Randomized, Double-blind, Placebo Controlled, Parallel, Multicentric, Phase IIa Clinical Trial to Evaluate Safety, Tolerability, Therapeutic Efficacy of Daily Oral Treatment NFX88 on Neuropathic Pain in Patients With Spinal Cord Injury
Phase: PHASE2
Conditions: Neuropathic Pain, Spinal Cord Injuries
Sponsor: Neurofix S.L.

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STUDY CODE:  NFX88-2A-2018 
EudraCT Nº:  
2018-004792-13 
 
 
 
Protocol Version:  Version 1  
 
Protocol Date: 
 28sth of December 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
The information contained in this document is confidential. It is to be used by investigators, potential 
investigators, consultants or applicable independent ethics committees. It is understood that this 
information will not be disclosed to others without written authorization from Neurofix S.L., except 
where required by applicable local laws. 

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FACILITIES 
 
SPONSOR:  
  
 
 
 
Miguel Ángel Ávila  
Neurofix S.L. 
Chief Executive Officer 
Parque Científico Universidad de Salamanca (USAL). M2 
Despacho Neurofix, Villamayor. 
37185. Salamanca, Spain. 
Phone: (+34) 619202098 
E-mail: miguelangel.avila@neurofixpharma.com 
SCIENTIFIC EVALUATION: 
Pablo V. Escribá 
Neurofix S.L. 
Chief Scientific Officer 
Parque Científico Universidad de Salamanca (USAL). M2 
Despacho Neurofix, Villamayor. 
37185. Salamanca, Spain. 
Phone: (+34) 656186154 
E-mail: pablo.escriba@neurofixpharma.com 
STUDY MEDICAL 
COORDINATION:  
 
Antonio Oliviero 
Hospital Nacional de Parapléjicos de Toledo 
Neurólogo y Jefe de Grupo de Investigación 
Finca de la Peraleda, S/N. 
45071.  Toledo, Spain. 
Phone: (+34) 646330976/693800575 
E-mail: antonio.oliviero@hotmail.com 
PHARMACOVIGILANCE/SERIOUS 
ADVERSE EVENT REPORTING: 
 
 
Laura Florez / Mª Eugenia Díaz 
Qualified Person of Pharmacovigilance (QPPV) / Deputy 
QPPVQualitecFarma® 
C/del Musgo 2, Edificio Europa II, 2ª planta, oficina H.  
28023. Madrid, Spain. 
Phone: (+34) 913728399/400 
E-mail: drug.safety@qualitecfarma.com 
DRUG MANAGEMENT: 
           
Itziar Echevarría López  
Qualified Person Laboratorium Sanitatis s.l. 
C/ Leonardo da Vinci, 11. Parque Tecnológico de Álava, 
Miñano. 
01510. Álava, España 
Telephone number: +34 902 760 000 / +34 664 039 107 
E-mail: itziare@labsan.es 

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STATISTICAL/RANDOMISATION 
AND DATA MANAGEMENT 
FACILITY: 
Ángel Pueyo 
Director 
Cátedra de Investigación, Desarrollo e Innovación 
Biomédica 
Universidad Católica San Antonio de Murcia (UCAM). 
Campus de los Jerónimos, Nº 135, Guadalupe.  
30107. Murcia, Spain. 
Phone: (+ 34) 649862053 
E-mail: pueyo.angel@investiganet.es 
CONTRACT RESEARCH 
ORGANIZATION (CRO) 
Óscar Mesa del Castillo 
General Manager 
QualitecFarma®  
Calle del Musgo 2, Edificio Europa II, 2ª planta, oficina H.  
28023. Madrid, Spain. 
Phone: (+34) 913728399/400 
E-mail: clinical.trials@qualitecfarma.com 

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SPONSOR’S AGREEMENT WITH PROTOCOL 
 
Study code: NFX88-2A-2018 
 
Protocol title: 
A randomized, double-blind, placebo controlled, parallel 
group, multicentric, phase IIa clinical trial to evaluate the 
safety, tolerability and therapeutic efficacy of daily oral 
treatment with NFX88 on neuropathic pain in patients 
with spinal cord injury. 
Version: 
1, dated 28-Dec-2018 
 
 
I have carefully read, reviewed and approve this protocol. My signature, in conjunction with 
the signature of the investigator, confirms the agreement of both parties that the clinical study 
will be conducted in accordance with the protocol and all applicable laws and regulations 
including, such as, among others, the International Conference on Harmonisation Guideline 
for GCP and the ethical principles that have their origins in the Declaration of Helsinki and 
agrees in writing to the strict observance of the Law on the Protection of personal data. 
 
 
 
 
 
 
Signature 
 
Date (DD/MMM/YYYY) 
Miguel Ángel Ávila  
Neurofix S.L. 
Chief Executive Officer 
 
 
 
01/02/2019

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INVESTIGATOR’S AGREEMENT WITH PROTOCOL  
 
Study code: 
 
NFX88-2A-2018 
Protocol title: 
A randomized, double-blind, placebo controlled, 
parallel group, multicentric, phase IIa clinical trial 
to evaluate the safety, tolerability and therapeutic 
efficacy of daily oral treatment with NFX88 on 
neuropathic pain in patients with spinal cord injury. 
Version: 
1, dated 28-Dec-2018 
 
I have carefully read and reviewed the study protocol. After reading and understanding the 
requirements and conditions of the study protocol, I agree to conduct the clinical study 
according to the international GCP principles, the requirements of the regulatory authorities 
for verification of source documents and study audit/inspection and the ethical principles that 
have their origins in the Declaration of Helsinki and agrees in writing to the strict observance 
of the Law on the Protection of personal data.  
 
I agree to use the study material and to follow the described procedures only as specified in 
the protocol. 
 
My signature, in conjunction with the signature of the sponsor, confirms the agreement of both 
parties. 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
Date (DD/MMM/YYYY) 
Dr.:  
Principal Investigator 
Site:  
 
 

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TABLE OF CONTENTS 
FACILITIES 
2 
SPONSOR’S AGREEMENT WITH PROTOCOL 
4 
STUDY MEDICAL COORDINATOR AGREEMENT WITH PROTOCOL 
5 
INVESTIGATOR’S AGREEMENT WITH PROTOCOL 
6 
TABLE OF CONTENTS 
7 
LIST OF ABBREVIATIONS 
11 
PROTOCOL SYNOPSIS 
14 
1. BACKGROUND 
19 
1.1 
Relevant preclinical results ................................................................................................ 20 
1.1.1 
2OHOA .............................................................................................................. 20 
1.1.2 
Experimental animal models of SCI .................................................................. 22 
1.1.3 
Summary of toxicological data .......................................................................... 22 
1.1.4 
Acute Toxicity ................................................................................................... 23 
1.1.5 
Repeat-Dose Toxicity Studies ............................................................................ 24 
1.2 
Overview of Clinical Studies ............................................................................................. 24 
1.3 
Evaluation of the patient with spinal cord injury ............................................................... 25 
2. STUDY RATIONALE 
26 
2.1 
Risk / Benefit Assessment .................................................................................................. 27 
2.2 
Dose Justification ............................................................................................................... 27 
3. STUDY OBJECTIVES 
28 
3.1 
Primary Objective .............................................................................................................. 28 
3.2 
Secondary Objective .......................................................................................................... 28 
4. STUDY DESIGN 
28 
4.1 
Study Overview .................................................................................................................. 28 
4.2 
Visit sequence: ................................................................................................................... 29 
4.3 
Screening/Baseline ............................................................................................................. 30 
4.4 
Randomisation.................................................................................................................... 30 
4.5 
Treatment Period ................................................................................................................ 30 
4.6 
Follow-Up / End of Study .................................................................................................. 30 
4.7 
Study Outcome ................................................................................................................... 31 
4.7.1 
Safety Endpoints ................................................................................................ 31 
4.7.2 
Efficacy Endpoints ............................................................................................. 31 
5. SELECTION OF STUDY POPULATION 
31 
5.1 
Study Population ................................................................................................................ 31 
5.2 
Sample Size and Power ...................................................................................................... 31 
5.3 
Inclusion Criteria ................................................................................................................ 32 
5.4 
Exclusion Criteria............................................................................................................... 32 
5.5 
Withdrawal Criteria ............................................................................................................ 33 
5.6 
Criteria for Removal of a Subject ...................................................................................... 33 

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5.7 
Replacement of Subjects .................................................................................................... 34 
6. STUDY TREATMENTS 
34 
6.1 
Identity of Experimental Drug ........................................................................................... 34 
6.1.1 
Chemical Name .................................................................................................. 34 
6.1.2 
Chemical Structure ............................................................................................ 34 
6.1.3 
Molecular Formula and Molecular Weight ........................................................ 34 
6.1.4 
Arms of Treatment and Regimens ..................................................................... 34 
6.1.5 
Qualitative and Quantitative Composition ......................................................... 35 
6.2 
Comparator (Blinded) ........................................................................................................ 35 
6.3 
Method of Assigning Subjects to Treatment Groups ......................................................... 35 
6.4 
Blinding .............................................................................................................................. 36 
6.5 
Code breaks ........................................................................................................................ 36 
6.6 
Storage Conditions ............................................................................................................. 36 
6.7 
Receiving, Dispensing and Return of Investigational Products ......................................... 37 
6.8 
Packaging and Labelling .................................................................................................... 37 
6.9 
Concomitant Therapy ......................................................................................................... 38 
6.9.1 
Standard Therapy for Neuropathic Pain ............................................................ 38 
6.9.2 
Allowed/Additional Medications and Treatments ............................................. 38 
6.9.3 
Prohibited Medications and Treatments ............................................................ 38 
6.9.4 
Maintenance Medication .................................................................................... 38 
7. STUDY PROCEDURES AND GUIDELINES 
38 
7.1 
Clinical Assessments .......................................................................................................... 38 
7.1.1 
Concomitant Medications .................................................................................. 38 
7.1.2 
Demographics .................................................................................................... 38 
7.1.3 
Medical History ................................................................................................. 39 
7.1.4 
Neurological Examination ................................................................................. 39 
7.1.5 
Vital Signs.......................................................................................................... 39 
7.1.6 
Adverse Events .................................................................................................. 39 
7.2 
Clinical Laboratory Measurements .................................................................................... 39 
7.2.1 
Haematology ...................................................................................................... 39 
7.2.2 
Clinical Chemistry ............................................................................................. 39 
7.2.3 
Urinalysis ........................................................................................................... 40 
Urine will be obtained for determination of colour, appearance, specific gravity, pH, 
leukocyte, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, creatinine. ... 40 
7.2.4 
Pregnancy Test ................................................................................................... 40 
7.3 
Other tests .......................................................................................................................... 40 
7.3.1 
12-lead ECG ...................................................................................................... 40 
7.4 
Drug Administration Procedure ......................................................................................... 40 
7.5 
Other Safety Measurements ............................................................................................... 40 
7.6 
Efficacy Measurements ...................................................................................................... 41 
7.7 
Mobile Application ............................................................................................................ 41 

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8. EVALUATIONS PER VISIT 
42 
8.1 
Screening Visit (SV): 7 days to V1 .................................................................................... 42 
8.2 
Treatment period ................................................................................................................ 42 
8.2.1 
Visit 1 (V1): Day 1 (±3 days), Randomisation day and start of treatment ........ 42 
8.2.2 
Visit 2 (V2): Day 30 (±3 days) .......................................................................... 43 
8.2.3 
Visit 3 (V3): Day 60 (±3 days) .......................................................................... 43 
8.2.4 
Visit 4 (EoT): Day 90 (±3 days), end of treatment ............................................ 44 
8.3 
Post Treatment Period ........................................................................................................ 44 
8.3.1 
Visit 5 (EoS/FU): Day 120 (±3 days), end of study or follow up visit .............. 44 
8.3.2 
Withdrawal Visit (see reasons for withdrawal in section 5) .............................. 45 
9. SAFETY ASSESMENT 
45 
9.1 
Safety Parameters ............................................................................................................... 45 
9.1.1 
Definition of adverse events .............................................................................. 45 
9.1.2 
Laboratory test abnormalities ............................................................................ 46 
9.1.3 
Definition of serious adverse events .................................................................. 47 
9.1.4 
Definition of adverse events of special interest (AESI) ..................................... 47 
9.2 
Assessment of safety parameters........................................................................................ 47 
9.2.1 
Assessment of severity ....................................................................................... 47 
9.2.2 
Assessment of relationship ................................................................................ 48 
9.3 
Documentation and Reporting of Adverse Events ............................................................. 48 
9.4 
Serious Adverse Event Reporting Requirements and Documentation ............................... 49 
9.4.1 
Reporting of deaths ............................................................................................ 50 
9.4.2 
Other Events Requiring Reporting ..................................................................... 51 
9.5 
Study Recording Period and Follow-Up for AEs and SAEs .............................................. 51 
9.5.1 
Follow-up of unresolved adverse events ............................................................ 52 
10. STATISTICAL METHODS 
52 
10.1 Variable examination and baseline comparisons. .............................................................. 52 
10.2 Safety Assessment (Main Objective) ................................................................................. 52 
10.3 Efficacy Assessment (Secondary Objective) ..................................................................... 52 
11. REGULATORY REQUIREMENTS 
53 
11.1 Liabilities ........................................................................................................................... 53 
11.2 Statement of Investigator ................................................................................................... 53 
11.3 Delegation of Investigator Duties ...................................................................................... 53 
11.4 Institutional Review Board/Independent Ethics Committee (IRB/IEC) ............................ 54 
11.5 Case Report Form (CRF) ................................................................................................... 54 
11.6 Record Retention ................................................................................................................ 54 
11.7 Quality Assurance .............................................................................................................. 54 
11.8 Monitoring of The Study .................................................................................................... 54 
11.9 Data Management and Processing ..................................................................................... 55 
11.10 Premature Termination or Suspension of a Study .............................................................. 55 
11.11 Adherence to Protocol ........................................................................................................ 55 

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12. REFERENCES 
55 
ANNEX 1. ASIA-ISNSCI SCALE 
60 
ANNEX 2. MODIFIED ASHWORTH SCALE (MAS) 
62 
ANNEX 4. PAINDETECT SCALE 
64 
ANNEX 5. PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) SCALE 
66 

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LIST OF ABBREVIATIONS 
 
2OHOA  
2-Hydroxy-9-cis-Octadecenoic Acid, 2-hydroxyoleic acid 
AE 
Adverse Event 
AEMPS 
Agencia Española del Medicamento y Productos Sanitarios (Spanish 
Medicines Agency and Medical Devices)  
Ag/Ab 
Antigen/Antibody 
AIS 
ASIA Impairment Scale 
ALT/SGPT 
Alanine Aminotransferase  
APP 
Electronic Application 
ANOVA 
Analysis of Variance 
A-OA 
Albumin-Oleic Acid  
A-2OHOA 
Albumin-2-hydroxyoleic acid 
AIS 
Abbreviated Injury Scale 
ASIA 
American Spinal Injury Association 
AST/SGOT 
Aspartate Aminotransferase 
AUC 
Area Under the Curve  
BBB 
Blood Brain Barrier 
b.i.d./b.d. 
"bis in die" from Latin, means twice a day, twice daily 
ca. 
“circa” from Latin, means around, about, approximately 
CK 
Creatine Kinase 
Cmax 
Maximum plasma concentration 
CNS 
Central Nervous System 
CRO 
Contract Research Organization 
CRF/eCRF 
Case Report Form/electronic CRF 
CYP450 
Cytochrome P450 
DLT 
Dose Limiting Toxicity 
DM 
Data Manager 
DSUR 
Development Safety Update Report 
e.g. 
“exemplia gratia” from Latin, means for example, example given 
ECG 
Electrocardiogram 

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EoS 
End of Treatment 
EoT 
End of Study 
ESR 
Erythrocyte Sedimentation Rate  
FU 
Follow-up 
g 
Grams 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase  
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
h 
Hour 
Hb 
Hemoglobin 
HCG 
Human Chorionic Gonadotropin 
HDL 
High Density Lipoprotein 
hERG 
human Ether-à-go-go-Related Gene 
IASP 
International Association for the Study of Pain 
i.e. 
“id est” from Latin, means that is 
i.t. 
Intra thecal 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IMP 
Investigational Medicinal Product 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ISNCSCI 
International Standards for Neurological Classification of Spinal Cord 
Injury 
kg 
Kilogram 
L 
Litter 
MAS 
Modified Ashworth Scale 
MCV 
Mean Corpuscular Volume  
mg 
Milligram(s) 
min 
Minute 
mL 
Millilitres 
MLD 
Minimum Lethal Dose 

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MNLD 
Maximum Non-Lethal Dose 
MTD 
Maximum Tolerated Dose 
NOAEL 
No Observed Adverse Effect Level. 
OA 
Oleic acid  
PD 
Progressive disease 
PD-Q 
PainDETECT Questionnaire 
p.o. 
“per oral” from Latin, means oral route 
PGIC 
Patient’s Global Impression of Change 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SC 
Steering Committee 
SCI 
Spinal Cord Injury 
SF 
Screening Failure 
SOP 
Standard Operating Procedure 
TCA 
When Trichloroacetic Acid  
Tmax 
Time to reach peak plasma concentration 
t.i.d./t.d.s. 
"ter in die"/ “ter die sumendum” from Latin, means three times a day) 
VAS 
Visual Analogue Scale 
Verbatim 
"verba/uerba” from Latin, means using exactly the same words as 
were originally used.  
WV 
Withdrawal Visit 
 

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PROTOCOL SYNOPSIS 
 
Protocol code 
NFX88-2A-2018 
Protocol version 
Version 1, 28th December 2018 
Title 
A randomized, double-blind, placebo controlled, parallel group, 
multicentric, phase IIa clinical trial to evaluate the safety, 
tolerability and therapeutic efficacy of daily oral treatment with 
NFX88 on neuropathic pain in patients with spinal cord injury. 
EudraCT nº 
2018-004792-13 
Study code 
NFX88-2A-2018 
Sponsor 
NEUROFIX S.L. 
Contract Research 
Organization  
QualitecFarma®  
 
Clinical phase 
IIa (proof of concept) 
Study Design 
Multicentric, Randomized, Double Blind, Parallel Group (NFX88 
vs Placebo-Controlled) Clinical Trial.  
Study Type 
Interventional 
Anticipated start date Q2 2019 (Jun2019) 
Duration of Study 
Recruitment phase: ~6 months 
Completion of recruitment: Q3 2019 (Dec2019) 
End of the Study: Q2 2020 (Apr2020, 4 months after the last 
patient enrolled) 
Ethic Committee 
Comité de Ética de Investigación con medicamentos Regional 
(CEIm-R) de la Comunidad de Madrid  
Total number of Sites 
4 National sites have been pre-selected. 
Competitive recruitment. 
Study Population  
Spinal cord injury patients with neuropathic pain.  
Objectives  
Primary objective: 
The trial primary goal will be to evaluate the safety and 
tolerability of NFX88 in spinal cord injury patients with 
neuropathic pain over 90 days. 
Secondary objective: 
The trial will also explore the preliminary therapeutic efficacy 
associated with NFX88 through the analysis of validated 

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measurement scales (VAS, PD-Q, PGIC).  
Planned number of 
patients and  
Study Arms 
Total: up to 60 completed patients 
A. Experimental Arms 
1) 1.05 g/day NFX88: 15 patients. 
2) 2.10 g/day NFX88: 15 patients. 
3) 4.20 g/day NFX88: 15 patients. 
B. Control Arm  
1) Placebo: 15 patients. 
Inclusion criteria 
 
Patients eligible for enrolment in the study must meet all the 
following inclusion criteria: 
1. Able and willing to provide written informed consent. 
2. Male or Female 18 to 65 years of age. 
3. Traumatic complete or incomplete spinal cord injury with C4-
T12 level and more than three months since injury. 
4. Diagnosed of neuropathic pain with an average pain score ≥ 4 
measured using the VAS scale during the last week. 
5. Stable treatment, for at least 1 month, with pregabalin 150-300 
mg/day, that should be maintained at the same dose for 90 
days until the end of the study treatment. 
6. Normotensive patients defined as patients with blood pressure 
values between 90-160 for systolic pressure and 50-115 for 
diastolic pressure.  
7. Patients who have been treated with stable doses of 
neuroactive 
drugs 
(antidepressants, 
anticonvulsants, 
antispastic and similar medicines) at least during the last 
month can also be recruited. 
8. Availability for the entire study period, absence of intellectual 
problems likely to limit the validity of consent to participate in 
the study or the compliance with protocol requirements; 
willingness to adhere to the protocol requirements, ability to 
cooperate 
adequately, 
to 
understand 
and 
follow 
the 
instructions of the physician or designee. 
9. Women who are not postmenopausal (at least 12 months) or 
surgically sterile must have a negative pregnancy test at 
screening and at the end of study and either abstain from 
sexual intercourse or use a highly effective method of birth 
control for the duration of the study and after 12 weeks after 
the last dose of study drug.  

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10. For men: agreement to remain abstinent or use contraceptive 
measures and agreement to refrain from donating sperm for the 
duration of the study and after 12 weeks from the last dose of 
study drug. 
Exclusion criteria 
Patients meeting any of the following criteria must NOT be 
enrolled in the study: 
1. Patients treated with opiates (major and minor) and 
cannabinoids (synthetic, natural or analogous).  
2. Patients with blood pressure higher than those accepted in the 
inclusion criteria. 
3. History of alcohol, drug abuse within 6 months prior to 
screening. 
4. Psychiatric patients or those with moderate or severe cognitive 
impairment. 
5. Patient who is pregnant or lactating. 
6. Patient who shows evidence of significant liver or kidney 
disease, or any other conditions known to interfere with the 
absorption, distribution, metabolism or excretion of drugs or 
known to potentiate or predispose to undesired effects. 
7. Patient who has clinically significant diseases and/or infections 
captured in the medical history or evidence of clinically 
significant findings on physical examination and/or clinically 
significant ordinary laboratory evaluations (haematology, 
biochemistry, and urinalysis) or ECG. 
8. Patient who is currently participating in another clinical trial of 
an investigational drug or medical device within 90 days prior 
to screening. 
9. Inability to comply with study protocol. 
10. Patient unable to swallow tablets. 
11. History of cancer except local basal or squamous cell 
carcinoma of the skin that has been excised.  
Experimental drug 
NFX88  
Pharmaceutical Form: coated tablets  
Strength: 350 mg  
Control drug 
Placebo  
Pharmaceutical Form: coated tablets 
Strength: 0 mg  
 
 

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Dosing regimen and 
treatment 
Doses:  
A. Experimental Arms 
1) 1.05 g/day NFX88  
2) 2.10 g/day NFX88  
3) 4.20 g/day NFX88  
B. Control Arm  
4) 0.00 g/day Placebo coated tablets 
Frequency: 3 times a day (t.i.d.) 
Duration of the treatment: 90 days 
Total duration of the trial: 1-7 Screening days, 90 treatment 
days (approximately 3 months) and 30 Follow-up days 
Study assessments 
Assessment points: 
SV: Screening (-7days from V1), V1: randomisation (day 1 of 
treatment), V2: evaluation (30 +/- 3 days from V1), V3: 
evaluation (60 +/- 3 days from V1), EoT/WV: end of treatment 
(90 +/- 3 days from V1)/ withdrawal visit (any time), EoS/FU: 
end of study/follow-up (120 +/- 3 days from V1). 
Safety and tolerability: 
Safety and tolerability of NFX88 administered for 3 months will 
be assessed by the number, severity, and type of AE, including 
changes in:  
- 
Vital signs (Time Frame: VS, V1, V2, V3, EoT or WV and 
FU/EoS). 
- 
ECG (Time Frame: SV, V2, V3, EoT or WV and FU/EoS). 
- 
Clinical laboratory parameters (Time Frame: SV, V2, V3, 
EoT or WV and FU/EoS). 
- 
Effect of NFX88 on spasticity score as determined by MAS 
(Time Frame: SV, V1, V2, V3, EoT or WV and FU/EoS). 
- 
Effect of NFX88 on sensory and motor function by ASIA 
scale (Time Frame: SV, V1, V2, V3, EoT or WV and 
FU/EoS).  
Efficacy: 
Effect of NFX88 in changes of neuropathic pain reduction scales: 
- 
VAS (Time Frame: SV, V1, V2, V3, EoT or WV and 
FU/EoS). 
- 
PD-Q (Time Frame: SV, V1, V2, V3, EoT or WV and 

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FU/EoS). 
- 
PGIC (Time Frame: V3, EoT or WV) 
Randomisation 
procedure 
1: 1: 1: 1 
Primary parameters 
Safety and tolerability: the safety outcome measures for this 
study are: 
- 
Incidence of serious adverse events 
- 
Incidence of severe adverse events 
- 
Incidence of specific laboratory abnormalities 
- 
Incidence of relevant changes in vital signs 
- 
Incidence of relevant changes in 12-lead ECGs  
- 
No changes in MAS and AIS scales. 
Secondary 
parameters 
Efficacy:  
The efficacy outcome measure for this section is: 
- 
Improvement in neuropathic pain scales VAS, PD-Q, and 
PGIC. 
Planned analysis 
The planned analysis for the primary and secondary endpoints 
will be done when the last patient has completed treatment period. 
 

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1. BACKGROUND 
Spinal cord injury (SCI) is a condition usually resulting from accidental causes affecting 
conduction of sensory and motor signals across the site(s) of lesion(s), as well as the 
autonomic nervous system. According to location and severity of damage along the spinal 
cord, the symptoms can vary widely, from pain or numbness to paralysis to incontinence. SCI 
worldwide incidence ranges from 3.6 to 195 cases per million inhabitants, depending on the 
geographic area of study. The prevalence of SCI in the European Union is around 2-3 cases 
per 10,000 inhabitants, showing also geographic differences (Singh et al., 2014). Based on 
neurological levels, different studies showed that ca. 30% patients are tetraplegic, ca. 55% are 
paraplegic and about 15% have Conus-Cauda Equina injury. According to the severity of the 
lesion, ca. 70% of SCI patients have complete lesions and about 30% have incomplete lesions 
(Afsar et al, 2014). Up to 70 % of patients with spinal cord injuries develop disordered 
sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent 
or sustained involuntary activation of muscles (spasticity) (Rekand T et al, 2012a) and over 
80% patients reported the presence of pain: musculoskeletal pain (59%), at-level neuropathic 
pain (41%), below-level neuropathic (34%) and visceral pain (5%) (Siddall PJ et al, 2003).  
Although, neuropathic pain prevalence rates ranged from 26% to 96%, with a fairly even 
spread between these extremes (2009 Dijkers M et al, 2009; Rekand T et al, 2012b).  
Neuropathic pain is defined as proposed by the International Association for the Study of Pain 
(IASP) as “pain initiated or caused by a primary lesion or dysfunction of the nervous system” 
(Merskey H & Bogduk N, 1994). In general, patients indicate that the worst life-quality 
worsening symptom is neuropathic pain (Hagen EM & Rekand T, 2015). It begins within the 
first few months of injury, and is usually progressive for about 3-5 years, before reaching a 
plateau and may persist for many years after the acute injury (Calmels P et al, 2009). The pain 
is usually severe in nature (VAS ≥7), and complicates treatments, impacts sleep, and mood. 
This neuropathic pain resulting in a substantial negative impact on patient function and quality 
of life (Baastrup C & Finnerup NB, 2008).  
Post SCI pain may be very broadly attributable to increased neuronal excitability. This 
increased excitability may be due to either an enhancement of excitatory mechanisms or a loss 
or reduction in inhibition. A number of molecular changes will occur after SCI including 
changes in sodium ion channels, voltage-gated calcium channels, glutamate and gamma-
aminobutyric acid (GABA) metabolism, serotonergic, noradrenergic, N-methyl-D-aspartate 
(NMDA) and opioid receptors. Drugs such as antiepileptics, tricyclic antidepressants and 
opioids have an effect on these changes. However, oral pharmaceutical intervention is often 
inadequate, commonly resulting in a reduction of only 20-30% in pain intensity (Baastrup C & 
Finnerup NB, 2008) and the side effects can be quite significant (Afsar et al, 2014; Teasell 
RW et all, 2010). 
The most commonly recommended oral pharmacological agents for chronic pain fall into 3 
major categories: antidepressants, anticonvulsants, and analgesics. Pregabalin (Lyrica®) is 
recommended as the first choice of first-line medications and Gabapentin (Fanatrex®, 
Gabapin®, Gabrion®, etc.) is recommended as the next choice when pregabalin is not an 
option or has been proven ineffective (Guy SD et al, 2016). However, in many instances other 
drugs are concomitantly prescribed in combination treatments that may have a negative impact 
on patient´s hepatic health status. Treatment of topical agents such as capsaicin or lidocaine as 

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well as with intradermal Botulinum toxin injections may be useful approaches but need to be 
studied on populations with SCI. Further studies are needed for evaluation of efficacy of those 
measures on pain after SCI (Hagen EM & Rekand T, 2015). 
Considering that (i) neuropathic pain affects more than 50% of individuals with SCI, (ii) being 
considered sometimes the mayor problem following SCI, (iii) that current pharmacological 
treatments are only partially successful in relieving pain, and (iv) taking in account that recent 
advantages in pain research indicate multiple mechanisms underlying the initiation and 
maintenance of neuropathic pain, it is possible to find a more rational treatment and potential 
new targets for therapeutic interventions in patients with neuropathic pain. 
Synthetic lipid analogues were not considered of clinical interest until recently. However, (i) the 
protection of the CNS by the BBB (a succession of lipid membranes), (ii) the high amount of 
lipids in the CNS and (iii) the lipid nature of most inflammation mediators that worsen 
neurological damage, suggest the cell membrane is a promising target for pharmacological 
therapy and that rationally designed lipids could have application in the treatment of CNS 
conditions. NEUROFIX’s design process is based in lipid-soluble and biocompatible 
molecules that can safely travel from the blood flow to the neurons and glial cells, reaching 
the CNS at nontoxic doses with no undesired effects.  Specifically, our aim in this study is to 
explore the efficacy (Proof of Concept) of NFX88 in alleviate the neuropathic pain in spinal 
cord injury patients. 
NFX88 is a small molecule, sodium--hydroxy-9-cis-octadecenoate (2-hydroxyoleic acid, 
2OHOA, a non-hydrolysable oleic acid (OA) analogue), that regulates the production of lipid 
neuroinflammatory mediators through interaction with phospholipases and PPAR. Both 
entities are involved in regulation of enzymatic and GPCR-mediated signalling that prevents 
neuroinflammation, neuropathic pain in a rat model of spinal cord injury (Ávila-Martin et al., 
2015). In addition, it participates in neuron growth factor expression induction and 
myelinization via its -hydroxyl-carboxyl moiety, being more efficacious than pregabalin to 
reduce neuropathic pain in animal models (Ávila-Martin et al., 2015; Ávila-Martin et al., 
2017).  
1.1 
Relevant preclinical results 
1.1.1 
2OHOA 
The pre-clinical experience is fully described in the current version of the 2OHOA 
Investigator’s Brochure. 
Key findings are summarized below.  
Analysis of the fatty acid composition from cell tumour lines (A549 human adenocarcinoma 
cells, S767 and U118 human glioma cells) shows that 2OHOA is preferentially incorporated 
into the glycerophospholipid fraction of the plasma membrane, particularly the phosphatidyl 
ethanolamine (PE) and phosphatidyl choline (PC) fractions, probably replacing its analogue 
oleic acid (Barceló-Coblijn et al, 2011; Martin et al., 2012). Based on the human liver 
microsomal enzymes in vitro studies on CYP450 inhibition, 2OHOA is believed to have a low 
potential to cause drug-drug interactions, though there is the potential for clinically important 
interactions with 2OHOA through its inhibition of CYP2C9. The results from the two 
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For this reason, as a precaution certain concomitant medication was prohibited in the clinical 
trial already conducted in patients with cancer, protocol code MIN-001-1203 and, where 
concomitant use of other drugs metabolized by CYP2C9 was unavoidable, and subjects 
closely monitored as appropriate. However, due to its structure closely related to oleic acid, 
2OHOA has been seen to be a very safe compound as doses up to 3 grams/kg per day (p.o.) 
did not cause deaths in rats (Terés et al., 2012). Recent data showed that, in addition to its 
incorporation to phospholipids, cholesterol esters or acyl-glycerols, 2OHOA is preferentially 
metabolized via α-oxidation, which yields as main metabolite heptadecenoic acid (17:1n-9), a 
fatty acid identical to oleic acid with 17 C atoms, instead of 18 (Fernandez-Garcia et al., 
2018). 
The dog disposition of 2OHOA was observed at the three tested doses (100, 400 and 1,000 
mg/kg/day) on days 1 and 28 of treatment. Quantifiable levels were seen at 0 h on day 28 and 
2OHOA was still present in plasma at 144 hours after the last dosing. The systemic exposure 
to 2OHOA was influenced by the administered dose level and by the duration of treatment. 
The mean accumulation ratios calculated for 400 and 1,000 mg/kg/day dose groups indicated a 
slight trend towards drug accumulation, especially at the dose of 400 mg/kg/day due to a high 
individual variability. 2OHOA did not show a trend toward accumulation in the 100 mg/kg 
/day dose group for which an overall accumulation ratio of 1.16 was calculated. A slight 
influence of the sex on the extent of exposure was observed after the administration of 
2OHOA. In general, females showed a higher systemic exposure to the drug at the dose levels 
of 100 and 1,000 mg/kg/day but no clear influence of sex was observed at the intermediary 
dose of 400 mg/kg/day. Calculated elimination half-lives at low and intermediate doses were 
similar, both for day 1 and day 28. Values ranged between 7.10-11.21 hours for low dose and 
6.76-8.68 hours for intermediate dose. Elimination half-life could not be calculated on day 1 at 
the highest dose but was 66.16 hours on day 28 at the dose of 1,000 mg/kg This last half-life 
value was calculated from the recovery animals 15M, 16M, 31F and 32F in which blood 
collection was done up to 144 hours after last dosing on day 28. The mean residence time 
correlated with the findings observed for the elimination half-life. The rat disposition of 
2OHOA was observed at the three tested doses (40, 245 and 1500 mg/kg/day) on days 1 and 
28 of treatment. Systemic exposure was influenced by the administered dose level and by the 
duration of treatment. No influence of the sex on the extent of exposure was observed after the 
administration of 2OHOA. The half-life values suggested that the administered dose 
influenced the elimination half-life of 2OHOA, with the elimination half-life being longer as 
the dose increased from 40 to 1500 mg/kg, suggesting a saturation of the clearance processes. 
However, the half–lives obtained on days 1 and 28 for the dose of 245 mg/kg were similar 
(3.47 and 3.67 hours), suggesting that the duration of treatment did not influence the 
elimination of 2OHOA. The mean residence time was higher as the dose increased from 40 to 
1,500 mg/kg.  
The blood distribution of 2OHOA (cell pellet, free in plasma and bound to plasma proteins) 
was determined in blood obtained from Wistar rats. The results show that [3H]2OHOA was 
mainly bound to plasma proteins (75.2% when trichloroacetic acid (TCA) was used for 
precipitation and 63.8% when it was used Methanol), it was also incorporated to blood cells 
(21.6% with TCA and 27.8% with methanol) and a small part was free (1.4% with TCA and 
8.8% with methanol) in plasma. 

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The tissue distribution was determined in NUDE (Swiss) Crl:NU(Ico)-Foxn1nu mice which 
developed SF767 cells-derived tumors after oral dosing of [3H] 2OHOA. The doses used for 
oral administration by gavage were 100, 200 and 600 mg/kg administered every 24 hours 
during 1, 7 and 28 days of treatment. Organ samples were obtained at the end of the treatments 
(1, 7 and 28 days). The results show a dose- and time-dependent accumulation of [3H]2OHOA 
in all organs studied including brain and tumours. The accumulation of radioactive 
product/metabolite was determined in feces of nude mice treated for 28 days with 100, 200 
and 600 mg/kg/day. From this data it can be concluded that 2OHOA and/or its metabolites 
is/are excreted in faeces, and that there is a dose-dependent relationship in the amount of 
product measured in faeces. 
1.1.2 
Experimental animal models of SCI 
Sensorimotor dysfunction following incomplete SCI is often characterized by paralysis, 
spasticity and pain (Gómez-Soriano J et al, 2016). Intrathecal (i.t.) administration of the 
albumin-oleic acid (A-OA) complex in rats with SCI, produced partial improvement of these 
symptoms (Ávila-Martin G et al 2011). Comparison of the expression between healthy, SCI, 
and SCI rats treated with A-2OHOA (albumin-2-hydroxyoleic acid) revealed relevant changes 
in the expression of genes associated with neuronal morphogenesis and growth, neuronal 
survival, pain and inflammation (Ávila-Martin et al., 2017). 
NFX88 (2OHOA) it has been seen that reduces neuropathic pain, both after p.o. or i.t. 
treatments (Ávila-Martin et al., 2015; Ávila-Martin et al., 2017). The efficacious in the 
modulation of nociception and prevent a pain-related anxiety in the spared nerve injury (SNI) 
model in Wistar rats, is mediated by an inhibition of spinal dorsal horn microglia activation 
(Ávila-Martín G. et al. 2015). 
The analgesic effect of 2OHOA on both nociceptive and cerebrally mediated behavioural tests 
was assessed at a dose of 400 mg/kg. This dose was chosen according to previous studies, 
which demonstrated that 2OHOA was antihypertensive when administered in rats between 
doses of 100-900 mg/kg, p.o., every 12 h for 7 days (Alemany et al, 2006), and a lack of 
obvious toxic effects based on cytohistological analysis of different organs following 
administration at 600 mg/kg in Sprague Dawley rats (Alemany et al, 2004) and at 1,200 
mg/kg, p.o. every 12 h for 7 days in athymic nude mice (Martinez et al., 2005).  
1.1.3 
Summary of toxicological data 
2OHOA has been tested in a standard range of safety pharmacology studies ie, dog 
cardiovascular and respiratory function tests, and the rat Irwin test. There were no noticeable 
effects on the cardiovascular or respiratory parameters in the anaesthetized dog or any 
behavioural, autonomic or motor effects in the rat at the doses studied.  
Respiratory System 
There was no effect of 2OHOA on Respiration Rate and Tidal Volume in male Wistar rats 
following a single dose with 40 and 245 mg/kg of oral 2 OHOA. At a dose of 1,500 mg/kg, 
2OHOA had effects on respiratory function of freely moving conscious rats. The effects 
included a decrease in respiratory rate, an increase in tidal and minute volumes and the 
appearance of clinical signs. Clinical signs included the pushing of their noses along the 

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bottom of the chamber, shaking their heads, longer pauses between breaths and gasping for 
breath. 
Cardiovascular System 
The 14-Day oral (capsules), toxicokinetic and safety pharmacology study in Beagle dogs 
comprised 6 groups with 2 males and females each: (1) 0 mg/kg/day, (2) 20 mg/kg/day, (3) 
200 mg/kg/day, (4) 600 mg/kg/day, (5) 900 mg/kg/day and (6) 1,200 mg/kg/day. There were 3 
cases where QT and QTc prolongation comparing day 1 and day 13 measurements could be 
observed (1 female dosed at 600 mg/kg/day and 1 female and 1 male dosed at 1,200 mg/kg/d). 
No similar cases were seen in groups 1, 2, 3 or 5. No clear pattern of dose-dependent effect on 
cardiac repolarization was identified. 
The 28 Day oral (capsules) toxicity study in Beagle dog study comprised 4 groups: groups 1 
and 4 (with 5 males and 5 females, each) and groups 2 and 3 (with 3 males and 3 females, 
each). The following doses were administered: (1) 0 mg/kg/day, (2), 100 mg/kg/day, (3) 400 
mg/kg/day and (4) 1,000 mg/kg/day. Administration of 2OHOA for a period of 4 weeks at the 
dose of 1,000 mg/kg/day led to changes in the electrocardiogram: a left bundle brunch block-
like pattern was seen in all five males in this group, and three of 5 females before and after 
dosing in week 4 of treatment. Macroscopic changes in the heart were seen in two males in 
this dose group, and in one female in the 400 mg/kg/day group. Furthermore, chronic 
myocarditis was observed in two males and two females after 4 weeks of treatment with 
2OHOA (1,000 mg/kg/day). There were no histopathological findings in other dose groups. 
Similar changes were not present in animals undergoing a 3-week recovery period and 
therefore these changes are considered reversible.  
The effect of 2OHOA on hERG tail current recorded from stably transfected HEK293 cells 
study incubations of 2OHOA were made at concentrations of 1, 3, 10 and 30 µM. The 
conclusion of the study that 2OHOA produced slight inhibition of hERG channels at 0.24 µM 
(corresponding to nominal concentration of 1 µM) is possibly misleading.  Other in vitro 
studies show similar effects of fatty acids on hERG channels (Guizy et al, 2005; Den Ruijter et 
al, 2010). Notwithstanding that, it is well known that fatty acids are not arythmogenic, and 
their net effect, based on molecular, physiological and clinical data, has been shown to be 
cardio protective as a consequence of their beneficial effects on the lipid profile. Importantly, 
the isolated cases of QT prolongation from in vivo studies in dogs were observed only at very 
high doses (at least 600 mg/kg/day p.o), much larger than the exposure to subjects in the 
proposed study.  Collectively, this information does not seem to indicate a cardio-toxic effect 
of 2OHOA. 
The effects of 2OHOA on behavioural and physiological response were assessed by the 
modified Irwin study at doses of 100, 300 and 1,000 mg/kg following oral administration in 
the mouse. No effect was observed in any control animals or in any of the animals treated with 
2OHOA at these doses. Mortality was not observed in any of the treatment groups. 
1.1.4 
Acute Toxicity 
In acute single dose toxicity studies to determine the minimum lethal dose (MLD) and 
maximum non-lethal dose (MNLD), 2OHOA was administered orally at a dose of 3,000 
mg/kg in Wistar rats and CD-1 mice. No mortality was recorded in these studies. As it was 
considered that 3,000 mg/kg was a sufficiently high dose, the MNLD and MLD were not 

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determined, but it was concluded that the MLD is considered to be greater than 3,000 mg/kg in 
these species. Following acute i.p. administration in rats at doses up to 700 mg/kg, the MNLD 
was established to be 125 mg/kg and the MLD at 250 mg/kg. 
1.1.5 
Repeat-Dose Toxicity Studies  
Rat: Oral administration of 2OHOA for 28 days at the of 40, 250 and 1,500 mg/kg/day to rats 
at dose levels up to 1,500 mg/kg caused salivation which was attributed to the taste of the 
investigational substance, At the highest dose, treatment-related clinical signs were observed, 
and haematological and biochemical changes were recorded (increased levels of bilirubin and 
various enzymes) as well as histopathology of several organs. In rats treated with 245 mg/kg 
slight blood biochemical changes were observed. In the 40 mg/kg dose group a lower sperm 
count was observed at the end of treatment which had recovered at the end of the recovery 
period. Based on this, 40 mg/kg/day 2OHOA can be established as the NOAEL in rats. 
Dog: Oral administration of 2OHOA for 28 days at 100, 400 and 1,000 mg/kg/day to dogs 
produced no findings related to the cardiovascular system except at the highest dose of 1000 
mg/kg/day. There were also dose-dependent effects on the GI tract consisting mainly of loose 
faeces and discoloured diarrhoea and vomiting. 2OHOA administration led to an increase in 
aspartate transaminase (AST) / alanine transaminase (ALT) / CK parameters in males and 
females treated with 600 mg/kg/day. No treatment-related effects were recorded in 
haematology, coagulation and urine parameters or on organ weights. In view of these results, 
taking into account the cardiac effects present in electrocardiographic and histopathological 
evaluations, as well as the changes in biochemistry parameters and the clinical signs noted, the 
NOAEL in dogs can be defined as 400 mg/kg/day.  
A standard battery of genetic toxicology studies has established that 2OHOA is not genotoxic. 
Carcinogenicity, reproductive and developmental toxicity studies will be completed at later 
stages of development.  
1.2 
Overview of Clinical Studies 
The API contained in NFX88 is the same as the molecule present in LP561 (i.e., 2-
hydroxyoleic acid), which successfully completed a phase I study in humans with advanced 
solid tumours. This is an investigational medicinal product (IMP) currently authorized in 
Spain for the use in humans in the context of clinical trials. Both NFX88 and LP561 have oral 
administration, being the dose used with LP561 in clinical trials (up to 16 g per day, p.o., 
b.i.d.) much higher than those to be used in the present study (up to 4.2 g per day, p.o., t.i.d.). 
The phase I clinical trial to investigate the safety, tolerability and exploratory therapeutic 
efficacy of 2OHOA in adult patients with advanced solid tumours was the first study in 
patients and has now been completed. 2OHOA was administered to 54 patients (32 patients in 
the Dose Escalation Phase to determine the maximum tolerated dose (MTD) of 2OHOA and 
22 patients in the Safety Expansion Phase of the study to identify the Recommended Phase II 
dose (RP2D) of 2OHOA. Five sites participated in the study, three in Spain and two in the 
UK. 
Data from seven dose cohorts (0.5, 1, 2, 4, 8, 12, and 16 g of 2OHOA daily) indicates that the 
study drug is generally well-tolerated apart from some anticipated gastrointestinal (GI) effects 
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one subject (Grade 3 diarrhoea) from cohort #6 (12 g/day), and in 3 patients (Grade 2 or 3 GI 
AEs) from cohort #7 (16 g/day) which were either probably or certainly related to the study 
medication. The DLTs observed in these four patients, meant that the MTD had been reached. 
The MTD was defined as 12 g/day of 2-OHOA. 
There were no serious adverse reactions (SARs) reported. A total of twenty-one serious 
adverse events (SAEs) were recorded, none of which was considered to be related to the study 
drug. There were no safety findings which were a cause of concern.  
Pharmacokinetic data after single and repeat b.i.d. and t.i.d oral administration in fasted state, 
the 2OHOA absorption was rapid showing a median Tmax value of 1 hour, which was delayed 
in fed state (2-6 hours). The single dose administration of 2OHOA in fed state reduced the 
mean Cmax around 18-34% but did not show a significant effect on the AUC.  
Following single and repeat dosing of 2OHOA, there was dose proportionality in terms of 
Cmax and AUC within the dose interval evaluated (0.5-16 g as total daily dose). After oral 
dosing, the volume of distribution at steady state (Vss/F) and the plasma clearance (Cl/F) were 
around 105 L and 26 L/h, respectively. The accumulation ratio based on AUC (RAUC) was 
around 1.5 and 2 after repeat b.i.d. and t.i.d administration, respectively. Based on this 
accumulation ratio, the effective half-life of 2OHOA was calculated to be around 8-9 hours.  
In summary, from a safety perspective, there has been exposure of a significant number of 
patients over a substantial period to the study drug and 2OHOA showed a favourable safety 
profile to date with dose limiting toxicity (DLT) emerging at the highest doses selected. The 
adverse event pattern and death rate due to progressive disease (PD) were as expected in this 
type of terminal cancer patient population. On the basis of the data reviewed in the latest 
DSUR and up to conclusion of the study, there are no findings that change the benefit/risk 
profile of 2OHOA. The safety profile of the 2OHOA remains acceptable for the intended 
clinical indications. 
1.3 
Evaluation of the patient with spinal cord injury 
The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), 
published by the American Spinal Injury Association (ASIA), is widely used to document 
sensory and motor impairments following SCI (Kirshblum et al, 2011). The International 
Standards examination used for neurological classification has two components (sensory and 
motor), which are separately described below. These elements are used in determining the 
level and degree or severity of the SCI.  
Generally, the higher up the level of the injury to the spinal cord, the more severe the 
symptoms. Tetraplegia refers to impairment or loss of motor and/or sensory function in the 
cervical segments of the spinal cord due to damage of neural elements within the spinal canal. 
Tetraplegia results in impairment of function in the arms as well as typically in the trunk, legs 
and pelvic organs, i.e. including the four extremities. Paraplegia refers to impairment or loss of 
motor and/or sensory function in the thoracic, lumbar or sacral (but not cervical) segments of 
the spinal cord, secondary to damage of neural elements within the spinal canal. With 
paraplegia, arm functioning is spared, but, depending on the level of injury, the trunk, legs and 
pelvic organs may be involved. The term incomplete injury is used when the degree of 
impairment results in the preservation of any sensory and/or motor function below the 

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neurological level that includes the lowest sacral segments S4-S5. Complete injury is used 
when there is an absence of sensory and motor function in the lowest sacral segments (S4-S5). 
The traumatic injury occurred in the cervical spine in 54% of the cases, in the thoracic spine in 
25%, and in the lumbar spine in 22%. The degree of impairment according to AIS was degree 
A (Complete injury) in 26% of the cases, degree B (Sensory incomplete) in 26%, degree C 
(Motor incomplete) in 19%, D (Motor incomplete) in 27% and E (Normal.) in 2% (Null A et 
al, 2017). One of the first signs of neurologic deterioration is the extension of the sensory and 
motor deficit cephalad. Moreover, spasticity may appear or worsen along time after injury. 
The most commonly used tools to evaluate the severity of injury and spasticity in clinical trials 
among patients with SCI are the ASIA and Modified Ashworth Scale (MAS), respectively 
(Craven BC and Morris AR, 2010). The AIS scale was developed by the ASIA in 2006 as part 
of the ASIA- ISNCSCI (Kirshblum et al, 2011). The MAS originally develop by Ashworth B 
et al, (1964) and subsequently modified by Bohannon and Smith (1987), is a six-category 
ordinal scale used to assess the resistance encountered during passive muscle stretching that 
does not require instrumentation and is quick to perform.  
Pain assessment in individuals with SCI is complex and requires a combination of standard 
general pain assessments, as well as medically specific questions unique to the patient's 
pathophysiology (Lee S et al, 2013).  The most commonly used tools to evaluate the efficacy 
of pharmacologic interventions for treatment of pain among patients with SCI, includes: 
Visual Analogue Scale (VAS), Patient Global Impression Change (PGIC) and PainDETECT 
questionnaire (PD-Q). 
VAS scale has been shown to be reliable and valid in the assessment of pain severity and is 
well accepted by pain researchers and clinicians (Teasell RW et al, 2010). The 7- point 
Guy/Farrar PGIC (Guy W, 1976; Farrar JT et al, 2001) is recommended as the outcome 
measure of the global improvement of pain (Bryce TN et al, 2017). The PD-Q consists of 7 
questions that address the quality of neuropathic pain symptoms (Mathieson S and Lin C, 
2013), was primarily validated in German (Freynhagen R et al, 2006) and subsequently 
validated in several languages, including Spanish (De Andrés J el al, 2012). PD-Q was 
recommended as complementary neuropathic pain assessment tool in SCI to monitor pain 
severity and/or its time-dependent course, providing evidence that the scope for PD-Q can be 
expanded to individuals with SCI (Franz S et al, 2017).  
2. STUDY RATIONALE 
Usually, patients report neuropathic pain either after the medullary lesion or a few months 
later. The usual patient managing is receiving treatment with an increasing number of drugs, 
such as pregabalin, amitriptyline, gabapentin, and others (Hagen & Rekand, 2015; Singh et al., 
2014). These compounds cause relevant side effects, such as nausea, somnolence, dry mouth 
and/or eyes, constipation, cardiotoxicity, sedation, gastro-intestinal effects, dizziness, rash, 
headaches, peripheral oedema, etc. None of these side effects have been reported for NFX88 
at therapeutic doses in the previous phase I clinical trial for other indication, and if the phase II 
study proposed demonstrates the same efficacy observed in animals, an improvement in the 
quality of life would be expected for those patients when managing neuropathic pain with this 
compound. In fact, NFX88 was found to be more efficacious than pregabalin in an animal 
model of neuropathic pain (Ávila-Martin et al., 2015). Therefore, due its high safety and 
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is reasonable to investigate the potential efficacy and the safety and tolerability for the 
treatment of neuropathic pain in patients with SCI. 
2.1 
Risk / Benefit Assessment 
The studies carried out with NFX88 demonstrate its efficacy in animal models and its safety in 
humans. This clinical trial will provide proof of concept about the safety, tolerability and 
efficacy in humans, specifically, it will shed light on the efficacy of NFX88 for the treatment 
of neuropathic pain in patients with spinal cord injury. At this moment, neuropathic pain 
management is carried out with drugs initially purposed for other conditions. Due to low 
prevalence, spinal cord injury is considered an orphan disease for which the number of 
treatments available for the different symptoms it causes is limited. 
The working hypothesis is that the treatment with NFX88 will be safe and well tolerated in 
patients with spinal cord injury, as demonstrated in the phase I / II study previously conducted 
in patients with cancer. For that reason, we will evaluate the tolerability, safety and 
effectiveness of NFX88 in the relief of neuropathic pain in patients with spinal cord injury. It 
is expected that the NFX88 will be superior to placebo (both plus pregabalin as common 
treatment) which would avoid the addition of different drugs in the management of this type of 
patient with the consequent reduction of the well-known side effects. Therefore, it is expected 
that the treatment with NFX88 will demonstrate a reduction in neuropathic pain determined by 
validated questionnaires. 
2.2 
Dose Justification  
This molecule has been previously tested in humans up to doses of 16 g per day (p.o.) and has 
demonstrated high safety. Moreover, in a pilot study with 5 subjects, 3 reported benefit against 
pain in a range of 0.5-2 g per day (unpublished results).  
In an animal model of neuropathic pain, it was observed the maximum NFX88 efficacy at a 
daily dose of 400 mg/kg (p.o.). According to the FDA dose equivalence tables (2005), this 
dose would correspond in humans to about 60 mg/kg, which would be about 4 g per day (p.o.). 
In the present study, it is planned to investigate from 1.05 up to 4.20 g per day (p.o.), doses 
that proved to be safe in the phase I study carried out in humans with advanced solid tumors.  
The previous data from phase I study indicates that the study drug is safe and generally well 
tolerated at doses range to proposed will be used in this phase 2A clinical trial. The GI effects 
in the phase I study were observed at the high dose cohorts (12 and 16 g/day).  In that case, the 
GI symptoms could had been the result of the high amount of excipients in the formulation, 
such as mannitol (ca. 15 g per day at dose of 16 g/day of 2OHOA). However, in this clinical 
trial, the doses range to be used will much lower than that dose (1.05-4.20 g/day). Taking in 
account that the amounts of API and excipients will be below that previously used, the 
company does not anticipate any relevant adverse events and considers no additional studies 
for NFX88 will be needed. Although we do not expect adverse effects, if any adverse effect 
related to gastrointestinal tract or of any other nature appear, it will be handled based on the 
physician's criteria with standard medication.  Before the first patient enrolled, a steering 
committee (SC) will be constituted to evaluate safety and tolerability data of patients in the 
trial. Any serious adverse event will be assessing, and the SC could decide patient treatment 
discontinuation or any other urgent measure. 

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3. STUDY OBJECTIVES 
This proof-of-concept clinical trial is carefully designed to establish the safety profile of 
NFX88 in neuropathic pain after spinal cord injury (SCI) and explore the relationship between 
three (1.05, 2.10 and 4.20 g) doses administered and the induction of improvement in 
neuropathic pain, based on the score obtained using the specific questionnaires to evaluate 
pain.  
In summary, this small-scale study is designed to demonstrate that the NFX88 is safe and well 
tolerated, as well as preliminary evidence of improvement in the score of VAS, PD-Q, and 
PGIC scales. 
3.1 
Primary Objective 
The primary objective is to assess the safety and tolerability of NFX88 in spinal cord injury 
patients with neuropathic pain over ninety-day treatment period. 
3.2 
Secondary Objective 
The secondary objective is to explore the preliminary therapeutic efficacy associated with 
NFX88 through the analysis of validated measurement scales: VAS, PD-Q and PGIC. 
4. STUDY DESIGN 
4.1 
Study Overview 
This is a Phase IIa (proof of concept), randomized, double-blind, placebo controlled, parallel 
group, multicentric, clinical trial to evaluate the safety, tolerability and efficacy of daily oral 
treatment with NFX88 in SCI patients who are not receiving opiates or cannabinoids and 
present neuropathic pain with an average pain score ≥ 4 measured with a VAS scale during the 
last week at screening 
Up to 60 completed patients are planned. Each subject will be administered with four tablets 
of study drug three times a day through 90 days. Enrolled patients, whom will continue their 
pre-established dose of pregabalin (range between 150 up to 300 mg/day), will be randomized 
to receive one of the doses of NFX88 or placebo. Subjects will be assigned to the treatments in 
random order. Evaluations will be taken at screening and at each of the 5 study evaluation 
visits. 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following treatment regimens will be used: 
- 
Experimental treatment NFX88 at the following doses 1.05, 2.10 and 4.20 g/day  
- 
Placebo  
A schematic diagram of the study design is shown in Figure 1. The Schedule of Study Visits is 
presented in Table 1. See protocol sections 7 and 8 for full details of assessments and 
procedures. Visit windows ± 3 days will be allowed in this protocol for all the visits 
scheduled. 

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Figure 1. Schematic Diagram of the Study Design 
If the patient misses an administration or visit for any reason, it should be documented as 
missed on the electronic Case Report Form (eCRF) and the visit rescheduled as soon as 
possible and/or continued with the next dose of the medication.  
The patient can be considered evaluable when he/she adheres to the protocol in at least 75% of 
the treatment with NFX88 or placebo (at least 68 days of complete doses treatment) and not 
forgotten more than one week of consecutive doses. It is very important to avoid those 
forgiven doses. Patients who become “not evaluable” for this reason will be considered as 
“drop outs” in the protocol analysis and will be substituted by a new patient allocated to the 
same treatment arm. However, data from drop out patients should be included for intention to 
treat analysis. 
4.2 
Visit sequence: 
Patients will be examined in 6 scheduled visits (see section 8 for specific measurements taken 
in each visit): 
1. SV: Screening visit at day -7 of randomisation 
2. V1: Randomisation visit this is day 1 of treatment 
3. V2: Evaluation visit on day 30 +/- 3 after V1 
4. V3: Evaluation visit on day 60 +/- 3 after V1 
5. EOT:  End of treatment visit on day 90 +/- 3 after V1 

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6. FU: Follow-up visit after end of treatment on day 120 +/- 3 after V1 
7. WV: Withdrawal visit only for those who withdraw before EOT visit. 
4.3 
Screening/Baseline 
Patients should undergo a baseline visit within 7 days prior to their study randomisation. The 
Principal Investigator or his/her designee will obtain written informed consent before any 
study related procedures are performed. 
4.4 
Randomisation 
Eligible patients will be randomized into the study on visit 1 (V1), to start with the study 
medication the same day (V1), following the procedures described in section 6.3 (Method of 
Assigning Subjects to Treatment Groups) of this protocol. 
4.5 
Treatment Period 
The administration of the oral treatment will be carried out daily under the patient's 
responsibility. The accountability of study drug will be recorded in the medical record during 
study visits at Site. Patients will begin the study treatment on V1 and will take four tablets 
three times a day of the investigational drug or placebo. The last visit of the treatment will be 
made 90 days after the first treatment date (visit window ± 3 days). See protocol section 7.4. 
(Drug Administration Procedure) for more drug administration details. 
During the treatment period the patient shall attend four visits to the Site: during V1, V2, V3 
and EOT (window of ± 3 days are permitted) and to carry out the assessments and procedures 
noted on Table 1. 
However, patients will be advised to return to the clinical site for an unscheduled visit, if 
judged necessary by the physician in charge, for safety reasons. 
Changes in VAS and PD-Q score induced by NFX88 treatment compared to placebo will be 
clinically evaluated by SV, V1, V2, V3, EoT or WV and FU/EoS. PGIC score will be 
evaluated by V3 and EoT or WV. See section 7.6 (Efficacy Measurements) for details of 
scales.  
Reasonable effort should be made to comply with protocol assessments and procedures the 
designated days in order to avoid patient will attend visits at site more frequently than in a 
monthly basis. 
A beta HCG serum pregnancy test will be performed at screening date to have the test results 
prior to drug administration. The pregnancy test will be repeated at the end of the study or 
during the withdrawal visit (find more details in protocol section 7.2.4 (Pregnancy Test).). A 
urine pregnancy test will be made the date of randomisation to women who are of childbearing 
age. 
 
4.6 
Follow-Up / End of Study 
After completion of the Treatment Period, all patients will be followed up to assess evaluation 
of disease, if applicable, drug-related events, and patient evaluation according to Good 

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Clinical Practices and WHO guidelines. Patients will attend the study site to perform a follow-
up visit, 120 days (± 3 days) after V1, randomisation day. 
For patients whose participation in this clinical study is discontinued during the course of the 
trial, every effort will be made to perform the post-study tests as soon as possible after 
discontinuation. 
The physician in charge will assess each routine laboratory test. In case of an abnormal value, 
the clinician will determine if it is clinically significant or not. Clinically significant laboratory 
values will be reported as adverse events on the eCRF. The laboratory values will be included 
in the clinical final report. 
4.7 
Study Outcome 
4.7.1 
Safety Endpoints 
Safety and tolerability of NFX88 administered for 90 days will be evaluated by assessing the 
number, severity, and type of AE, including changes in vital signs, safety laboratory values, 
ECGs, and MAS (e.g. to monitor spasticity worsening) and ASIA (e.g. to monitor 
neurological worsening) scores.  
4.7.2 
Efficacy Endpoints 
Efficacy of NFX88 treatment compared to placebo in pain improvement will be measured as: 
- 
Reduction from V1 to EoT in pain intensity in the VAS scale.  
- 
Reduction from SV to EoT in the likelihood of neuropathic pain in PD-Q scale.  
- 
Global improvement at EoT in patient’s condition according to the PGIC scale. 
5. SELECTION OF STUDY POPULATION 
5.1 
Study Population 
Male or Female 18 to 65 years of age, with spinal cord injury due to complete or incomplete 
C4-T12 trauma for more than three months. Diagnosed of neuropathic pain with a pain score ≥ 
4 in VAS scale during the last week prior to randomisation date, and who have stable 
treatment, for at least the last month with pregabalin in the range of 150 up to 300 mg/day. 
Patient who withdraws subsequent to the screening assessments but before receiving the 
investigational product will not be considered in the statistical analyses, but they will be 
included in the eCRF as Screening Failure (SF). Patients that drop out after randomisation will 
be substituted as explained in section 5.7 (Replacement of Subjects) of this protocol.   
5.2 
Sample Size and Power 
Patients will be included in the study up to achieve sixty (60) completed patients (1:1:1:1, 
treatment arm: placebo arm ratio) as described in section 6.3 (Method of Assigning Subjects to 
Treatment Groups) of this protocol. The main objective of the trial is to detect adverse events 
(AE) in the group with medication (45 patients) compared with placebo (15 patients). The 
power of this trial is the probability to see cases of AE caused by the drug in the treatment 
arms. This power depends on the true (unobservable) risks of those AE (the higher the risk the 
higher the chances of seeing cases). The table below shows the power of the trial to show 

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cases of AE depending of the true unobservable risk. For example, if the true risk of a certain 
adverse event while on treatment was 5% then we would have a probability of 68% of finding 
at least one of these events in the intervention arm, but if the true risk was 5% then we would 
have a 90% chance of finding this event in the trial. For higher true risks the power is even 
higher. 
True unobservable Risk of AE of patient in treatment arm 
2.5% 
5% 
10% 
15% 
Prob. of seeing at least one case of the AE (power) 
68% 
90% 
99% 
99.9% 
5.3 
Inclusion Criteria 
Patients eligible for enrolment in the study must meet all the following inclusion criteria: 
1. Able and willing to provide written informed consent. 
2. Male or Female 18 to 65 years of age. 
3. Traumatic complete or incomplete spinal cord injury with C4-T12 level and more 
than three months since injury. 
4. Diagnosed of neuropathic pain with an average pain score ≥ 4 measured using the 
VAS scale during the last week. 
5. Stable treatment, for at least 1 month, with pregabalin 150-300 mg/day, that should 
be maintained at the same dose for 90 days until the end of the study treatment. 
6. Normotensive patients defined as patients with blood pressure values between 90-160 
for systolic pressure and 50-100 for diastolic pressure.  
7. Patients who have been treated with stable doses of neuroactive drugs 
(antidepressants, anticonvulsants, antispastic and similar medicines) at least during 
the last month, can also be recruited. 
8. Availability for the entire study period, absence of intellectual problems likely to 
limit the validity of consent to participate in the study or the compliance with 
protocol requirements; willingness to adhere to the protocol requirements, ability to 
cooperate adequately, to understand and follow the instructions of the physician or 
designee. 
9. Women who are not postmenopausal (at least 12 months) or surgically sterile must 
have a negative pregnancy test at screening and at the end of study and either abstain 
from sexual intercourse or use a highly effective method of birth control for the 
duration of the study and after 12 weeks after the last dose of study drug.  
10. For men: agreement to remain abstinent or use contraceptive measures and agreement 
to refrain from donating sperm for the duration of the study and after 12 weeks from 
the last dose of study drug. 
5.4 
Exclusion Criteria 
Patients meeting any of the following criteria must NOT be enrolled in the study: 
1. Patients treated with opiates (major and minor) and cannabinoids (synthetic, natural or 
analogous).  

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2. Patients with blood pressure higher than those accepted in the inclusion criteria. 
3. History of alcohol, drug abuse within 6 months prior to screening. 
4. Psychiatric patients or those with moderate or severe cognitive impairment. 
5. Patient who is pregnant or lactating. 
6. Patient who shows evidence of significant liver or kidney disease, or any other 
conditions known to interfere with the absorption, distribution, metabolism or 
excretion of drugs or known to potentiate or predispose to undesired effects. 
7. Patient who has clinically significant diseases and/or infections captured in the medical 
history or evidence of clinically significant findings on physical examination and/or 
clinically significant ordinary laboratory evaluations (haematology, biochemistry, and 
urinalysis) or ECG. 
8. Patient who is currently participating in another clinical trial of an investigational drug 
or medical device within 90 days prior to screening. 
9. Inability to comply with study protocol. 
10. Patient unable to swallow 12 1-gram tablets. 
11. History of cancer except local basal or squamous cell carcinoma of the skin that has 
been excised. 
5.5 
Withdrawal Criteria 
The patient will be advised in the Informed Consent Form (ICF) that they have the right to 
discontinue treatment or withdraw from the study at any time without prejudice, and may be 
withdrawn at the Investigator’s, or the Sponsor’s discretion at any time in order to protect their 
health.   
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawal of patients should be avoided. Patients who 
are withdrawn from the study may be replaced, please refer to study statistical plan for more 
details.  
Reasonable effort should be made to contact any patient lost to follow-up during the course of 
the study in order to complete assessments and retrieve any outstanding data and study 
medication. 
In the event that the patient drops out of the study or is withdrawn from the study, the 
withdrawal date and reason should be properly documented by the Investigator or his/her 
designee in the medical chart and eCRF. 
5.6 
Criteria for Removal of a Subject 
Participation in the clinical study and/or treatment could be discontinued by the physician in 
charge of the study or by the sponsor for any of the following reasons: 
- 
Serious adverse event. 
- 
Significant protocol deviation (e.g. dosing regimen compliance, failure to comply with 
clinic visits scheduled). 

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- 
Routine laboratory value (s) greater than or equal to 4 times the reference values or if it is 
clinically significant. 
- 
Pregnancy. 
- 
The subject is uncooperative during the study. 
- 
The patient’s death 
Details of reasons for removal patients will be recorded in the eCRF, reported to the Sponsor 
and documented in the medical chart and clinical study report. 
5.7 
Replacement of Subjects 
Whenever a patient dropped out of the study, after randomisation but before end of treatment, 
for any of the reasons mentioned in this protocol, a new patient who meets criteria will be 
allowed to be enrolled to replace the lost participant whenever possible to complete the study 
sample size ensuring at least 15 patients for each arm with complete follow up. The new 
patient will be assigned to the same arm as the patient that has dropped out.  The data from the 
drop-out patient will be kept and analysed. Please refer to study statistical plan for more 
details. 
6. STUDY TREATMENTS 
6.1 
Identity of Experimental Drug 
The drug substance is the sodium salt of 2-hydroxy-9-cis-octadecenoic acid (2OHOA)  
6.1.1 
Chemical Name 
2-hydroxy-9-cis-octadecenoic acid sodium salt 
6.1.2 
Chemical Structure 
  
Figure 2. Chemical structure of 2OHOA. 
6.1.3 
Molecular Formula and Molecular Weight 
C19H33O3Na; MW 320.44 
6.1.4 
Arms of Treatment and Regimens  
Total: up to 60 completed patients 
A. Experimental Arms 
1) 1.05 g/day NFX88: At least 15 patients. 
2) 2.10 g/day NFX88: At least 15 patients. 
3) 4.20 g/day NFX88: At least 15 patients. 

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B. Control Arm  
4) Placebo: At least 15 patients. 
6.1.5 
Qualitative and Quantitative Composition 
Name: NFX88  
Active ingredient: 2OHOA (2-Hydroxy-9-cis-Octadecenoic Acid or 2-Hydroxy Oleic Acid) 
Evaluating doses: 1.05, 2.10 and 4.20 g/day 
Pharmaceutical form: 350 mg coated tablet  
Posology: three times a day (at meal times: breakfast, lunch and dinner) 
Presentation: Triflex (PP/AL/PVC/PVDC)/Aluminium unit dose blisters containing 12 x 1 
tablet 
Excipients dose: 890 mg 
Manufactured by: Laboratorium Sanitatis SL 
6.2 
Comparator (Blinded) 
Name: NFX88 Placebo 
Active ingredient: N/A 
Pharmaceutical form: Coated tablet 
Posology: three times a day (at meal times: breakfast, lunch and dinner) 
Presentation: Triflex (PP/AL/PVC/PVDC)/Aluminium unit dose blisters containing 12 x 1 
tablet 
Excipients dose: 1200 mg + 4% of coating approx.. 
Manufactured by: Laboratorium Sanitatis SL  
6.3 
Method of Assigning Subjects to Treatment Groups 
Up to 60 completed patients. 
All eligible patients, who fulfil all inclusion criteria and do not meet any exclusion criteria, 
will be randomly assigned to NFX88 arms or placebo treatment groups in a 1:1:1:1 ratio. A 
centralized randomisation list will be generated in order to assign active treatment or placebo 
to 1, 2, 3 or 4 arms of de study as specified here. 
- 
To ensure the 1:1:1:1 distribution of the up to 60 completed patients we will use block 
randomisation. The randomisation will be by blocks multiples of 4 (so 4, 8 12…) but the 
size of the blocks will be kept secret by the Data Manager (DM). This will minimise the 
chances of anyone involved in the study of guessing the allocation of a next patient. In the 
final report the details of the randomisation procedure will be revealed. 
- 
To ensure blinding we will follow a central allocation procedure:  A randomisation lists 
will be generated by the DM and incorporated into to the electronic data management 
system. When a new patient is recruited, the system will pull the next allocation in the 

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randomisation list and will communicate the Site investigator what steps to follow. In this 
way, the allocation remains blinded to the patient and the Site investigator.   
Patients enrolled in this study are not allowed to be randomised in this study again. 
6.4 
Blinding 
Due to the objectives of the study, the identity of placebo and NFX88 treatment will both be 
blinded. Patients will be randomised to receive any of them in a double-blind model such that 
neither the investigator nor the patient will know which combination is being administered. 
There is no known protocol required or laboratory procedures that would influence the 
integrity of the blind. 
Blinding of the study medication becomes ensured as both NFX88 and Placebo packaging will 
be identically presented. Personal involved in conducting the study may not have access to the 
randomisation code before the blind is officially broken.  
Study patients will be notified by informed consent form that they will receive a blind 
treatment, without being informed about which product (Investigational or Comparator) is 
being administered.  
The treatment assignment will be kept separate from the study team up to database lock.  
6.5 
Code breaks 
Blinding is critical to the integrity of this clinical drug trial. However, in the event of a 
medical emergency or pregnancy in an individual subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that subject may 
be broken by the Investigator. 
Only in case of an emergency, the individual treatment code for each study patient indicating 
the treatment assignment will be available to the Investigator and will be revealed by opening 
the treatment envelope kept at the Site containing the randomisation code. 
Before breaking the blind of an individual subject's blinded treatment, the Investigator should 
have determined that the information is necessary, i.e., that it will alter the subject's immediate 
management.  
The Investigator must also immediately inform the Sponsor and CRO that the code has been 
broken notifying the date and reason for unblinding and keeping those data recorded on the 
eCRF as soon as possible.  
Before unblinding, the Investigator should discuss this action with the Sponsor, the study 
medical coordinator and the CRO, except in those cases where urgent measures have to be 
taken for safeguarding patients’ life. Unblinding will only be granted if knowledge of the 
study treatment is essential for the appropriate clinical management or welfare of the patient. 
When unblinding the investigator should notify the sponsor as soon as possible.  
6.6 
Storage Conditions 
The study medication (NFX88 or Placebo) will be sent by the Sponsor directly to the 
Pharmacy of the investigational Sites for its storage in a key locked cupboard in a restricted 

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area, at a temperature always between 15 and 25ºC, for its dispensation when a new patient is 
registered into the study. 
6.7 
Receiving, Dispensing and Return of Investigational Products 
For each product to be administered (NFX88 or Placebo) 3 kits will be prepared per 
randomized patient. 1 kit per month/visit (V1, V2 and V3) will be given to patient for home 
administration. The kit will consist of 4 packages. Each package will contain 9 blisters; each 
blister with 12 tablets.  The 4 packages will be named from Nº 1 to Nº 4, and each one would 
be content placebo or NFX88 tablets depending of the study arm the patient was to be 
assigned. 
Study treatment administration will be performed under patient responsibility beginning on V1 
until the last treatment visit (EoT), 90 days after the first treatment (visits window ± 3 days). 
Three times in a daily basis, patients will take 4 tablets of investigational drug (one from each 
one of 4 package) with water at meals time. 
Accountability of study drug will be registered on the medical history during each visit at the 
study Site. 
Medication packages of each product will be dispensed to the patients at V1, V2 and V3; and 
controlled by V2, V3 and EoT or WV. In all cases, NFX88 or Placebo formulations packages 
will contain 432 tablets for administration throughout 30 days of treatment period. 
The Site delegated staff/Pharmacy will maintain an accurate record of the shipments received 
by the Site and dispensing of the drug product, using a drug accountability form. An accurate 
drug disposition record will be kept specifying the date and amount dispensed to each subject. 
This inventory record must be available for monitoring/audit by the sponsor and inspection by 
regulatory authority at any time. Copies of this record will be provided to the sponsor at the 
end of the study. 
The Investigator will not use any drug samples for other purposes (e.g., treating other non-
study patients or deviating from the protocol regarding dose regimen, duration of treatment, 
etc.). The Investigator will under no circumstances give any drug samples to a third party. The 
Investigator agrees not to destroy any labels, empty boxes or unused drug supply without 
sponsor’s permission. 
After completion of the trial, the unused study medication will be shipped to the Sponsor or 
will be destroyed after authorization by the Sponsor by an authorized person according to GCP 
regulations. 
6.8 
Packaging and Labelling 
All packaging operations will be performed by Laboratorium Sanitatis s.l. in accordance with 
Good Manufacturing Practice for Medicinal Products. 
An external label will be prepared for the individual medication packages and internal labels 
for each dose to be administered. The label will contain the information as required by the 
relevant regulatory and national requirements. 
Labelling will be performed according to Annex 13 of the Good Manufacturing Practice 
(GMP) guidelines of the European Commission (EC), ICH GCP guidelines, and local law. 

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6.9 
Concomitant Therapy  
6.9.1 
Standard Therapy for Neuropathic Pain  
Medical treatment with pregabalin must be maintained at the same dose (150-300 mg/day) and 
form of administration from the beginning until the follow-up visit (FU).  
All subjects must be maintained on the same medications throughout the study period, as 
medically possible, without the introduction of new chronic therapies. Patients who have been 
treated with stable doses of neuroactive drugs (antidepressants, anticonvulsants, antispastic 
and similar medicines) at least during the last month prior to beginning of trial must be 
maintained on the same medications and the same doses throughout the study period.  
All concomitant therapies will be recorded on appropriate pages of the eCRF.  
6.9.2 
Allowed/Additional Medications and Treatments  
- 
Anti-inflammatory drugs are allowed to pain relief.  
- 
Anyone considered necessary for the treatment of any concomitant disease during 
treatment. 
6.9.3 
Prohibited Medications and Treatments 
The opiates (major and minor) and cannabinoids (synthetic, natural or analogous) are 
prohibited during the study and their administration will be considered a protocol violation.  
6.9.4 
Maintenance Medication 
Patients would continue the usual therapy with pregabalin, until the follow-up visit. 
Investigators will offer the best therapeutic option after patients end trial participation. 
Decisions regarding treatment will be a consensus between investigator and patient 
7. STUDY PROCEDURES AND GUIDELINES 
7.1 
Clinical Assessments 
Prior to conducting any study-related activities, written informed consent must be signed and 
dated by the subject and the investigator or designee. 
Patients should be closely monitored for the onset of related evidence of severe reactions. 
A schedule of events representing the required testing procedures to be performed for the 
duration of the study is summarized in Table 1 and explained in the following sections.  
7.1.1 
Concomitant Medications 
All concomitant medication will be documented at Screening Visit (SV), at visits: V1, V2, V3, 
end of treatment (EoT) and follow-up (FU) visits, and when applicable at withdrawal visit 
(WV).   
7.1.2 
Demographics  
Demographic information (date of birth, sex, race, weight), alcohol and smoking habits will be 
recorded at Screening. 

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7.1.3 
Medical History  
Relevant medical history, including history of primary diagnosis and neuropathic pain, 
previous medication received and information regarding underlying diseases will be recorded. 
7.1.4 
Neurological Examination 
To verify the patient's diagnosis, a neurological examination will be performed and recorded 
in the ASIA scale according with the International Standards for Neurological and Functional 
Classification (ISNSCI), which establishes a classification according to 5 degrees determined 
by the absence or preservation of motor and sensory function, indicating the severity of injury. 
See Annex 1. 
7.1.5 
Vital Signs 
Body temperature, blood pressure and pulse rate will be performed after resting for 5 minutes.  
7.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to 
study drug will be recorded on the (eCRF). 
7.2 
Clinical Laboratory Measurements  
Approximately 10 mL of blood and urine will be collected for each clinical laboratory 
evaluation (haematology, clinical chemistry and urinalysis). These samples will be taken 5 
times during the study, for a total of approximately 50 mL collected throughout the study for 
each patient. 
7.2.1 
Haematology 
Blood will be obtained and sent to each site’s clinical haematology laboratory for a complete 
blood count (haemoglobin, haematocrit, red blood cell count, white blood cell count, white 
blood cell differential, and platelet count), erythrocyte sedimentation rate (ESR), and mean 
corpuscular volume (MCV). 
7.2.2 
Clinical Chemistry 
Blood will be obtained and sent to each Site’s clinical chemistry laboratory for determination 
of serum glucose, urea, creatinine, sodium, potassium, chloride, calcium, phosphorus, Protein 
(total), albumin, cholesterol, triglycerides, aspartate aminotransferase (AST/SGOT), alanine 
aminotransferase (ALT/SGPT), gamma-glutamyl transferase (GGT), alkaline phosphatase and 
high-density lipoprotein (HDL).   
The physician in charge or designee will assess each routine laboratory abnormal value to 
determine if it is clinically significant. For the patients included in the study, the laboratory 
values and the assessments will be documented in the study raw data and reported in the final 
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7.2.3 
Urinalysis 
 Urine will be obtained for determination of colour, appearance, specific gravity, pH, leukocyte, 
protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, creatinine.  
7.2.4 
Pregnancy Test 
A Beta HCG serum pregnancy test will be performed from female subjects who are of 
childbearing age prior to their participation in the study and at EoS or WV (See Table 1). A 
urine pregnancy test will be made the date of randomisation to women who are of childbearing 
age and who, despite using a contraceptive method, have doubts about a possible pregnancy 
during the study treatment period. 
7.3 
Other tests 
7.3.1 
12-lead ECG  
Cardiac dysfunction will be monitored by 12-lead ECGs, including assessment of QT Interval 
(in triplicate and ≥ 1 minute between measures) 
7.4 
Drug Administration Procedure 
The study drugs will be taken by each subject strictly according to the protocol scheme. 
Four oral doses of the assigned administration will be taken three times a day at meal times 
(breakfast, lunch and dinner) by the patients according to protocol scheme: patient to place 
NFX88 or placebo tablets directly from the blister onto their mouth and swallowed one after 
the other, with water until completing the 4 doses. Every tablet must be swallowed whole and 
must not be chewed or broken.  
7.5 
Other Safety Measurements 
Extension of the cephalic sensory deficit and increased spasticity might mean a worsening of 
the neurological deficit. Non-worsening of spasticity and motor score will be obtaining as the 
non-increase of the scales values MAS (Annex 2) and ASIA (Annex 1), respectively, from the 
beginning to the end of the treatment. 
- Modified Ashworth Scale (MAS): This tool is completed by the physician. MAS tests 
resistance during passive soft-tissue stretching and is used as a simple measure of spasticity. 
The physician asks the patient to move a limb though its full range of movement and scores 
the patient according to the following scale. Scores range from 0-4, with 6 choices (0, 1, 1+, 
2, 3 and 4). A score of 0 indicates normal tone, and 4 indicates rigidity. See the scale in 
Annex 2.  
- ASIA Scale: This tool is completed by the physician. Injuries are classified in general terms 
of being neurologically “complete” or “incomplete” based upon the sacral sparing definition. 
“Sacral Sparing” refers to the presence of sensory or motor function in the most caudal sacral 
segments as determined by the examination. It divides spinal cord injuries into 5 categories 
(A-E), A score of A indicates “Complete: No sensory or motor function is preserved in sacral 
segments S4-S5” and E indicates “Sensory and motor functions are normal”. A complete 
injury is defined as the absence of sacral sparing (i.e. sensory and motor function in the 
lowest sacral segments, S4-5), whereas an incomplete injury is defined as the presence of 

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sacral sparing (i.e. some preservation of sensory and/or motor function at S4-5). Moreover, 
this evaluation provides information about sensory motor level. The expected results 
important for safety are no changes or improvement of sensory and motor sub-scale, no 
changes or lowering of the neurological level and no changes or improvement of ASIA. See 
the scale in Annex 1. 
7.6 
Efficacy Measurements 
The improvement in pain will be obtained from:  
* the decrease in the scale values of VAS (Annex 3) and PD-Q (Annex 4) from the baseline to 
the end of treatment. 
* the score on the PGIC scale (Annex 5) at V3, EoT or WV.  
- Visual analogue scale (VAS): Pain intensity. Patients are asked to rate the intensity of their 
pain on average. 10-cm horizontal line presented to patients, with “no pain” as an anchor at 
the left end and “worst pain ever” as an anchor on the right end of the line; patients are 
instructed to estimate pain intensity by marking on the line the place where pain intensity 
falls since last week. See the scale in Annex 3. 
- Pain-DETECT (PD-Q): The questionnaire consists of 7 questions that address the quality 
of neuropathic pain symptoms; it is completed by the patient and no physical examination 
is required. The first five questions ask about the gradation of pain, scored from 0 to 5 
(never = 0, hardly noticed = 1, slightly = 2; moderately = 3, strongly = 4, very strongly = 5). 
Question 6 asks about the pain course pattern, scored from –1 to 2, depending on which 
pain course pattern diagram is selected. Question 7 asks about radiating pain, answered as 
yes or no, and scored as 2 or 0 respectively. The final score between 1 and 38, indicates the 
likelihood of a neuropathic pain component. A score of ≤ 12 indicates that pain is unlikely to 
have a neuropathic component (< 15%), while a score of ≥ 19 suggests that pain is likely to 
have a neuropathic component (> 90%). A score between these values (12-19) indicates that 
the result is uncertain, and a more detailed examination is required to ensure a proper 
diagnosis. See the scale in Annex 4. 
- Patient Global Impression of Change (PGIC): This tool is completed by the patient and 
evaluates from patient’s perspective the improvement or worsening of his/her condition after 
a treatment approach has been tried. One question is used that is suited to the situation (From 
the beginning of treatment in this hospital until now, how would you describe the change (if 
any) in pain related to your post-traumatic condition?; response ranging from “Very much 
worse” to “Very much improved”. Score assigned by de physician range from 1 to 7:  Very 
much improved (7), Much improved (6), Minimally improved (5), No change (4), Minimally 
worse (3), Much worse and Very much worse (1). See the scale in Annex 5.  
7.7 
Mobile Application 
Patients will be closely monitored during treatment and follow-up periods of the study by 
means of an electronic application (app) which will work a central system management alerts 
to remind patients some of the trial procedures. They must use this app daily for entering data 
on treatment compliance. The subjects may also receive warning messages from the electronic 
app advising them to contact the site PI or appointed study staff, if necessary. 

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8. EVALUATIONS PER VISIT  
8.1 
Screening Visit (SV): 7 days to V1 
1. Review the study and obtain written informed consent. 
2. Record demographic and baseline characteristics (date of birth, sex, race, weight, 
alcohol and smoking habits). 
3. Record a detailed medical history, including a history primary diagnosis and staging of 
neuropathic pain, diagnosis date, and prior treatments.  
4. Females of child-bearing potential must be a negative serum pregnancy test and must 
be willing to practice appropriate contraceptive methods for the duration of the study 
(e.g. oral contraceptive, double barrier method, intra-uterine device, intra muscular 
contraceptive).  
5. Perform neurological examination, complete the information and record scoring of 
ASIA scale. 
6. Record scoring of MAS scale. 
7. Vital signs (blood pressure, pulse rate, temperature). 
8. Make sure the patient completes the information and record scoring of VAS and PD-Q 
questionnaires. 
9. Confirm patient eligibility (inclusion/exclusion criteria). 
10. Review of intercurrent illness (es), concomitant diseases. 
11. Record concomitant medication. 
12. Collect blood and urine for clinical laboratory test: haematology, clinical chemistry, 
urinalysis and pregnancy test for women of child-bearing potential. 
13. Obtain a 12-lead electrocardiogram, including QT interval. 
14. Perform any other examination according to investigator discretion. 
15. Schedule subject for Visit 1 in 1-7 days. 
8.2 
Treatment period 
8.2.1 
Visit 1 (V1): Day 1 (±3 days), Randomisation day and start of treatment 
1. Patient eligibility confirmation. 
2. Urine pregnancy test for women of child-bearing potential.  
3. All male patients must take adequate contraceptive precautions during the study.  
4. Vital signs (blood pressure, pulse rate, temperature). 
5. Randomisation NFX88 (1.05, 2.10 and 4.20 g) vs Placebo (1:1:1:1 ratio). 
6. Make sure the patient completes VAS and PD-Q questionnaire and record the scoring. 
7. Record scoring of MAS and ASIA scales. 

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8. Review of intercurrent illness (es), concomitant diseases. 
9. Concomitant medication review. 
10. Assessment and recording of AEs. 
11. Training session for mobile device App 
12. Perform any other examination according to investigator discretion. 
13. Dispensation of study drug. 
14. Schedule subject for Visit 2 in 30 days. 
8.2.2 
Visit 2 (V2): Day 30 (±3 days) 
1. Vital signs (blood pressure, pulse rate, temperature). 
2. Collect blood and urine for clinical laboratory test: urinalysis, haematology and clinical 
chemistry.  
3. Make sure the patient completes VAS and PD-Q questionnaire and record the scoring. 
4. Record scoring of MAS and ASIA scales. 
5. Obtain a 12-lead electrocardiogram, including QT interval. 
6. Dispensation and accountability of study drug. 
7. Review subject dosing compliance. 
8. Review of intercurrent illness(es), concomitant diseases. 
9. Record changes to concomitant medications. 
10. Record any Adverse Events.  
11. Perform any other examination according to investigator discretion. 
12. Schedule subject for Visit 3 in 60 days from V1. 
8.2.3 
Visit 3 (V3): Day 60 (±3 days) 
1. Vital signs (blood pressure, pulse rate, temperature). 
2. Collect blood and urine for clinical laboratory test: urinalysis, haematology and clinical 
chemistry.  
3. Make sure the patient completes VAS, PD-Q and PGIC questionnaires and record the 
scoring. 
4. Record scoring of MAS and ASIA scales.  
5. Obtain a 12-lead electrocardiogram, including QT interval. 
6. Dispensation and accountability of study drug. 
7. Review subject dosing compliance. 
8. Review of intercurrent illness (es), concomitant diseases. 
9. Record changes to concomitant medications. 

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10. Record any Adverse Events.  
11. Perform any other examination according to investigator discretion. 
12. Schedule subject for Visit 4 in 90 days from V1. 
8.2.4 
Visit 4 (EoT): Day 90 (±3 days), end of treatment 
1. Vital signs (blood pressure, pulse rate, temperature). 
2. Collect blood and urine for clinical laboratory test: urinalysis, haematology and clinical 
chemistry.  
3. Make sure the patient completes VAS, PD-Q and PGIC questionnaires and record the 
scoring. 
4. Record scoring of MAS and ASIA scales. 
5. Obtain a 12-lead electrocardiogram, including QT interval. 
6. Accountability of study drug. 
7. Review subject dosing compliance. 
8. Review of intercurrent illness(es), concomitant diseases. 
9. Record changes to concomitant medications. 
10. Record any Adverse Events.  
11. Perform any other examination according to investigator discretion. 
12. Schedule subject for Follow-up visit in 120 days from V1.  
8.3 
Post Treatment Period 
8.3.1 
 Visit 5 (EoS/FU): Day 120 (±3 days), end of study or follow up visit  
For those patients who complete the treatment period and perform Follow-Up visit as per 
protocol, the Follow-Up visit will be considered the End of Study visit.  
1. Vital signs (blood pressure, pulse rate, temperature). 
2. Collect blood and urine for clinical laboratory test: urinalysis, haematology, clinical 
chemistry and pregnancy test for women of child-bearing potential  
3. Make sure the patient completes VAS and PD-Q questionnaire and record the scoring. 
4. Record scoring of MAS and ASIA scales.  
5. Obtain a 12-lead electrocardiogram, including QT interval. 
6. Review of intercurrent illness(es), concomitant diseases. 
7. Record changes to concomitant medications. 
8. Record Adverse Events (only those open or new due to an AE related or suspected to 
be related to study drug). 
9. Females of child-bearing potential must be a negative serum pregnancy test. 
10. Perform any other examination according to investigator discretion. 

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8.3.2 
Withdrawal Visit (see reasons for withdrawal in section 5) 
Those patients that are withdrawn before completing the treatment period or follow-up period 
will need to perform a visit, which should be scheduled once this decision is taken. Whenever 
feasible the following assessments should be done for withdrawn patients:  
1. Vital signs (blood pressure, pulse rate, temperature). 
2. Collect blood and urine for clinical laboratory test: urinalysis, haematology, clinical 
chemistry and pregnancy test for women of child-bearing potential.  
3. Make sure the patient completes VAS, PD-Q and PGIC questionnaires and record the 
scoring. 
4. Record scoring of MAS and ASIA scales.  
5. Obtain a 12-lead electrocardiogram, including QT interval. 
6. Accountability of study drug. 
7. Review subject dosing compliance. 
8. Review of intercurrent illness(es), concomitant diseases. 
9. Record changes to concomitant medications. 
10. Record any Adverse Events.  
11. Females of child-bearing potential must be a negative serum pregnancy test. 
12. Perform any other examination according to investigator discretion. 
 
9. SAFETY ASSESMENT 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
9.1 
Safety Parameters 
9.1.1 
Definition of adverse events 
An adverse event (AE) is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. Abnormal laboratory values or test results occurring after 
informed consent constitute AE only if they induce clinical signs or symptoms, are considered 
clinically significant, require therapy (e.g., hematologic abnormality that requires transfusion 
or haematological stem cell support), or require changes in study medication(s). 
Except for screening failures, AE that begin or worsen after informed consent should be 
recorded in the AE eCRF. Conditions that were already present at the time of informed 
consent should be recorded in the Medical Record and eCRF. AE monitoring should be 
continued for at least 30 days following the last dose of study treatment. AE (including 
laboratory abnormalities that constitute AEs) should be described using a diagnosis whenever 

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possible, rather than individual underlying signs and symptoms. When a clear diagnosis 
cannot be identified, each sign or symptom should be reported as a separate AE. 
AE will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0. If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, and life-threatening, corresponding to Grades 1-4, will be used. CTCAE 
Grade 5 (death) will not be used in this study; rather, information about deaths will be 
collected though the End of Treatment or Study Completions Forms. 
The occurrence of AE should be sought by non-directive questioning of the patient (subject) 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events may also be detected when they are reported by the patient (subject) during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each AE should be evaluated to determine: 
- 
The severity grade (CTCAE Grade 1-4) 
- 
Its duration (Start and end dates) 
- 
Its relationship to the study treatment (Reasonable possibility that AE is related) 
- 
Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
- 
Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy). 
- 
Whether it is serious, where a serious adverse event (SAE) is defined as in Section 19.1.3. 
- 
All AE should be treated appropriately. If a concomitant medication or non-drug therapy 
is given, this action should be recorded on the AE eCRF. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
9.1.2 
Laboratory test abnormalities 
Abnormal results will be verified to rule out laboratory error. Laboratory abnormalities that 
constitute an AE in their own right (because are considered clinically significant, induce 
clinical signs or symptoms, require concomitant therapy or require changes in study 
treatment), should be recorded on the AE eCRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anaemia instead of low haemoglobin). Laboratory 
abnormalities that meet the criteria for AE should be followed until they have returned to 
normal or an adequate explanation of the abnormality is found. When an abnormal laboratory 
or test result corresponds to a sign/symptom of an already reported AE, it is not necessary to 
separately record the laboratory /test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an AE, should not be reported as 
AE.  

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9.1.3 
Definition of serious adverse events 
Serious adverse event (SAE) is defined as one of the following: 
- 
It is fatal or life-threatening 
- 
It requires inpatient hospitalization or prolongation of existing hospitalization  
- 
It results in persistent or significant disability/incapacity 
- 
It constitutes a congenital anomaly/birth defect 
- 
It is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Note that treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a 
serious adverse event. 
If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to Neurofix s.l. or designee (QualitecFarma s.l.). 
9.1.4 
Definition of adverse events of special interest (AESI) 
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring and rapid communication by the 
investigator to Sponsor. An AESI may be serious or non-serious. The quick reporting of 
AESIs allows ongoing analysis of these events to characterize and understand them in 
association with the use of this investigational product. 
NFX88 has confirmed an excellent pattern of safety and tolerability with no relevant adverse 
event observed at any administered dose in previous Phase I studies conducted. In that study, 
some gastrointestinal symptoms appeared in doses of 16 g per day (which could be the result 
of the large amount of excipients, mainly mannitol). However, provided that in this study, the 
amounts of API and excipients will be lower than those used in the previous study, the 
company does not include the monitoring of AESIs. 
However, considering that gastrointestinal symptoms has appeared in one of the previous 
studies with NFX88, sponsor contemplates to closely monitor the occurrence of this symptom 
during the present study in order to obtain more information on NFX88 safety profile and its 
relationship with the appearance of gastrointestinal symptoms. 
9.2 
Assessment of safety parameters 
9.2.1 
Assessment of severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. Severity will be graded according to the NCI CTCAE v5.0. 
The determination of severity for all other events not listed in the CTCAE should be made by 
the investigator based upon medical judgment and the severity categories of Grade 1-5 as 
defined below: 

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It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the above criteria. A Grade 3 AE need 
not necessarily be considered an SAE. For example, a Grade 3 headache that persists for 
several hours may not meet the regulatory definition of an SAE and would be considered a 
non-serious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 
9.2.2 
Assessment of relationship 
Assessment of relationship to either investigational product or study procedures will be made 
by investigator. 
9.3 
Documentation and Reporting of Adverse Events 
Adverse events will be recorded using a recognized medical term or diagnosis that accurately 
reflects the event. Adverse events will be assessed by the investigator for severity, relationship 
to the investigational product, possible aetiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to Neurofix s.l. or designee (QualitecFarma 
s.l.). 
The following variables will be collected at least for each AE: 
- 
AE (verbatim) 
- 
The date <<and time>> when the AE started and stopped 
- 
Changes in NCI CTCAE grade  
- 
Whether the AE is serious or not 
- 
Investigator causality rating against NFX88 (yes or no) 
- 
Action taken regarding NFX88 or placebo treatment 
- 
Outcome 
Patients will be questioned on their health status in each study visit before departing from the 
clinical Site. Open-ended questions will be asked. Out of those occasions, patients will have 
opportunity to contact the investigator to report any adverse event taking place.  

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Classification will be performed by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA), version 21.0 or higher.  
9.4 
Serious Adverse Event Reporting Requirements and Documentation 
For patients who sign the main study ICF, SAE collection starts at the time of main study 
informed consent whether the patient is a screening failure or not. SAEs will be followed until 
resolution or until clinically relevant improvement or stabilization. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Neurofix s.l. or designee (QualitecFarma s.l.) within 24 
hours of learning of its occurrence. Any SAEs experienced after this 30-day period should be 
only reported to Neurofix s.l. or designee (QualitecFarma s.l.) if the investigator suspects a 
causal relationship to the study treatment. Recurrent episodes, complications, or progression of 
the initial SAE must be reported to Neurofix s.l. or QualitecFarma s.l. as follow-up to the 
original episode within 24 hours of the investigator receiving the follow-up information. A 
SAE occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the SAE Reporting Form (see SAE 
Reporting Manual/QualitecFarma’s SOP). This includes SAE observed in the investigational 
drug group and in the placebo group (e.g., reference). This notification will contain a 
description of the observed symptoms and an assessment of causality. A detailed report will be 
sent in the following days containing, in addition the information below: 
- 
Date AE met criteria for serious AE 
- 
Date Investigator became aware of serious AE 
- 
AE is serious due to 
- 
Date of hospitalization 
- 
Date of discharge 
- 
Probable cause of death 
- 
Date of death 
- 
Autopsy performed 
- 
Description of AE 
- 
Causality assessment in relation to Study procedure(s) 
The investigator must assess and record the relationship of each SAE to the study treatment in 
source documents and CRF, complete the SAE Report Form in English, and send the 
completed, signed form by email or fax within 24 hours to the responsible person in Neurofix 
s.l. or designee (QualitecFarma s.l.). 
The contact data of responsible personnel for pharmacovigilance in QualitecFarma s.l. is listed 
below: 
Laura Florez / Mª Eugenia Díaz 

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Phone: (+34) 913 728 399 / 400 
email: drug.safety@qualitecfarma.com 
The original copy of the SAE Report Form and the e-mail confirmation must be kept with the 
CRF documentation at the study Site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
A SAE will be considered as "unexpected" when the nature or severity is not consistent with 
information in the relevant source document(s). The sponsor or designee is responsible for 
assessing whether the SAE is expected or not.  
If the SAE is not previously documented in the Investigator’s Brochure (new occurrence) and 
is thought to be related to the Neurofix’s study treatment, Neurofix s.l. or designee 
(QualitecFarma s.l.) with advice of the medical advisory board may urgently require further 
information from the investigator for deciding on meeting requirements for expedited report to 
the AEMPS. Neurofix s.l. or designee (QualitecFarma s.l.) may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSAR) will be 
collected and reported to the competent authorities in accordance with Regulation (EU) No 
536/2014 and national regulatory requirements in Spain (RD 1090/2015).    
9.4.1 
Reporting of deaths 
All deaths that occur during the study or within the protocol-defined 30-day post-last-dose of 
NFX88 safety follow-up period must be reported as follows: 
1. Death that is clearly the result of disease progression should be documented but should 
not be reported as a SAE. 
2. Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to as a SAE within 24 hours. The report should 
contain a comment regarding the co-involvement of progression of disease, if appropriate, 
and should assign main and contributory causes of death. 
3. Deaths with an unknown cause should always be reported as a SAE. An autopsy maybe 
helpful in the assessment of the cause of death, and if performed an anonymized copy of 
the autopsy results should be forwarded to Neurofix s.l. or designee (QualitecFarma s.l.) 
within the usual timeframes. 
4. Deaths that occur following the protocol-defined 30-day post-last-dose of NFX88 
treatment safety follow-up period will be documented “as events for survival analysis” but 
will not be reported as an SAE. 

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9.4.2 
Other Events Requiring Reporting 
Pregnancy 
Patients who become pregnant during the study should discontinue the study immediately. 
Patients should be trained to notify the Investigator as soon as possible if they became 
pregnant during any phase of the study or immediately following the end of the study. 
The investigator or designee will record pregnancy on a Pregnancy Report Form and report 
Neurofix s.l. or designee (QualitecFarma s.l.) within 24 hours of the knowledge of its 
occurrence. Because of the possibility that the foetus/embryo could have been exposed to the 
study drug through the parent and for the subject’s safety, the pregnancy follow-up will also 
be properly recorded to ensure quality and completeness of the data belonging to the study 
drug and will include an assessment of the possible causal relation between the study drug and 
any pregnancy outcome, including spontaneous or voluntary termination, details of birth, 
presence or absence of any birth defects, congenital anomalies, or maternal and/or new-born 
complications.  
Women of child-bearing potential  
Women who are not postmenopausal (at least 12 months) or surgically sterile must have a 
negative serum pregnancy test at screening and at the end of study or WV. Furthermore, they 
must have a negative urine pregnancy test at randomisation. 
Women of child-bearing potential must agree to use a highly effective method of birth control 
or to abstain from sexual intercourse for the duration of the study and after 12 weeks after the 
last dose of study drug. 
Male subject’s partners pregnancy 
Men patients must agree to use effective contraception or remain abstinent, and refrain from 
donating sperm for the duration of the study and after 12 weeks after the last dose of study 
drug. 
Male patients should be instructed to notify the Investigator if it is determined that during the 
study or after completion of the study that their partner became pregnant during the treatment 
phase of the study. 
Whenever possible any pregnancy should be followed to term, any premature terminations 
reported, and the status of the mother and child should be reported to the Neurofix s.l. or 
designee (QualitecFarma s.l.) after delivery. 
9.5 
Study Recording Period and Follow-Up for AEs and SAEs 
For the purposes of this study, the period of observation of clinical events extends from the 
signed ICF until 30 days after the last administration of the study drug. During this period, all 
clinical events spontaneously reported by the subject, observed by the clinical staff or obtained 
by general questioning will be recorded on a AE form sheet reported in the eCRF. 
During the study, all AEs and SAEs should be proactively followed up for each subject. Every 
effort should be made to obtain a resolution for all events, even if the events continue after 
discontinuation/study completion. 

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The investigator is responsible for following all SAEs until resolution, until the subject returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
9.5.1 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last visit in the study will be followed up by the 
investigator if medically indicated, but without further recording in the eCRF. After 30 days, 
only patients with ongoing investigational product-related SAEs will continue to be followed 
for safety. Neurofix s.l. or designee (QualitecFarma s.l.) retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) until the end of the study, if judged 
necessary. 
10. STATISTICAL METHODS 
(A separate Statistical Analysis Protocol is developed for this trial. Here we describe the main 
methods that will be used for the statistical analysis). 
10.1 Variable examination and baseline comparisons. 
A descriptive analysis of baseline variables and descriptive comparisons in the four trial arms 
will be performed. No inference tests are needed at baseline as this is a randomized study.  
Categorical variables will be described with proportions and continuous variables will be 
described with means, standard deviations, medians and quartiles to examine their possible 
non-symmetrical distribution. Key continuous outcome variables will be examined for 
skewness and outliers, and suitable transformations (such as logarithms and roots) will be tried 
if needed to normalize the variable. 
10.2 Safety Assessment (Main Objective) 
Sample: The safety population will include all patients who were randomised, including those 
that withdrew for any reasons. 
Coding: For the analysis, each adverse event (AE) will be coded as a binary variable 
(Present/Absent) in each study subject. AEs defined as “unsafe levels” of some laboratory 
parameter or clinical biomarker will be also coded as binary. If the same AE can occur at 
different degrees of severity several binary variables will be constructed. 
Analysis:  Tables with counts and proportions of each AE in each arm will be compiled. For 
the intervention arms, exact confidence intervals for the proportion of each AE will be 
estimated. Comparison of the risk of each EA between arms will be done with Fisher’s exact 
tests. To increase power, the patients from the three intervention doses will be analysed 
together in one intervention arm. If some AE turned out to be relatively common, a logistic 
regression model will be built to examine if there is a dose-response effect on the probability 
of such adverse event. 
10.3 Efficacy Assessment (Secondary Objective) 
Sample: The efficacy analysis will include all patients who were randomised, had at least 
75% of treatment compliance and completed the appropriate questionnaires of VAS, PD-Q 
and PGIC. 

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Coding: The efficacy variable VAS will be coded as a continuous variable. It cannot have 
outliers as is limited between 0 and 10 by construction. PD-Q will be coded as continuous 
(from 0 to 38) but also a categorical variable with categories (<12, 12-19 and >10) as 
explained in section 7.5 and annex 4). PGIC will be coded as a categorical. 
Analysis: The efficacy variables VAS will be analysed with a regression model to evaluate if 
changes from baseline (V1) to the last available questionnaire (ideally EOT) depend on 
treatment, while adjusting for baseline to account for the possible “regression to the mean” 
effect [Senn SS, 2007]. If there are large imbalances of times between the two questionnaires 
between the trial arms, we will adjust the models for this covariate. Model’s residuals will be 
checked visually and through normality tests. Separate models will be built using the original 
scale of the variable and its log-transformation, to study the possible proportional effect of the 
intervention. PD-Q will be analysed in an analogous way as VAS as a continuous variable. 
However, we will also analyse PD-Q as a categorical variable with a multinomial regression to 
evaluate if the probability of having a neuropathic component of the pain depends on 
treatment. PGIC will be analysed as a categorical variable with multinomial logistic regression 
(recoding in three categories: worsening, no change and improvement due to the small sample 
size).  All analyses will be done twice: first using the treatment variable as binary 
(placebo/intervention) and then coding the treatment into four categories of doses (where 
placebo arm has dose =0).  
 
 
11. REGULATORY REQUIREMENTS 
11.1 Liabilities 
It is the Sponsor’s responsibility to guarantee enough insurance coverage should any serious 
events or deaths result directly or not from the execution of the present protocol. 
11.2 Statement of Investigator 
The Investigator’s agreement with protocol will be signed by the site Investigator responsible 
for the medical decisions and care provided to the patients prior to the commencement of his 
responsibilities with respect to the clinical trial, as required by the Regulatory Authorities. The 
undertaking form will be maintained with the trial records and will be made available upon 
request. 
11.3 Delegation of Investigator Duties 
The qualified investigator will ensure that all personnel involved in the trial are adequately 
qualified and informed about the protocol, any amendments to the protocol, the study 
treatments, and their trial-related duties and functions. 
The qualified investigator will maintain a list of sub-investigators and other appropriately 
qualified professionals to whom he delegates significant trial-related duties. 
The qualified investigator should delegate the supervision of the investigational product 
administration to a designated person, this individual must have the appropriate medical 
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11.4 Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
Guidelines as drawn up by the IRB/IEC will be followed with regard to the treatment of 
human patients in the study. These guidelines meet the requirements of the Declaration of 
Helsinki and Regulation (EU) No 536/2014. 
This protocol and the ICF among other required documentation will be submitted to an 
IRB/IEC prior to initiation of the study and the study will not start until the Board has 
approved the documents. Notification of the Board’s approval will be appended to the final 
report. 
Before inclusion in the study, each prospective subject will be given a full explanation of the 
purpose of the study, the procedures to be carried out and the potential hazards. Once this 
essential information is provided to the patient and once the physician in charge or designee 
has the conviction that the patient understands the implications of participating in the study, 
he/she will be required to read, sign and date a properly executed written informed consent 
form prior to enrolment. Patients will be assured that they may withdraw from the study at any 
time without jeopardizing their medical care. They will be given a copy of their informed 
consent form. 
If an amended or revised ICF is introduced during the study, each subject’s further consent 
should be obtained. 
11.5 Case Report Form (CRF) 
eCRF will be limited access by user at any time on-line in the eCRF webpage. Please review 
Study eCRF manual and procedures for additional information.  
Corresponding Users and Passwords will be provided once Site is activated and has received 
applicable training. 
Once all eCRF are completed and reviewed, the eCRF will be approved and signed by the 
Investigator.  
11.6 Record Retention 
All essential documents and records will be maintained at Sponsor for a period of 25 years. 
These documents may be retained for a longer period if needed by the Sponsor. 
11.7 Quality Assurance 
QualitecFarma will be responsible for maintaining an adequate study quality and quality 
control (QC) systems with written SOPs to ensure that the trial is conducted, and data are 
generated, documented and reported in compliance with the protocol, Good Clinical Practice 
(GCP), Good Laboratory Practice (GLP) and the applicable regulatory requirements. 
The study will be conducted according to ICH E6 GCP.  
11.8 Monitoring of The Study 
The Sponsor or its representative may visit the study facilities at any time in order to maintain 
current and personal knowledge of the study through review of the records, comparison with 
source documents, observation and discussion of the conduct and progress of the study. Sites 

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involved will permit trial-related monitoring visits, audits, IRB/IEC review, and regulatory 
inspection(s) by providing direct access to source data/documents. 
11.9 Data Management and Processing 
Data will be entered by the investigator in the eCRF that will feed the study database. Study 
investigators, trial monitor and statisticians will have access to the data with different permits 
according to their role and their needs, but they will be blinded to the patient’s allocation. 
Allocation information will be saved in a restricted table of the database that will be fully 
revealed only after the end of the trial when the main analysis has been performed. Un-
blinding of a specific patient will be possible upon request of the trial investigator or the 
patient’s physician if a SAE is detected. 
The eCRF will have basic data checking possibilities and will alert of any suspected incorrect 
value when the data is entered. The system will also have a facility for data validation by the 
trial monitor.  Once the trial is finalised and the dataset closed, the statisticians will proceed to 
do data checking for outliers and suspicious values running different statistical algorithms. If 
any of these are found, they will be checked back with the trial investigators and the patient’s 
records.  When all these issues are solved, a final data set for analysis will be saved and 
closed.  On this data, the statistician will proceed to run the different analysis for main and 
secondary outcomes. 
At all times, the system will keep the data safe by limiting the access to authorise personnel 
with appropriate security restrictions such as passwords and encryption. The system will 
comply with data security regulations of the European Union and Spain.  
11.10 Premature Termination or Suspension of a Study 
The Sponsor or its representative may terminate the study at any time for scientific or 
corporate reasons. 
If the trial is prematurely terminated or suspended for any reason, Sponsor, CRO or the 
qualified investigator should promptly inform the trial patients, should assure appropriate 
therapy and follow-up for the patients and, where required by the applicable regulatory 
requirement(s), should inform the Regulatory Authority(ies). All procedures should be done 
according to defined SOPs.  
11.11 Adherence to Protocol 
Excluding an emergency in which proper treatment is required for the protection, safety and 
well-being of the study patients, the study will be conducted as described in the approved 
protocol and performed according to ICH/GCP guidelines. Any deviation from the protocol 
will be recorded and explained. 
If major amendments to the protocol and/or major amendments or revisions to the ICF are 
required, the modifications will be documented and submitted to an IRB/IEC and Health 
Authority(ies) for approval. 
12. REFERENCES 
1. Afsar SI et al. Spinal Cord Injury: Treatment & Rehabilitation. Int J Phys Med 
Rehabil 2014; 2: 5. 

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2. Alemany R, Vogler O, Terés S, Egea C, Baamonde C, Barceló F, Delgado C, Jakobs 
KH and Escriba PV. Antihypertensive action of 2-hydroxyoleic acid in SHRs via 
modulation of the protein kinase A pathway and Rho kinase. Journal of Lipid 
Research Volume 47, 2006. 
3. Alemany, R., Teres, S., Baamonde, C., Benet,  M., Vogler, O., Escriba, P.V. (2004). 
2-hydroxyoleic acid: A new  hypotensive molecule. Hypertension 43, 249–254. 
4. Ashworth B. Preliminary trial of carisoprodol in Multiple Sclerosis. Practitioner 
1964: 192: 540-542.Ataoaylu E, Tiftik T, Kara M, Tuna H, Ersaz M, et al. Effects of 
chronic pain on quality of life and depression in patients with spinal cord injury. 
Spinal Cord 2013; 51: 23-26. 
5. Avila-Martin G, Galan-Arriero I,  Ferrer-Donato A, Busquets X, Gomez-Soriano J, 
Escribá PV and Taylor J. Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and 
open–field induced anxiety after spared nerve injury. Eur J Pain 2015; 19: 111-122. 
6. Avila-Martin G, Galan-Arriero I, Gómez-Soriano J, Taylor J (2011) Treatment of Rat 
Spinal Cord Injury with the Neurotrophic Factor Albumin-Oleic Acid: Translational 
Application for Paralysis, Spasticity and Pain. PLoS ONE 6(10): e26107. 
https://doi.org/10.1371/journal.pone.0026107. 
7. Avila-Martin G, Mata-Roig M, Galán-Arriero I, Taylor JS, Busquets X, Escribá PV 
(2017). Treatment with albumin-hydroxyoleic acid complex restores sensorimotor 
function in rats with spinal cord injury: Efficacy and gene expression regulation. PLoS 
ONE 12(12): e0189151. 
8. Baastrup C & Finnerup NB. Pharmacological management of neuropathic pain 
following spinal cord injury. CNS Drugs 2008; 22: 455-475. 
9. Barceló-Coblijn G, et al. Sphingomyelin and sphingomyelin synthase (SMS) in the 
malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy. Proc 
Natl Acad Sci U S A. Dec 6; 2011; 108(49); 19569–19574. 
10. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of 
muscle spasticity. Physical Therapy 1987; 67: 206-207.Calmels P, Mick G, Perrouin-
Verbe B, Ventura M. Neuropathic pain in spinal cord injury: identification, 
classification, evaluation. Ann Phys Rehabil Med. 2009; 52(2): 83–102.  
11. Bryce TN, Wang H, Weidner N. Spinal Cord Injury Pain Instrument and 
painDETECT questionnaire: Convergent construct validity in individuals with Spinal 
Cord Injury. Eur J Pain. 2017 Nov;21(10):1642-1656. doi: 10.1002/ejp.1069. Epub 
2017 Jun 27. 
12. Calmels P et al. Neuropathic pain in spinal cord injury_identification, classification, 
evaluation. Ann Phys Rehabil Med. 2009; 52(2): 83-102. 
13. De Andrés J et al. Cultural adaptation and validation of the PD-Q scale into Spanish. 
Clin J Pain. 2012 Mar-Apr 28 (3) 243-53. 
14. Den Ruijter HM, et al. Incorporated fish oil fatty acids prevent action potential 
shortening induced by circulating fish oil fatty acids. Front Physiol, 2010, 1:1-5. 

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15. Dijkers M. Prevalence of chronic pain after traumatic spinal cord injury: a systematic 
review. J Rehabil Res Dev. 2009; 46(1): 13-29. 
16. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001;94:149–158. 
17. Fernandez-Garcia P, Rossello CA, Rodriguez-Lorca R, Beteta-Göbel R, Fernandez-
Diaz J, Llado V, Busquets X, Escriba PV. The opposing contribution of 
sphingomyelin synthases, SMS1 and SMS2, to glioma progression and their value in 
the therapeutic response to 2OHOA. Submitted. 
18. Franz S, Schuld C, Wilder-Smith EP, Heutehaus L, Lang S, Gantz S, Schuh-Hofer S, 
Treede RD, Bryce TN, Wang H, Weidner N. Spinal Cord Injury Pain Instrument and 
painDETECT questionnaire: Convergent construct validity in individuals with Spinal 
Cord Injury. Eur J Pain. 2017 Nov;21(10):1642-1656. doi: 10.1002/ejp.1069. Epub 
2017 Jun 27. 
19. Freynhagen R, Baron R, Gockel U, et al. PD-Q: a new screening questionnaire to 
identify neuropathic components in patients with back pain. Curr Med Res Opin 2006. 
22: 1911-20. 
20. Gómez-Soriano J, Bravo-Esteban E, Pérez-Rizo E, Ávila-Martín GM, Galán-Arriero 
I, Simón-Martínez C et al (2016) Abnormal cutaneous flexor reflex activity during 
controlled isometric plantar flexion in human spinal cord injury spasticity syndrome. 
Spinal Cord 54:687-94. 
21. Guizy M, et al. w-3 and w-6 polyunsaturated fatty acids block HERG channels. Am J 
Physiolo Cell Physiol, 2005, 289:C1251-1260. 
22. Guy SD et al. The CanPain SCI Clinical Practice Guidelines Neuropathic Pain. Spinal 
Cord 2016; 54: S14-S23. 
23. Guy W. ECDEU Assessement Manual for Psychopharmacology, Revised 1976. US 
Government Printing Office; 1976. Rockville, Md. 
24. Hagen EM & Rekand T. Management of Neuropathic Pain Associated with Spinal 
Cord Injury. Pain Ther. 2015 Jun;4(1):51-65.  
25. Kirshblum SC et al. International standards for neurological classification of spinal 
cord injury (Revised 2011). The Journal of Spinal Cord Medicine 2011 34(6)535-546. 
26. Lee S et al. Central Neuropathic Pain in Spinal Cord Injury. Crit Rev Phys Rehabil 
Med. 2013 25(3-4) 159–172. 
27. Martinez, J., Vogler, O., Casas, J., Barcelo, F., Alemany, R., Prades, J., Nagy, T., 
Baamonde, C., Kasprzyk, P.G., Teres, S., Saus, C., Escriba, P.V. (2005). Membrane 
structure modulation, protein kinase C alpha activation, and anticancer activity of 
minerval. Mol Pharmacol 67, 531–540. 
28. Mathieson S and Lin C. painDETECT Questionnaire. Journal of Physiotherapy. 
Journal of Physiotherapy 2013 Vol. 59(3)211. 

NFX88-2A-2018 
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29. Merskey H and Bogduk N. IASP Task Force on Taxonomy. Classification of chronic 
pain. Description of chronic pain syndromes and definition of pain terms. 2nd ed. 
Seattle: IASP Press, Seattle, © 1994; 2005. 
30. Null A, Tjurina U, Erts R, Vetra A. A profile of traumatic spinal cord injury and 
medical complications in Latvia. Spinal Cord Series and Cases (2017) 3:17088. 
31. Rekand T et al (a). Spasticity following spinal cord injury. Tidsskr Nor Legeforen 
2012(8); 132: 970-3. 
32. Rekand T et al (b). Chronic pain following spinal cord injury. Tidsskr Nor Legeforen 
2012(8); 132:974-9. 
33. Senn SS (2007).  Statistical issues in drug development (2nd edn). Stephen Senn, 
John Wiley & Sons Ltd, Chichester, 2007 
34. Siddall PJ1, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the 
prevalence and characteristics of pain in the first 5 years following spinal cord injury. 
Pain. 2003 Jun;103(3):249-57. 
35. Singh A, Tetreault L, Kalsi-Ryan S, Nouri A, Fehlings G. Global prevalence and 
incidence of traumatic spinal cord injury. Clin Epidemiol 2014; 6:309-331. 
36. Teasell RW et all. A systematic review of pharmacologic treatments of pain after 
spinal cord injury. Arch Phys Med Rehabil 2010; 91: 816-831. 
37. U.S. Department of Health and Human Services. Food and Drug Administration 
(FDA). Center for Drug Evaluation and Research (CDER). Guidance for Industry. 
Estimating the máximum safe starting dose in initial clinical trials for therapeutics in 
adult healthy volunteers. Parmacology and Toxicology, July 2005. 
 
 
 

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Table 1.  Schedule of Study Visits 
ASSESSMENTS 
SCREENI
NG VISIT 
START OF 
TREATMENT
/BASELINE 
TREATMEN
T VISIT 
TREATMENT 
VISIT 
END OF 
TREATMENT 
FOLLOW-UP 
VISIT/END 
OF STUDY 
WITHDRAWAL 
VISIT 
SV 
V1 
V2 
V3 
V4/EOT 
V5/FU/EOS 
WV 
D -7 
D 1 a 
D 30 a 
D 60a 
D 90a 
D 120a 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
Demographic, alcohol and smoking habits 
X 
 
 
 
 
 
 
Neurological Examination (ASIA scale) 
X 
X 
X 
X 
X 
X 
X 
VAS questionnaire 
X 
X 
X 
X 
X 
X 
X 
Vital signs (temperature, blood pressure, pulse rate) 
X 
X 
X 
X 
X 
X 
X 
Urinalysis, Haematology and chemistry sample 
collection 
X 
 
X 
X 
X 
X 
X 
Pregnancy test sample collection (blood) 
X(b) 
X(u) 
 
 
 
X(b) 
X(b) 
12-lead ECG, QT interval 
X 
 
X 
X 
X 
X 
X 
PD-Q questionnaires 
X 
X 
X 
X 
X 
X 
X 
MAS scale 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
Intercurrent illness (es), concomitant diseases. 
X 
X 
X 
X 
X 
X 
X 
Drug Dispensation 
 
X 
X 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
 
X 
Subject dosing compliance 
 
 
X 
X 
X 
 
X 
PGIC questionnaire 
 
 
 
X 
X 
 
X 
Training session for mobile device App 
 
X 
 
 
 
 
 
Other Examination 
X 
X 
X 
X 
X 
X 
X 
a  
3 days  
u: Urine  
b: Blood 

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Annex 1. ASIA-ISNSCI Scale 
 

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Annex 2. Modified Ashworth Scale (MAS) 
ESCALA DE ASHWORTH MODIFICADA 
Fecha:  
 
Código del paciente: 
 
Nombre del Centro, Ciudad:   
 
 
Espasticidad según la Escala de Ashworth: [0] [1] [1+] [2] [3] [4] marcar lo que proceda 
 
No hay cambios en la respuesta del músculo en los movimientos de flexión o extensión. 0 
Ligero aumento en la respuesta del músculo al movimiento, solo mínima resistencia 
(catch). 
1 
Ligero aumento en la resistencia del músculo al movimiento en todo el resto del arco de 
movimiento. 
1+ 
Moderado incremento en la resistencia del músculo durante la mayor parte del arco de 
movimiento articular, pero se puede completar el arco de movimiento. 
2 
Marcado incremento en la resistencia del músculo; el movimiento pasivo es difícil. 
3 
Las partes afectadas están rígidas cuando se mueven pasivamente. 
4 
  
MIEMBRO 
SUPERIOR 
MIEMBRO 
INFERIOR 
NOTAS 
DERECHA 
  
  
  
IZQUIERDA 
  
  
  

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Annex 3. Visual Analogue Scale (VAS) 
ESCALA VISUAL ANALÓGICA (EVA) 
Fecha:  
 
Código del paciente: 
 
Nombre del Centro, Ciudad:   
 
 
 
Marque sobre la línea, entre los dos extremos, cuánto dolor siente en esta última semana. 
 
 
 
Firma del paciente: 
 
 
 
 
 
 

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Annex 4. PainDETECT Scale 
 

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Annex 5. Patient Global Impression of Change (PGIC) Scale 
 
 
ESCALA DE IMPRESIÓN DEL CAMBIO GLOBAL DEL PACIENTE 
Fecha:  
 
Código del paciente: 
 
Nombre del Centro, Ciudad:   
 
 
Desde el comienzo del tratamiento en este hospital hasta ahora, ¿cómo describiría el cambio 
(si existe) en el dolor relacionado con su condición post traumática? 
Marque con una (X) una sola respuesta. 
 
Gran mejoría  
 
 
Mejoría  
 
 
Leve mejoría  
 
 
Sin cambio  
 
 
Leve empeoramiento  
 
 
Empeoramiento  
 
 
Gran empeoramiento  
 
 
 
Firma del paciente: