single line through the error, leaving the incorrect entry legible. The subject should date 
the correction, but not initial it. The investigator should not make any changes to these 
documents. 
The sponsor’s data management function will be responsible for data processing, in 
accordance with the sponsor’s data management procedures. Database lock will occur only 
after quality assurance procedures have been completed. 
13.3 Data management 
All data to be collected will be entered on a case report form (CRF) and are to be considered 
source data. Automatic print outs as well as patient records and electronic patients are 
considered source data.  
Investigators will enter the information required by the protocol into an electronic data collection 
system via internet (eCRF). The eCRF will be developed by the data manager for the study. 
Detailed information on the eCRF completion will be provided during the site initiation visits. 
Each site will also be provided with an eCRF completion manual. In general, all persons who 
will enter data into the eCRF will be trained by an e-learning tool. After the successful 
completion of the training all participants will receive a training certificate. The access to the e-
learning tool and to the eCRF is password controlled. Plausibility checks will be performed 
according to a data validation plan. Inconsistencies in the data will be queried to the 
investigators via the electronic data collection system; answers to queries or changes of the 
data will directly be documented in the system. Laboratory and antibody test data will be 
received electronically. Plausibility checks will be performed to ensure correctness and 
completeness of these data. After all data are entered and all queries are solved, the database 
will be closed. 
13.4 Direct Access to Source Data 
The investigator is obliged to allow study specific monitoring, auditing, and inspections by the 
competent ethics committee, enable direct access at source data and source documents as 
well as support the respective person at his best knowledge.  
13.5 Monitoring 
This study will be monitored regularly by a qualified monitor chosen by the CTC-A according 
to GCP guidelines and the respective SOPs. Monitoring procedures include one or more visits 
designed to clarify all prerequisites before the study commences. Interim monitoring visits will 
take place on a regular basis according to a mutually agreed schedule. 
During these visits, the monitor will check for completion of the entries on the eCRF/CRF; for 
compliance with the clinical study protocol, ICH-GCP principles, the Declaration of Helsinki, 
and regulatory authority requirements; for the integrity of the source data with the eCRF/ CRF 
entries; and for subject eligibility. Monitoring also will be aimed at detecting any misconduct or 
fraud. In addition, the monitor will check whether all AEs and SAEs have been reported 
appropriately within the time periods required. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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The investigator and all staff will be expected to cooperate with the monitor by providing any 
missing information whenever possible. The investigator must be available to answer 
questions arising during regular monitoring visits. In addition, the investigator is required to: 
 
Have all data properly recorded in the eCRF and subject files prior to each monitoring 
visit. 
 
Have the source documentation available at the monitoring visits. 
 
Record all IP dispensed in the eCRF and the drug inventory records. 
All subjects who give their informed consent, including those screened, but not entered into 
the study, will be listed on the subject screening/enrolment log. Further details of monitoring 
activities will be set forth in the monitoring manual. 
13.6 Auditing 
Audits will be performed according to the corresponding audit program, including the possibility 
that a member of the sponsor’s quality assurance function may arrange to visit the investigator 
in order to audit the performance of the study at the study site, as well as all study documents 
originating there. Auditors conduct their work independently of the clinical study and its 
performance. 
Audits may also be performed by contract auditors. In this case, the sponsor’s quality 
assurance function will agree with the contract auditor regarding the timing and extent of the 
audit(s). In case of audits at the investigational site, the monitor will usually accompany the 
auditor(s). 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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14 Data Handling and Record Keeping 
14.1 Conclusion of Documentation 
By signing the CRF (eCRF/ eSignature), the investigator confirms that all investigations have 
been completed and conducted in compliance with the clinical study protocol, and that reliable 
and complete data have been entered into the eCRF. 
14.2 Corrections to data 
If corrections are necessary, the subject should be instructed to make a correction by drawing 
only a single line through the error, leaving the incorrect entry legible. The subject should date 
the correction, but not initial it. The investigator should not make any changes to these 
documents. 
The sponsor’s data management function will be responsible for data processing, in 
accordance with the sponsor’s data management procedures. Database lock will occur only 
after quality assurance procedures have been completed. 
14.3 Record keeping 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application (whether pending or contemplated) in an ICH region, or at least 2 years 
have elapsed since the formal discontinuation of IP clinical development. These documents 
should be retained for a longer period, however, if required by applicable regulatory 
requirements or by agreement with the sponsor. 
Essential documents at the investigational site include (among other documents): 
 
Subject files. 
 
Subject identification code list (i.e., provided by template to the investigator, along with 
the ISF, at the beginning of the study), which identifies the subject by number, name, 
and date of birth. 
 
A signed copy of the final clinical study protocol and any amendment. 
 
CD/DVD with eCRF data, and any associated subject-related source data (or, where 
applicable, authorized copies of source data). 
 
Signed informed consent forms. 
 
Copies of site investigators’ and co-workers’ curricula vitae. 
 
Copies of all direct correspondence with the IEC/IRB and with the regulatory 
authority(ies). 
 
Copies of laboratory normal ranges and methods. 
 
Copies of study supply receipt forms and drug inventory forms. 
 
Copies of all correspondence between the investigator and the monitor, and between 
the investigator and the sponsor. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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 
Copies of safety information reported during the study and submitted by the sponsor. 
14.4 Archiving of Documents 
The investigator will keep the subject’s files and original data as long as possible and according 
to the local methods and facilities. The investigator should maintain the trial documents as 
specified in the ICH-GCP-Guideline for at least 10 years. The investigator/institution should 
take measures to prevent accidental or premature destruction of these documents. 
14.5 Destruction of study documents 
Study documents may not be destroyed by study site personnel prior to the retention period 
specified above without the prior written consent of the sponsor. The principal investigator must 
inform the sponsor in due time if the principal investigator leaves the institution during the 
retention period. This rule also applies when the institution closes within the retention period. 
 
15 Oversight Committee 
15.1 Data Monitoring Committee 
The Data Monitoring Committee (DMC) will be formed of an independent group of experts that 
advises NICOFA and the study investigators. The members of the DMC serve in an individual 
capacity and provide their expertise and recommendations. The DMC will periodically review 
and evaluate the accumulated study data for participant safety, study conduct and progress, 
and, when appropriate, efficacy, and make recommendations to NICOFA concerning the 
continuation, modification, or termination of the trial. The DMC considers study-specific data 
as well as relevant background knowledge about the disease, test agent, or patient population 
under study (see DMC Charta). 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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16 Publication Policy 
The study results will be published in appropriate international scientific journals, and 
publishing details will be given in the clinical study agreement. The study will be registered and 
study results will be disclosed by the principal investigator in one or more public clinical study 
registry(ies), according to national/international use. The registration will include a list of the 
investigational sites. 
 
17 Finance and Insurance 
17.1 Financing 
This is an investigator-initiated study. The study is financed by the German Research 
Foundation (DFG). The financial aspects of this study are specified in separate agreements 
between the institution, the sponsor (CTC-A) and the investigator.  
17.2 Insurance 
From the beginning of the study until its termination, each subject is insured against any health 
impairment occurring as a result of participation in the study in accordance with the laws and 
regulations of the country in which the study is performed. 
The subject will be informed by the investigator and through the subject’s informed consent 
form about the existence of this insurance and the resulting obligations. The insurance 
conditions will be handed out to the subject, if requested or if required by local law. Any medical 
deviation from the clinical study protocol that is deemed to have occurred through the subject’s 
own fault is not covered by this insurance. 
The sponsor is usually not liable for injuries/cases of death that occur solely as a consequence 
of the subject’s underlying disease or condition, or from diagnostic or therapeutic measures 
not specifically required by the agreed clinical study protocol. The sponsor is also usually not 
liable for events resulting from negligence of the investigator, clinical study staff, and/or CRO, 
including failure to act according to ICH-GCP principles or to comply strictly with the agreed 
clinical study protocol. A patient's insurance in accordance with § 40 (1) and (3) No.8 AMG is 
submitted (the insurance policy number will be filed subsequently). 
In addition, a travel accident insurance is completed. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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18 Statement of compliance 
Investigational Site(s) 
I have thoroughly read and reviewed the clinical study protocol. Having understood the 
requirements and conditions of the clinical study protocol, I agree to perform the clinical study 
according to the clinical study protocol, the case report form, ICH-GCP principles (EU Directive 
2001/20/EG), the Declaration of Helsinki, and regulatory authority requirements (§40-42 AMG). 
I have received the current SmPC (instruction of use). Having been adequately informed about 
the IP development to date, I also agree to: 
 
Sign this clinical study protocol before the study formally starts. 
 
Wait until I have received approval from the appropriate IEC/IRB before enrolling any 
subject in this study. 
 
Obtain informed consent for all subjects prior to any study-related action performed. 
 
Start the study only after all legal requirements in my country have been fulfilled. 
 
Permit study-related monitoring, audits, IEC/IRB review, and regulatory inspections. 
 
Provide direct access to all study-related records, source documents, and subject files 
o for the monitor, auditor, IEC/IRB, or regulatory authority upon request. 
 
Use the IP and all study materials only as specified in the clinical study protocol. 
 
Report to the responsible drug safety officer, within 24 hours, any adverse event (AE) 
that is serious, whether considered treatment related or not. 
Furthermore, I understand that: 
 
Changes to the clinical study protocol must be made in the form of an amendment that 
has the prior written approval of RWTH University and – as applicable – of the 
appropriate IEC/IRB and regulatory authority. 
 
The content of the clinical study protocol is confidential and proprietary to RWTH 
University 
 
Any deviation from the clinical study protocol may lead to early termination of the study 
site. 
 
With my signature below, I also acknowledge receipt of the study protocol. 
  
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
PM12TL02_AMG_Protocol_V01_2017 
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19 Signatures 
The study protocol is accepted by 
The Sponsor’s Representative 
Dr. med. Susanne Isfort 
Managing Director CTC-A 
RWTH Aachen University Hospital 
Aachen, 05. December 2018 
 
 
The Biostatistician 
Prof. Dr. Ralf-Dieter Hilgers 
Chair of Department of Medical 
Statistics 
RWTH Aachen University Hospital 
Aachen, 05. December 2018 
 
 
Principal Sponsor- Investigator  
Univ.-Prof. Dr. med. Jörg Schulz 
Head of Department of Neurology, 
RWTH Aachen University Hospital 
Aachen, 06. December 2018 
 
 
Co-Investigator 
Univ.-Prof. Dr. med. Kathrin 
Reetz 
Associate Professor of Neurology 
Department of Neurology 
RWTH Aachen University Hospital 
Aachen, 06. December 2018 
 
 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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20 References 
 
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 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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choroid plexus in vitro. J Neurochem. 33, 291-8. 

 Protocol AMG 
-NICOFA- 
CTC-A-No.: 15-138 
 
 
V03.4, 05.12.2018 
Principal Investigator 
Site 
EudraCT- No.: 
Univ.-Prof. Dr. med. Jörg Schulz 
      Department of Neurology – University Hospital Aachen 
2017-002163-17 
 
 
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Subramony, S.H., et al., 2005. Measuring Friedreich ataxia: Interrater reliability of a neurologic 
rating scale. Neurology. 64, 1261-2. 
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diabetes. Lancet. 1, 619-20. 
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