An Observational, Single-Arm Study to Describe Pain Intensity, Pain Relief and Safety of Neosaldina in the Treatment of Tension-Type Headaches in Healthy Subjects
Conditions: Healthy Volunteers, Tension-type Headache
Sponsor: Takeda




Title: An Observational, Single-Arm Study to Describe Pain Intensity, Pain Relief and Safety of 
Neosaldina® in the Treatment of Tension-Type Headaches in Healthy Subjects 
NCT Number: NCT03666858
Protocol Approve Date: 27-July-2018 
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 1 of 33 
Non-Interventional Study Protocol 
Title: 
An Observational, Single-Arm Study to Describe Pain Intensity, Pain Relief 
and Safety of Neosaldina® in the Treatment of Tension-Type Headaches in 
Healthy Subjects 
Short title: 
Pain intensity and Pain Relief of Neosaldina® for Tension-Type Headaches 
Study ID: 
Neosaldina-5001 
Sponsor: 
Takeda Distribuidora Ltda. 
Rua do Estilo Barroco, 721 
04709-011 - São Paulo/SP – Brazil 
Phone:+ 55 11 5188 4400 
Study phase: Medical Affairs, Post-Approval Company Sponsored (Observational) 
Date of version 1.0 of protocol: 27-july-2018 
Property
n-commercial use only and subject to the applicable Terms of Use

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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 4 of 33 
 
 
 
INVESTIGATOR SIGNATURE PAGE 
I confirm that I have read and that I understand this protocol and any other product 
information provided by the sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also to protect the rights, safety, privacy, and well-being of 
study subjects in accordance with the following: 
 
- 
The ethical principles that have their origin in the Declaration of Helsinki. 
- 
International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
- 
All applicable laws and regulations, including, without limitation, data privacy laws 
and regulations. 
- 
Regulatory requirements for reporting serious adverse events as defined in this 
protocol. 
 
 
 
 
 
 
Signature of Investigator 
Date 
Investigator Name 
Investigator’s Title 
Location of Facility (City, State/Provence) 
Brazil 
Location of Facility (Country) 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 7 of 33 
 
 
 
Table of Contents 
1 
Administrative information ...................................................................................................... 2 
1.1 
Contacts ........................................................................................................................ 2 
1.2 
Approval ....................................................................................................................... 3 
2 
Introduction .......................................................................................................................... 10 
3 
Study Objective(s) and Endpoint(s) ........................................................................................ 11 
3.1 
Objective(s) ................................................................................................................. 11 
3.1.1 
Primary Objective .......................................................................................... 11 
3.1.2 
Secondary Objective(s) .................................................................................. 11 
3.1.3 
Exploratory Objective(s) ................................................................................ 11 
3.2 
Endpoint(s) ................................................................................................................. 12 
3.2.1 
Primary Endpoint .......................................................................................... 12 
3.2.2 
Secondary Endpoints ..................................................................................... 12 
3.2.3 
Exploratory Endpoint ..................................................................................... 12 
4 
Study Administrative Structure ............................................................................................... 12 
4.1 
Study Sites .................................................................................................................. 12 
4.2 
Sponsor Personnel ....................................................................................................... 13 
4.3 
Contract Research Organisation (CRO) ......................................................................... 13 
5 
Ethics ................................................................................................................................... 13 
5.1 
Ethical conduct of the Study ......................................................................................... 13 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities .................... 14 
5.3 
Authorities .................................................................................................................. 14 
5.4 
Subject Information and Written Informed Consent ........................................................ 14 
6 
Study Design and Plan ........................................................................................................... 15 
6.1 
Study Schedule ............................................................................................................ 16 
6.2 
Discussion of Study Design .......................................................................................... 16 
6.3 
Selection of Study Population ....................................................................................... 17 
6.3.1 
Inclusion Criteria ........................................................................................... 17 
6.3.2 
Exclusion Criteria .......................................................................................... 17 
6.3.3 
Enrollment .................................................................................................... 18 
6.3.4 
Study Discontinuation Criteria ........................................................................ 18 
6.4 
Treatments .................................................................................................................. 19 
6.5 
Premature Termination or Suspension of Study or Investigational Site ............................. 19 
6.5.1 
Criteria for Premature Termination or Suspension of the Study ........................ 19 
6.5.2 
Criteria for Premature Termination or Suspension of Investigational Sites .......... 19 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 8 of 33 
 
 
6.5.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ............................................................. 19 
6.6 
Study Plan ................................................................................................................ 20 
7 
Safety Reporting ................................................................................................................... 22 
7.1 
Definitions .................................................................................................................. 22 
7.2 
Collection and Recording of Adverse Events, Special Situation Reports and Product  
Quality Issues .............................................................................................................. 25 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory  
Agencies ..................................................................................................................... 25 
8 
Data Quality Control and Assurance ....................................................................................... 26 
8.1 
Quality Control ............................................................................................................ 26 
8.2 
Audit from Quality Assurance Unit ............................................................................... 27 
8.3 
Inspection by IRB/IEC or Competent Authority ............................................................. 27 
8.4 
Data Management ........................................................................................................ 27 
8.4.1 
Data Collection Tools and Flow .................................................................... 28 
9 
Statistical Methods and Determination of Sample Size ............................................................. 29 
9.1 
Statistical Analysis Plan ............................................................................................... 29 
9.2 
Interim Analyses .......................................................................................................... 30 
9.3 
Determination of Sample Size ...................................................................................... 30 
10 Reports ................................................................................................................................. 31 
11 Publication, Disclosure, and Clinical Trial Registration Policy .................................................. 31 
12 Archiving of Study Documentation ......................................................................................... 31 
13 References ............................................................................................................................ 33 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 9 of 33 
 
 
 
List of Abbreviations and Definition of Terms 
AE: 
Adverse Event 
ADR: 
Adverse Drug Reaction 
APP: 
Application 
CA: 
Competent Authority 
CCSI: 
Core Company Safety Information 
CRF: 
Case Report Form 
CRO: 
Contract Research Organisation 
CV: 
Curriculum Vitae 
DSO 
Drug Safety Office 
GCP: 
Good Clinical Practice 
GPP: 
Good Pharmacoepidemiology Practices 
ICH: 
International Conference on Harmonisation 
ICHD: 
International Classification of Headache Disorders 
IDS: 
International Drug Safety 
IEC: 
Independent Ethics Committee 
IHS: 
International Headache Society 
IRB: 
Institutional Review Board 
NSAIDs: 
Nonsteroidal Anti-inflammatory Drugs 
PGA: 
Patient Global Assessments 
PSUR: 
Periodic Safety Update Report 
SAE: 
Serious Adverse Event 
SAP: 
Statistical Analysis Plan 
SADR: 
Serious Adverse Drug Reaction 
SPC: 
Summary of Product Characteristics 
SPID: 
Sum of Pain Intensity Difference 
TTH: 
Tension-Type Headache 
VAS: 
Visual Analogue Scale  
WHO: 
World Health Organization 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 10 of 33 
 
 
 
2 
Introduction 
Headache or Cephalalgia is defined as pain occurring anywhere in the region of the head or 
the neck representing a range of conditions (3). This group of disorders is extremely 
common, affecting half to three quarters of adults worldwide (4). The World Health 
Organization (WHO) (4) recognised it nearly 20 years ago as a global public-health priority, 
because it is not only painful, but also disabling (4, 5). 
In Brazil it is estimated a 1-year prevalence of 70.6% for all types of headache; this figure is 
similar to the rates described in other countries (6). It affects people of all ages, races and 
socioeconomic status and is more common in women (7). The literature review performed by 
Queiroz et. al (2015) (6) points a 1-year prevalence of 61.6% in men and 77.8% in woman in 
Brazil. 
Headaches are broadly divided into primary and secondary. Primary headaches refer to those 
without an anatomical or physiological explanation, while secondary headaches are result 
from underlying pathologies (5, 8). The commonly encountered primary headache disorders 
are migraine and tension-type headache (TTH). Migraine is usually severe, unilateral and 
throbbing in nature. It is often accompanied by photophobia or phonophobia, nausea and 
vomiting and it worsens with physical activity. TTH is characterized by bilateral location, 
pressing/tightening quality and of generally milder intensity compared to migraine. The 
accompanying symptoms of migraine (nausea, vomiting, photo- and phonophobia) are only 
rarely encountered in this type of headache. 
The International Headache Society (IHS) had proposed clear criteria to establish 
subcategories among the different types of headaches. This research is focused on TTH; 
therefore, the International Classification of Headache Disorders (ICHD) for this type will be 
presented. The third edition of ICHD guideline divided TTH into episodic and chronic types. 
The episodic type is further divided into an infrequent and a frequent type and the main 
difference between them is the number of episodes; while the first occur on average <12 
days/year, the latter occur ≥ 12 and <180 days/year. Episodic TTH is not associated with 
nausea, although the occurrence photo- or phonophobia is a possibility. Chronic TTH, on the 
other hand, can last hours to days, or be unremitting. Differently from episodic TTH, the 
chronic type may be associated with mild nausea; photo and phonophobia may also be 
present. 
TTH is the most prevalent headache in the general population, and the second-most prevalent 
disorder in the world (9). It has a global lifetime prevalence of 42% in men and 49% in 
women. The Brazilian study performed by Queiroz and collaborators found a 1-year 
prevalence of 29.5% (male 28.1% and female 30.3%) (6). Although is a common condition, 
the precise pathogenetic mechanism of TTH is still poorly clarified (10). Evidence has grown 
continuously that peripheral pain mechanism plays a role in infrequent and frequent episodic 
types, while central pain mechanism plays a more important role in chronic type (10). 
Although most of studies addressing the burden of headache focus on migraine, emerging 
data have been shown that the overall human cost of TTH is considerable. Song and 
collaborators (11) performed a study to investigate the prevalence and clinical impact of 
anxiety and depression among patients with TTH in the general population. As results, the 
authors found that these comorbidities were more prevalent in participants with TTH than in 
non-headache participants. In the study of Simic et al (2008) (12) patients with TTH had 
worse quality of life than controls. 
Although simple analgesics, such as dipyrone, paracetamol (acetaminophen) or Non-steroidal 
anti-inflammatory drugs  (NSAIDs) are often used for the treatment of TTHs and other 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 14 of 33 
 
 
 
Practice (GCP), ISPE GPP guideline and any local regulations. Special attention will be paid 
to data protection. 
The Sponsor and/or the appointed CRO will ensure that the protocol, any amendments and 
the Informed Consent Form are submitted to the relevant Independent Ethics Committees 
(IECs)/Institutional Review Boards (IRBs) according to local requirements. 
The sponsor is responsible for meeting the ICH requirement for yearly updates to the 
IECs/IRBs, if applicable. 
 
5.2 
Independent Ethics Committee / Institutional Review Board and Authorities 
IEC/ IRB 
According to applicable regulations, the appointed CRO or the Site Study Responsible will 
notify or obtain approval from the relevant IEC/IRB of the protocol, any amendments and the 
Informed Consent Form and study questionnaire. 
 
The appointed CRO or the Site Study Responsible will submit required documents to the IEC 
/ IRB, such as: 
 periodic updates on the progress of the study; 
 notification of the end-of-study; 
 a summary of the study results. 
 
 
The Sponsor or the appointed CRO will keep an updated list of all submission and approval 
dates of all documents submitted to the IEC / IRB and will provide the Site Responsible with 
a copy of this list. Copies of the documents will be distributed upon request. 
 
5.3 
Authorities 
The Sponsor or the appointed CRO will send required documents to the competent authority 
(CA) and/or other national or regional authorities. The Sponsor or the appointed CRO will 
keep an updated list of submission and approval dates and a copy of all documents submitted. 
 
5.4 
Subject Information and Written Informed Consent 
The Site Study Responsible must give the subject (and if applicable, parent or legal guardian) 
oral and written information about the study in a form that the subject (and if applicable, the 
parent or legal guardian) can understand, and obtain the subject’s (and if applicable, the 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 15 of 33 
 
 
 
subject’s assent and the parent’s or legal guardian’s) written consent before collection of 
identifiable subject information (hereinafter referred to as personal data). Before consenting, 
the subject (and if applicable, parent or legal guardian) must be left with ample time to 
consider and to pose questions. Since the study is observational the consent only concerns the 
data collection per se and is not consent to any interventional procedure or treatment. 
 
The subject must agree that sponsor personnel, their representatives or IEC/IRB or CA 
personnel (national or other) may require direct access to the subject’s data / personal records 
which were collected, processed and stored in an anonymous form. 
 
The subject must agree that his / her data will be processed and stored in an anonymous form 
for evaluation of this study and any later overviews. Data may also be transferred in 
anonymous form to third parties, e.g. other companies or authorities, that may be located in 
other countries with potentially different regulations for data. 
 
The subject and parent or legal guardian, if applicable, has the right to withdraw his/her 
consent at any time without prejudice. In the Informed Consent Form it is stated that if 
consent is withdrawn, any data collected before withdrawal of consent will be kept. The 
original, signed Informed Consent Forms must be kept on the Site. 
 
For details, see the Informed Consent Form. 
 
6 
Study Design and Plan 
This study is a ‘non-interventional study’ as defined in Directive 2001/20/EC and will follow 
the guidelines for GPP. 
This means that: 
 The assignment of a subject to a particular therapeutic strategy is not decided in advance 
by the study protocol but falls within current practice. 
 No additional diagnostic or monitoring procedures shall be applied to the subjects. 
 Epidemiological methods shall be used for the analysis of collected data. 
 Neosaldina® is prescribed in accordance with the terms of the marketing authorisation(s). 
 The prescription of Neosaldina® is clearly separated from the decision to include the 
subject in the study. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 16 of 33 
 
 
 
The principal investigator and sub-investigator will observe and assess each participant from 
the time of informed consent through the completion of observation according to the 
procedures depicted in section 6.6. 
 
6.1 
Study Schedule 
Planned Start of Study: 
Q3 2018 
Planned collection of first data point: 
Q4 2018 
Planned End of Study: 
Q1 2019 
Planned collection of the last data point: 
Q1 2019 
Planned completion of the Study Report: 
Q1 2020 
 
This study will have duration of around 6 months for observational phase. The Start of Study 
is defined as the date of first Site Initiation Visit. The recruitment period is expected to last up 
to 4 months. The End of study is defined as the last data point collected. 
The study report should be signed within 12 months after the collection of the last data point. 
 
 
The Sponsor will ensure that End-of-Study notification is submitted to the concerned 
authorities and IEC/IRB for each site, for each country and for the complete study, as locally 
required. 
 
The Sponsor will ensure that results are posted on “clinicaltrials.gov” and as required by local 
authorities. 
 
Based on upcoming knowledge, the Sponsor might choose to terminate the study 
prematurely. In such case the Committee(s), study sites, IECs/IRBs and authorities will be 
informed promptly. 
 
6.2 
Discussion of Study Design 
This is an observational, non-interventional study that aims to assess the pain intensity and 
pain relief of TTH after the uptake of Neosaldina®. 
To avoid potential confounders, the difference between the groups, stratified by their 
demographic characteristics and lifestyle will also be described. 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 17 of 33 
 
 
 
Because this is an observational study, some limitations should be minimized. To avoid 
selection bias, all eligible patients will be consecutively invited to the study and the 
enrollment period will be of 4 months. 
 
6.3 
Selection of Study Population 
6.3.1 Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the 
study: 
1. In the opinion of the investigator, the subject is capable of understanding and complying 
with protocol requirements. 
2. The subject or, when applicable, the subject’s legally acceptable representative signs and 
dates a written, informed consent form and any required privacy authorization prior to the 
initiation of any study procedures. 
3. Confirmed diagnosis of episodic TTH, as determined by the International Classification 
of Headache Disorders. 
4. Healthy subjects who were prescribed 2 tablets of Neosaldina® for episodic TTH. 
5. The subject is at least 18 years old. 
6. Patients receive treatment according to the Summary of Product Characteristics for 
Neosaldina®. 
7. Patients able to swallow capsules or tolerate oral medications. 
8. Patients with access to a mobile phone with the ability to download the app with the study 
questionnaire. 
9. Patients who have at least 1 episode of TTH per month. 
 
 
6.3.2 Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study: 
1. Currently participates or plans to participate in an interventional clinical trial. 
 
2. Patients who have hypersensitivity or intolerance to dypirone (or pyrazolonic derivatives) 
or other components of the product formula. 
3. Patients with a history of migraine, cluster headaches, chronic TTH or any other type of 
primary headache other than episodic TTH. 
4. Patients with suspected secondary headache. 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 18 of 33 
 
 
 
5. Patient with serious comorbidities (hypertension, blood dyscrasias, malignant neoplasms, 
any type of hepatitis or kidney disease, disorders of the hematopoietic system, insufficient 
function of the bone marrow or certain metabolic diseases, such as hepatic porphyria or 
congenital deficiency of glucose-6-phosphate dehydrogenase) or taking any medications 
which might confound the pharmacological effects of the study drug (e.g. 
immunosuppressive drugs, and beta blockers, anticonvulsivants, antidepressants) within 
30 days before the start of study. 
6. Women who may be pregnant or breastfeeding during the course of the study. 
7. Patients who have a history of alcohol abuse or other drugs according to Diagnostic and 
Statistical Manual of Mental Disorders (DSM–5). 
8. Patients presenting mental incapacity, unwillingness or language barriers unable to 
understand the guidelines specified in this protocol. 
9. Any other reason that, in the Investigator's opinion, makes the patient unsuitable to 
participate in this study. 
 
 
6.3.3 Enrollment 
Each Study Site Responsible (Investigator) should include consecutive subjects who meet 
eligibility criteria, from patients attending scheduled routine medical appointments. 
The expected recruitment of study subjects will occur during a 4-month period. A patient 
tracking log form will be used by each site. 
 
Subjects should be included in the study only once. 
 
 
Data erroneously collected from subjects for which signed informed consent is not available, 
will not be included in or will be deleted from the database. 
 
6.3.4 Study Discontinuation Criteria 
It will be considered a premature termination the situation in which the subject discontinues 
the participation, i.e. they are withdrawn from the study before completing the 45 days of 
follow up period (± 5 days from Day 1), due to any of the reasons listed below: 
1. 
Withdrawal of consent: subjects who for any reason withdraw the free and informed 
consent; 
2. 
Lost to follow-up (no return of the subject on the expected date of visit - drop-out 
from the protocol); 
3. 
Death; 
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Neosaldina-5001 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 19 of 33 
 
 
 
4. 
Study termination; 
5. 
Any situation that places the subject within one of the exclusion criteria. 
 
 
6.4 
Treatments 
Non-interventional/observational – no treatments/pharmacotherapy are instructed by the 
study protocol. The therapeutic approach will be performed according to regular clinical 
practice of the physicians. 
 
6.5 
Premature Termination or Suspension of Study or Investigational Site 
 
 
6.5.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
 New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the Neosaldina® 
such that the risk is no longer acceptable for subjects participating in the study. 
 Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
 
6.5.2 
Criteria for Premature Termination or Suspension of Investigational Sites  
A study site may be terminated prematurely or suspended if the site (including the 
investigator) is found in significant violation of GCP/GPP, protocol, or contractual 
agreement, is unable to ensure adequate performance of the study, or as otherwise 
permitted by the contractual agreement. 
 
6.5.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the Sponsor, an institutional review board (IRB)/independent ethics 
committee (IEC) or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the sponsor; the procedure will be followed by applicable 
investigational sites during the course of termination or study suspension. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

 
Neosaldina-5001 
MyHead 
 
 
6.6 
Study Plan 
After inclusion, a return visit will be schedule within 45 days from Day 1, complying with the allowed deviation (± 5 days). Patients will be 
instructed to insert the data in an application, downloaded onto mobile phone, whenever they had an episode of TTH and use Neosaldina® 
(see more information regarding data collection in the section 8.4.1). Two follow-up phone calls will be performed to verify the patients’ 
adherence to the protocol. These calls will be performed by a site personnel in days 15 and 30. 
Data collection overview: 
 
Activities 
Day 1 
Day 15 
(+/- 3 days) 
Day 30 
(+/- 3 days) 
Days 1-45 
Day 45 
(+/- 5 days) 
Routine visit 
X 
Informed consent 
X 
Inclusion/exclusion criteria 
X 
Routine physician examination, including concomitant 
medications and medical history 
X 
X 
Exposure variables 
X 
Follow-up 1 (phone call) 
X 
Follow-up 2 (phone call) 
X 
SPID
a
 
X 
Pain relief
a
 
X 
Duration of pain relief
a
 
X 
Return visit 
X 
PGA overall satisfaction 
X 
a) 
For each TTH episode 
 
 
 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 20 of 33 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 21 of 33 
 
 
 
 
Data will be collected from medical charts and during the routine clinical appointment. Main 
data collected for the study will include: 
 
 
Identification 
variables 
(collected in the 
baseline) 
 
Study ID 
 
Site ID 
 
Patient number 
 
Informed consent obtained date 
Demographic and 
anthropometric 
variables 
(collected in the 
baseline) 
 
Frequency of headache 
 
Medical appointment date 
 
Age 
 
Gender 
 
Ethnicity 
 
Occupation 
 
City of residence 
 
Monthly familiar income 
 
Weight 
 
Height 
 
Medical history 
 
Concomitant treatments 
 
Blood pressure 
Lifestyle behaviors 
(collected in the 
baseline) 
 
Smoking habits 
 
Alcohol consumption habits 
 
Physical activity 
 
Sleep quality and duration 
 
Use of bright light objects (computers, mobiles, TV, etc) 
 
Time spent working daily 
 
Type of activities during the day in two categories: 
1. mostly seated, standing, moving 
2. Making a great physical effort, using bright light objects 
(computers, mobiles, TV, etc), outdoor activities, on traffic, 
leading with people, working in risky situations (doctors, 
nurses, policeman, fireman), working in noisy 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 22 of 33 
 
 
 
 
 
environments, use of ear phones and its duration. 
Lifestyle behaviors 
(collected in every 
TTH episode) 
 
Level of stress (none, moderate, high) 
 
Date of the last menstruation cycle 
 
Use of ear phones and its duration 
Clinical variables 
(collected in every 
TTH episode) 
 
Location and type of pain 
 
Time and date of onset of pain 
 
Pain intensity and characteristics 
Treatment variables 
(collected in every 
TTH episode) 
 
Intake of Neosaldina 
 
Time of intake 
 
Number of tablets 
 
Pain intensity during 2h 
 
Time of first perceived pain relief 
Treatment variables 
(collected in the last 
visit) 
 
Treatment satisfaction according to the patient 
 
Treatment satisfaction according to the physician 
 
Medical history 
 
Concomitant treatments 
 
Blood pressure 
 
Additional details about variables and types of data fields will be provided in the eCRF. 
 
 
7 
Safety Reporting 
7.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, a new disease or worsening in severity or frequency 
of a concomitant disease, temporally associated with the use of a medicinal product, whether 
or not the event is considered causally related to the use of the product. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 23 of 33 
 
 
 
 
Although abnormal laboratory values are typically not considered AEs, the following 
considerations may result in an abnormal laboratory value being considered an AE: 
 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject/patient to receive specific corrective 
therapy 
 A laboratory abnormality that leads to discontinuation of therapy 
 A laboratory abnormality that the health care provider considers to be clinically significant 
 
 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 
 Results in death. Note that death is an outcome of an event. The event(s) causing death 
should be recorded. 
 In the view of the Health care provider, places the subject/patient at immediate risk of 
death (a life threatening event); however, this does not include an event that, had it 
occurred in a more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability/incapacity. 
 Results in a congenital anomaly/birth defect. 
 An SAE may also be any other medically important event that, in the opinion of the Health 
care provider, may jeopardize the subject/patient or may require intervention to prevent 
one of the other outcomes listed in the definition above. (Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room 
or convulsions occurring at home that do not require an inpatient hospitalization). 
 
Adverse Drug Reactions 
An adverse drug reaction (ADR) is an AE for which there is at least a reasonable suspicion of 
a causal relationship between an AE and a suspected medicinal product. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 24 of 33 
 
 
 
 
Product Quality Issues 
A Product Quality Issue (PQI) refers to defects related to the safety, identity, strength, 
quality, or purity of the product or with the physical characteristics, packaging, labeling, or 
design of the product. 
 
Special Situation Reports 
A Special Situation Report (SSR) includes any of the following events: 
 
 Pregnancy: Any case in which a pregnancy patient is exposed to a Takeda Product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda Product. Exposure is considered either through maternal exposure 
or via semen following paternal exposure. 
 Breastfeeding: Infant exposure from breast milk. 
 Overdose: All information of any accidental or intentional overdose. 
 Drug abuse, misuse or medication error: All information on medicinal product abuse, 
misuse or medication error (potential or actual). 
 Suspected transmission of an infectious agent: All information on a suspected (in the sense 
of confirmed or potential) transmission of an infectious agent by a medicinal product. 
 Lack of efficacy of Takeda Product. 
 Occupational exposure. 
 Use outside the terms of the marketing authorization, also known as “off-label”. 
 Use of falsified medicinal product. 
 
A SSR should be reported even if there is no associated AE. 
 
 
Relationship of an AE to studied drug(s) 
 Related (Yes): An AE that follows a reasonable temporal sequence from administration of 
the medication, vaccine or device (including the course after withdrawal of the 
medication), or for which a casual relationship is at least a reasonable possibility, i.e., the 
relationship cannot be ruled out, although factors other than the medication, vaccine or 
device, such as underlying diseases, complications, concomitant drugs and concurrent 
treatments, may also be responsible. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 25 of 33 
 
 
 
 
 Not related (No): An AE that does not follow a reasonable temporal sequence from 
administration of the medication, vaccine or device and/or that can reasonably be 
explained by other factors, such as underlying disease, complications, concomitant drugs 
and concurrent treatments. The investigator must make an assessment of causality using 
the above definition. Causality cannot be assumed in the absence of the investigator’s 
assessment.: 
 
7.2 
Collection and Recording of Adverse Events, Special Situation Reports and 
Product Quality Issues 
Collection and recording of SAEs, AEs, SSRs and PQI will commence once the study 
participant has provided informed consent. 
The investigator should notify Takeda within 1 working day of becoming aware of a SAE, or 
other serious events/issues that were spontaneously reported by participant. This is typically 
achieved by the investigator completing the adverse event report pages of an electric CRF 
and by submitting an AE Report Form to Takeda. 
The Investigator may be contacted by Takeda to obtain additional information on the event or 
for data clarification. The investigator shall make best effort to obtain the requested 
additional information, and will notify Takeda within 1 working day of obtaining the 
additional information. Non-serious AEs, SSRs and PQI must be recorded in the appropriate 
page of the CRF. 
 
7.3 
Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Agencies 
If required by national law or regulation, the Investigator shall report serious adverse drug 
reactions suspected of being related to the studied Takeda product to the applicable 
regulatory authorities and IRB/EC within the timelines required by such law or regulation. 
The investigator shall maintain records of all such submissions. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 27 of 33 
 
 
 
 
whenever possible, and consent to such access will be explicitly included in the Informed 
Consent Form. 
 
Additional details will be specified in the Monitoring Plan. 
 
 
8.2 
Audit from Quality Assurance Unit 
The Quality Assurance (QA) unit may audit the study, including the study sites, to ensure that 
study procedures comply with the protocol and standard operating procedures, and that 
collected data is correct and complete. 
 
8.3 
Inspection by IRB/IEC or Competent Authority 
Representatives from IRB/IEC or Competent Authority may in rare cases wish to inspect the 
study on site. Upon receiving notification of such inspection, the Study Site Responsible must 
immediately contact Takeda Brazil Research Team and must make the records available as 
requested. 
 
8.4 
Data Management 
Data Management will be carried out according to a Data Management Plan, which must be 
written and approved before the design of the study database is finalised. The data 
management provider should approve all data formats before the data collection tools are 
made available to the sites. 
 
If the written informed consent of a subject is known not to be available in spite of it being 
required, data for this subject is not entered into or is deleted from the database. 
 
If a subject is erroneously included in the study more than once only the data relating to the 
first inclusion will be kept in the database and be available for analysis. Data from later 
inclusions will be transferred to the first dataset when relevant, i.e. if collected within the 
time frame of the first follow-up period. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

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Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 30 of 33 
 
 
𝑧𝑧𝑧𝑧
 
 
the study intends to analyze the variables with normal distribution by the Student’s t-test, and 
those with non-normal distribution by Mann-Whitney nonparametric test. The Chi-square test 
will be used to assess possible differences between frequencies of categorical variables. 
Logistic regression will be used to build a multivariate model to assess the association 
between the primary outcome and exposure variables. 
 
All serious AEs and/or serious issues captured in the study database and reported by the 
investigator to Takeda in the AER Form (according to Section 7) and all the SAEs, AEs and 
SSRs received directly from the patients by Takeda will be reconciled at the end of the study 
and will be analysed and listed/tabulated in the final report. 
 
For details of the statistical analyses please refer to the Statistical Analysis Plan. 
 
 
9.2 
Interim Analyses 
No interim analyses are planned for this study. 
 
 
9.3 
Determination of Sample Size 
The sample size rationale was based on the primary endpoint. Thus, the calculation was 
performed in order to estimate a mean in a finite population, using the following equation: 
2 
2 
(1−𝛼𝛼𝛼𝛼)⁄2 
𝑛𝑛𝑛𝑛 = 
𝑑𝑑𝑑𝑑2 
To our best knowledge, there is no data in literature showing the results of SPID 0-2 in TTH 
population using Neosaldina®. However, a systematic review (19) conducted by Stephens et 
al (2016) reported the following mean and standard deviations for other analgesics: 
 
Drugs 
SPID 
Mean 
SD 
Paracetamol 1000 mg 
4,32 
1,98 
Paracetamol 1000 mg + cafeína 130 mg 
4,42 
1,88 
Ibuprofeno 400 mg 
4,56 
1,73 
Placebo 
3,69 
1,70 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 31 of 33 
 
 
 
 
As these data are not related to the same studied drug, a standard deviation of 3,00 was 
assumed. Therefore, considering an error of ± 0.5 a drop-out rate of 45% and a screen failure 
rate of 20%, 317 patients would be necessary to achieve a robust estimation of the population 
mean (95% Confidence Interval, level of significance 0.05). 
 
10 Reports 
A Non-Interventional Study Report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The Final Study Report should be available 
within one year from collection of the last data point, and the participating sites should be 
informed about the results when the report is finalised. 
 
11 Publication, Disclosure, and Clinical Trial Registration Policy 
The Sponsor aims to have the results of this study published. 
 
 
The Sponsor has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
 
Takeda may post the results of the study on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or 
regulations. 
 
12 Archiving of Study Documentation 
During the course of the study the Site Responsible must as a minimum file the below 
essential documents in the Study Site File: 
 Written agreement between the Sponsor and the Study Site Responsible; 
 The study protocol and any amendments; 
 Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Responsible; 
 Informed Consent Form in local language (notified to / approved by Independent Ethics 
Committees (IECs) / Institutional Review Boards (IRBs) as locally required), including 
the original signed Forms; 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 32 of 33 
 
 
 
 
 The list of participating subjects; 
 Written IEC / IRB approval / vote according to local regulations; 
 Authority approval according to local regulations; 
 The completed CRFs; 
 The progress reports. 
 Site staff training records. 
 Site staff signature delegation log. 
 
 
After final database lock the Site Responsible must as a minimum store the list of 
participating subjects and the signed Informed Consent Forms on site for 25 years. The Site 
Responsible should store additional study documentation for a longer period of time as 
required by any local regulations and/or hospital requirement. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Neosaldina-5001 
MyHead 
Study Protocol Ver. 1.0, 27-JUL-2018 
Page 33 of 33 
 
 
 
 
13 References 
1. 
Helsinki WMADo. Ethical principles for Medical Research Involving Human 
Subjects, Helsinki 1964, amended in Tokyo 1975, Venice 1983, Hong Kong 1989, South 
Africa 1996, Edinburgh 2000, and Seoul 2008. 
2. 
Epstein MoboI. Guidelines for Good Pharmacoepidemiology Practices (GPP). 
Pharmacoepidemiology and Drug Safety 2005;14:589-95. 
3. 
Keight R, Al-Jumeily D, Hussain AJ, Al-Jumeily M, Mallucci C, editors. Towards the 
discrimination of primary and secondary headache: An intelligent systems approach. 2017 
International Joint Conference on Neural Networks (IJCNN); 2017 14-19 May 2017. 
4. 
(WHO) WHO. Headache disorders. 2016. 
5. 
Steiner TJ, Buse DC, Al Jumah M, Westergaard ML, Jensen RH, Reed ML, et al. The 
headache under-response to treatment (HURT) questionnaire, an outcome measure to guide 
follow-up in primary care: development, psychometric evaluation and assessment of utility. 
The journal of headache and pain. 2018;19(1):15. 
6. 
Queiroz LP, Silva Junior AA. The prevalence and impact of headache in Brazil. 
Headache. 2015;55 Suppl 1:32-8. 
7. 
Ahmed F. Headache disorders: differentiating and managing the common subtypes. 
British journal of pain. 2012;6(3):124-32. 
8. 
Bernstein JA, Fox RW, Martin VT, Lockey RF. Headache and facial pain: differential 
diagnosis and treatment. The journal of allergy and clinical immunology In practice. 
2013;1(3):242-51. 
9. 
Wöber-Bingöl Ç, Wöber C, Uluduz D, Uygunoğlu U, Aslan TS, Kernmayer M, et al. 
The global burden of headache in children and adolescents – developing a questionnaire and 
methodology for a global study. The journal of headache and pain. 2014;15(1):86-. 
10. 
Ashina S, Bendtsen L, Ashina M. Pathophysiology of migraine and tension-type 
headache. Techniques in Regional Anesthesia and Pain Management. 2012;16(1):14-8. 
11. 
Song TJ, Cho SJ, Kim WJ, Yang KI, Yun CH, Chu MK. Anxiety and Depression in 
Tension-Type Headache: A Population-Based Study. PloS one. 2016;11(10):e0165316. 
12. 
Simic S, Slankamenac P, Kopitovic A, Jovin Z, Banic-Horvat S. Quality of life 
research in patients suffering from tension type headache. Medicinski pregled. 2008;61(5- 
6):215-21. 
13. 
Carvalho D, Rabello G, Figueiró J. Dipyrone plus caffeine versus dipyrone alone to 
acute treatment of mild to moderate primary headache attacks: a double blind, randomized, 
compared clinical study. Rev Bras Med. 2007;64(6):273-8. 
14. 
de Souza Carvalho D, Barea LM, Kowacs PA, Fragoso YD. Efficacy and tolerability 
of combined dipyrone, isometheptene and caffeine in the treatment of mild-to-moderate 
primary headache episodes. Expert review of neurotherapeutics. 2012;12(2):159-67. 
15.      MI D-R. Cir Ciruj 2008;76:241-6. 
16.      Johnson D. Clin Med 1970;77:33-6. 
17. 
Klapetek. Med Welt. 1973;24(18):745-7. 
18. 
F F, P T. Folha Med. 1981;82(1):61-2. 
19. Stephens G, Derry S, Moore R. Paracetamol (acetaminophen) for acute treatment of 
episodic tension-type headache in adults. Cochrane Database of Systematic Reviews. 
2016;CD011889(6):93. 
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