International Multicentre, Observational, Non-Interventional Prospective Study of Azilsartan Medoxomil in Patients With Arterial Hypertension Who Are Overweight or Obese in the Russian Federation and The Republic of Kazakhstan
Conditions: Hypertension
Sponsor: Takeda

This may include, but is not limited to, redaction of the following: 


•
Title: International, multicentre, observational, non-interventional prospective study of azilsartan 
medoxomil in patients with arterial hypertension who are overweight or obese in the Russian Federation 
and the Republic of Kazakhstan
NCT Number: NCT02756819
Protocol Approve Date: January 9, 2019
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 or company confidential information. 
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.

/ 
Azilsmedox-5 00 8 
(MACS-2014-100663) 
0 bservati onal/N on-Interventional 
Study Protocol 
version 2.4 09-Jan-2019 
Short title: 
Title: 
Study ID: 
Sponsor: 
Non-Interventional Study Protocol 
CONSTANT 
International multicentre, 
observational, 
non-interventional 
prospective study of azilsartan medoxomil in patients with arterial hypertension 
who are overweight or obese in the Russian Federation and the Republic of 
Kazakhstan 
CONSTANT 
International 
multicentre, 
observational, 
non-interventional 
prospective study of azilsmian medoxomil in patients with arterial hype1iension 
who are overweight or obese in the Russian Federation and the Republic of 
Kazakhstan 
Azilsmedox-5008 (MACS-2014-100663) 
Takeda Pharmaceutical LLC 
2, bld. 1, Usacheva str., Moscow 119048, Russian Federation 
Phone: + 7 495 933 5511 
Fax: + 7 495 502 1625 
Study phase: Non-interventional (Observational) Company Sponsored Study 
Date: 
09 January 2019 
Amendment Number: 
5 
Amendment History: 
Amendment 
Amendment 
Date 
Number 
Type 
Region 
02 December 2014 
Initial Protocol 
Not applicable 
the Russian Federation 
18 December 2015 
Substantial 
the Russian Federation and the Republic of Kazakhstan 
28June20 16 
2 
Non-Substantial 
the Russian Federation and the Republic of Kazakhstan 
16 March 2017 
3 
Non-Substantial 
the Russian Federation and the Republic of Kazakhstan 
14 August 2017 
4 
Non-Substantial 
the Russian Federation and the Republic of Kazakhstan 
09 January 2019 
5 
Non-Substantial 
the Russian Federation and the Republic of Kazakhstan 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Fmthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
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Azilsmedox-5008 
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version 2.4 09-Jan-2019 
1 Administrative information 
1.1 Contacts 
A separate contact information list will be provided to each site. 
Issue 
Serious adverse event and pregnancy 
reporting 
Medical Monitor 
(medical advice on protocol, compound, 
and medical management of patients) 
Responsible Medical Officer 
(carries overall responsibility for the 
conduct of the study) 
Issue 
Serious adverse event and pregnancy 
repo11ing 
The Russian Federation, Contact information 
The Republic of Kazakhstan, Contact information 
Medical Monitor 
(medical advice on protocol, compound, 
and medical management of patients) 
Responsible Medical Officer 
Page 2 of 67 
Protected Personal Data
Protected Personal Data

Azilsmedox-5008 
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Study Protocol 
1.2 Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual paiticipants in 
accordance with the requirements of this non-interventional study protocol and also in accordance 
with the following: 
The ethical principles that have their origin in the Declaration of Helsinki [1]; International 
Conference on Harmonisation E6 Good Clinical Practice: Consolidated Guideline [2]; Guidelines 
for Good Pharmacoepidemiology practices (GPP) [3]; Guidelines on Good Pharmacovigilance 
Practices (GVP) [4]; All applicable laws and regulations, including, without limitation, data 
privacy laws and regulations. 
SIGNATURES 
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Azilsmedox-5008 
(MACS-2014-100663) 
2 
Study summary 
Short Title of the Study 
Observational/Non-Interventional 
version 2.4 09-Jan-2019 
Study Protocol 
International multicentre, observational, non-interventional, prospective study of ailsartan 
medoxomil in patients with aiterial hypertension who are overweight or obese in the Russian 
Federation and the Republic of Kazakhstan 
Study sites 
The study sites will be selected according to following criteria: 
-
out-patient clinics, 
-
availability of cai·diologist specialists in out-patient clinics, 
-
significant patient flow with essential hypertension (the sites should treat at least 350 
patients with hype1tension per year). 
Number of sites: about 80 investigational sites from the Russian Federation and about 10 
investigational sites in the Republic of Kazakhstan. 
Objectives 
Primary objective: 
-
To evaluate the effect of Edarbi® on clinic systolic blood pressure (SBP) among HTN 
patients with overweight or obesity (V 4). 
Secondary objectives: 
-
To evaluate the effect of Edarbi® on clinic diastolic blood pressure (DBP) among HTN 
patients with overweight or obesity (V4); 
-
To evaluate the prop01tion of overweight or obese patients who respond to Edarbi® therapy 
(defined as decrease of SBP2: 20 mm Hg or decrease of DBP2:10 mm Hg) (V4); 
-
To evaluate the prop01iion of overweight or obese patients who achieved target BP 
(defined as SBP<l40 and DBP<90mm Hg) (V4); 
-
To evaluate the effect of Edarbi® on clinic SBP among HTN patients with overweight or 
obesity in subgroups of patients: BMI (overweight, obese), impaired glucose tolerance, 
metabolic syndrome, diabetes mellitus (V4); 
-
To evaluate the effect of Edarbi® on clinic DBP among HTN patients with overweight or 
obesity in subgroups of patients: BMI (overweight, obese), impaired glucose tolerance, 
metabolic syndrome, diabetes mellitus (V4); 
-
To evaluate the proportion of overweight or obese patients who achieve target BP 
(SBP<140 mm Hg, DBP<90 mm Hg) in subgroups of patients: overweight, obese (stages I-
III), impaired glucose tolerance, metabolic syndrome, diabetes mellitus (V4). 
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Study Protocol 
Safety Objective: 
-
To describe AEs characteristics. 
Methodology 
Study Design: international, multicentre, observational, non-interventional prospective study. 
Study plan: The definition of a Non-Interventional study is provided in EU Directive 2001/20/EC 
(of April 4, 2001) [5]. During participation in the study patients are observed according to the local 
routine practice. The assignment of a particular therapeutic strategy to the patient including all 
diagnostic procedures is decided in accordance with Russian guidelines "Diagnostics and 
treatment of hypertension" (2010) [ 6] and Kazakh protocol on clinical diagnosis and treatment of 
hypertension (2013) [7] and local routine practice. The patients would take Edarbi® according to 
the local Sm.PC. 
Number of patients 
Approximately 1916 patients. 
Diagnosis/Disease/Condition and main criteria for inclusion 
Inclusion criteria: 
1. Male and female patients 2'.: 18 years of age with HTN 1-2 grade 
2. Patients with: 
o Newly diagnosed arterial HTN or 
o 
inadequately controlled previously prescribed monotherapy with RAAS blocker or 
o inadequately controlled previously prescribed combination therapy with RAAS 
blocker + diuretic or RAAS blocker + calcium antagonisti. 
3. The physician decides to prescribe Edarbi®: 
o as monotherapy or 
o as a part of combination therapy including diuretics or calcium antagonists; 
4. Overweight or obesity of any degree (body mass index> 25 kg/m2); 
5. Is capable of understanding the written informed consent, provides signed and written 
informed consent, and agrees to comply with protocol requirements. In case the patient is 
blind or unable to read, informed consent will also be witnessed. 
Exclusion criteria: 
Any patient who meets any of the following criteria will not be qualified for entry into the 
study: 
1. Confirmed secondary HTN ; 
2. Contraindications for Edarbi® of respective approved local Sm.PC of Edarbi®; 
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3. Any reasons of medical and non-medical character, which in the op1mon of the 
physician can prevent patient participation in the study. 
4. Is an employee or family member of the investigator or study site personnel. 
5. Is currently paiticipating in a clinical trial. Paiticipation in non-interventional registries 
is permitted. 
6. Vulnerable patients who are unable to understand information about study or those who 
depend on investigator. 
Duration of data collection per patient 
Data collection per patient will be canied out within the framework of the routine practice. 
Due to the non-interventional study design it's not possible to appoint exact times for the study 
visits, although it is expected that the period of observation will be approximately 6 months. The 
frequency of the visits will be assigned by each physician according to their routine practice. It is 
anticipated that the patients will visit their physician every 3 months and more often at the 
beginning until the patient achieves target blood pressure. Information for the study will be 
collected from 4 patients' visits to the physician. 
Criteria for evaluation 
Population descriptors 
The main variables, which will be collected in the study, are presented in the table. 
Variables collected 
Baseline 
Observational 
Observational 
Final 
visit 
visit 
visit 1 (V2) 
visit 2 (V3) 
(Vl) 
(V4) 
Demographic information 
x 
Medical history (incl. risk factors, prior 
x 
diseases, prior HTN therapy etc) 
Physical examination and vital signs* 
x 
x 
x 
x 
HTN therapy (drugs, doses) 
x 
x 
x 
x 
Laboratory tests and instrumental 
x 
x 
x 
x 
exams* 
Concomitant medication 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
* All examinations (physical examination and vital signs, laboratoty tests and instrumental exams) are done 
in accordance with clinical routine practice and physician's decision. Instrumental exams are measurement of blood 
pressure, heart rate, ECG, 24-hour ambulat01y blood pressure monitoring. All examinations should be registered in 
the CRF only if they are done in routine practice. 
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Azilsmedox-5008 
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Primary outcomes: 
Observational/Non-Interventional 
version 2.4 09-Jan-2019 
Study Protocol 
-
Change from baseline in clinic SBP on Edarbi® therapy (Time Frame: Baseline and V4) 
Secondary outcomes: 
-
Change from baseline in clinic DBP on Edarbi® therapy (Time Frame: Baseline and V4); 
-
Proportion (%) of patients who respond to Edarbi® therapy (defined as decrease of SBP~ 
20 mm Hg or decrease ofDBP~lO mm Hg; Time Frame: Baseline and V4); 
-
Proportion(%) of patients who achieve target SBP <140 mm Hg (Time Frame: Baseline 
and V4); 
-
Changes from baseline in clinic SBP in subgroups of patients: BMI (overweight, obese), 
impaired glucose tolerance, metabolic syndrome, diabetes mellitus (Time Frame: 
Baseline and V4); 
-
Changes from baseline in clinic DBP in subgroups of patients: overweight, obese (stages 
I-III), impaired glucose tolerance (yes, no), metabolic syndrome (yes, no), diabetes 
mellitus (yes, no) (Time Frame: Baseline and V4); 
-
Proportion(%) of patients who achieve target BP (SBP<l40 mm Hg, DBP<90 mm Hg) in 
subgroups of patients: overweight, obese (stages I-III), impaired glucose tolerance (yes, 
no), metabolic syndrome (yes, no), diabetes mellitus (yes, no) (Time Frame: Baseline and 
V4). 
Safety Outcome: 
-
Incidence and type of adverse events. 
Statistical methods 
All continuous variables will be summarized using the following descriptive statistics: n 
(non-missing sample size), mean, standard deviation, median, 25 percentile, 75 percentile, 
maximum and minimum. The frequency and percentages of observed levels will be reported for 
all categorical measures. For variables marked "binary" exact (Clopper-Pearson) 95% confidence 
intervals will be calculated where appropriate. For categorical variables with more than 2 
categories 95% confidence intervals will be calculated using Goodman's method [8]. 
In general, all data will be listed, sorted by site, dose cohort and patient number, and when 
appropriate by visit number within patient. Summary tables will be based on all patients and 
structured with a column for each dose cohort in the increasing order and will be annotated with 
the total population size relevant to that table/dose coh01t, including any missing observations. 
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Azilsmedox-5008 
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3 
Table of Contents 
Observational/Non-Interventional 
version 2.4 09-Jan-2019 
Study Protocol 
1 
Administrative information .................................................................................................. 2 
1.1 
Contacts ...................................................................................................................... 2 
1.2 
Approval ..................................................................................................................... 3 
2 
Study summary ..................................................................................................................... 4 
3 
Table of Contents ................................................................................................................. 8 
4 
List of Abbreviations and Definition of Terms .................................................................. 12 
4.1 
List of Abbreviations ................................................................................................ 12 
4.2 
Definition of Terms .................................................................................................. 14 
5 
Introduction ........................................................................................................................ 15 
5.1 
Disease background .................................................................................................. 15 
5 .2 
Diug background ...................................................................................................... 15 
5 .2.1 
Drug description ......................................................................................... 15 
5.2.2 
Summary of trials and studies ..................................................................... 16 
5.3 
The study rationale .................................................................................................... 17 
6 
Study Objective(s) and outcomes ....................................................................................... 17 
6.1 
Study objectives ........................................................................................................ 17 
6.2 
Study outcomes ......................................................................................................... 19 
7 
Study Administrative Sttucture .......................................................................................... 20 
7.1 
Steering Committee .................................................................................................. 20 
7.2 
Study Sites ................................................................................................................ 21 
7.3 
Sponsor Personnel. .................................................................................................... 22 
7.4. Contract Research Organisation (CRO) ................................................................... 24 
7.5 
Essential Documents ................................................................................................. 25 
8 
Ethics .................................................................................................................................. 25 
8.1 
Ethical conduct of the Study ..................................................................................... 25 
8.2 
Independent Ethics Committee I Institutional Review Board and Authorities (IEC/ IRB) 
.................................................................................................................................. 26 
8.3 
Local Ethics Committee (LEC) ................................................................................ 27 
8.4 
Authorities approval ................................................................................................. 27 
8.5 
Patient Information Sheet and Informed Consent Fmm ........................................... 27 
8.6 
Signing oflnformed Consent Form .......................................................................... 28 
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8. 7 
Patient identification ................................................................................................. 29 
8.8 
Patient insurance ....................................................................................................... 29 
8.9 
Confidential and non-disclosure of personal data ..................................................... 30 
9 
Study Design and Plan ....................................................................................................... 31 
9.1 
Overall study design ................................................................................................. 31 
9 .2 
Study Schedule ......................................................................................................... 31 
9 .3 
Discussion of Study Design ...................................................................................... 32 
9.4 
The Study Population ................................................................................................ 32 
9.4.1 
Criteria inclusion ........................................................................................ 33 
9.4.2 
Criteria exclusion ........................................................................................ 33 
9.4.3 
Justification for criteria inclusion and exclusion ........................................ 34 
9.4.4 
Patient selection and procedure for avoiding of selection bias ................... 34 
9.4.5 
Discontinuation/withdrawal of patients from the study .............................. 35 
9.4.5.1. 
Criteria for Discontinuation or Withdrawal of a patient.. .......................... 35 
9 .4.5 .2. 
Procedures for Discontinuation or Withdrawal of a patient. ..................... 36 
9.5 
The study plan (plan of observation) ........................................................................ 36 
9.6. Premature Termination or Suspension of Study or Investigational Site ................... 37 
10 Conduct .............................................................................................................................. 38 
10. 1. Data source ............................................................................................................... 38 
10.2. Data collection overview .......................................................................................... 38 
10.3. Data collected on the Baseline visit.. ........................................................................ 39 
10.4. Data collected on the Observational visits 2, 3 and 4 ............................................... 40 
10.5. Data collected on the End of observation ................................................................. 41 
10.6. Treatments to be documented in the study .............................................................. .42 
10.6.1. Documentation of the study medication .................................................... .42 
10.6.2. HTN treatment ............................................................................................ 43 
10.6.3. Prior HTN treatment ................................................................................... 43 
10.6.4. Concomitant medication ............................................................................ .43 
10.6.5. Follow-up HTN treatment ......................................................................... .43 
10.6.6. Pregnancy ................................................................................................... 43 
10.7. Laboratory, instrumental exams, physical examination and vital signs to be documented 
in the study ................................................................................................................ 44 
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10.8. Body Mass Index (BMI) Calculation ....................................................................... .44 
10.9. Documentation of Medical history, Concurrent Medical Conditions and comorbidities 
.................................................................................................................................. 44 
11 Safety Reporting ................................................................................................................. 45 
11.1 Definitions ................................................................................................................ 45 
11.1.1. Adverse Event ............................................................................................. 45 
11.1.2. Additional Points to Consider for AEs ...................................................... .45 
11.1.3. SeriousAEs ................................................................................................ 47 
11.1.4. SeverityAEs ............................................................................................... 49 
11.1.5. Causality of AEs ......................................................................................... 49 
11.1.6. Strut and Stop Dates .................................................................................... 50 
11.1.7. Frequency ................................................................................................... 50 
11.1.8. Action Concerning Study Medication ........................................................ 50 
11.1.9. Outcomes of AEs ........................................................................................ 50 
11.2. Repmting of Adverse Events .................................................................................... 51 
11.2.1. Legislation for Pharmacovigilance ............................................................. 51 
11.2.2. AE Reporting Form .................................................................................... 52 
11.2.3. Collection and repo1ting of AE .................................................................. 52 
11.2.4. Collection and reporting of SAE and pregnancies ..................................... 53 
11.2.5. Safety repmting to Investigators, IRBs or IECs, and Regulatory Authorities53 
12 Data Quality Control and Assurance .................................................................................. 54 
12.1 Quality Control ......................................................................................................... 54 
12.1.1. Training of investigators ............................................................................. 54 
12.1.2. Quality reviews during the study conducting ............................................. 54 
12.1.3. Data checks and data queries ...................................................................... 55 
12.1.4. Quality Assurance Audits ........................................................................... 55 
12.2. Inspection by IRB/IEC or Competent Authority ...................................................... 56 
12.3. Data Management ..................................................................................................... 56 
12.3.1. Data Management Plan ............................................................................... 56 
12.3.2. Data privacy ................................................................................................ 56 
12.3.3. Case Report Form (CRF) ............................................................................ 56 
12.3.4. Coding of AEs and concomitant medications ............................................ 57 
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12.3.5. Record retention .......................................................................................... 58 
13 Statistical Methods and Determination of Sample Size ..................................................... 58 
13.l Patient Population ..................................................................................................... 58 
13 .2 The study data and Statistical Analysis methods ...................................................... 58 
13.2.1. Summary of study data ............................................................................... 59 
13.2.2. Statistical analysis methods ........................................................................ 59 
13.2.3. Analysis of Safety Data .............................................................................. 61 
13.2.4. Potential study biases .................................................................................. 61 
13.2.5. Data handling .............................................................................................. 61 
13.2.5.1. 
Missing data and invalid data .................................................................... 61 
13 .2.5 .2. 
Multiplicity ................................................................................................ 62 
13.3 Interim Analyses ....................................................................................................... 62 
13 .4 Determination of Sample Size .................................................................................. 62 
14 Repo1ts ............................................................................................................................... 63 
15 Publications ........................................................................................................................ 63 
15 .1 Publication and Disclosure ....................................................................................... 63 
15.2 Study Registration ..................................................................................................... 64 
16 Archiving of Study Documentation ................................................................................... 64 
17 References .......................................................................................................................... 65 
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4 
List of Abbreviations and Definition of Terms 
4.1 List of Abbreviations 
ACE: 
ADR: 
AE: 
ARB: 
ATl: 
BMI: 
BP: 
CA: 
CRF: 
CRO: 
CV: 
DBP: 
DMP: 
DSO: 
EC: 
eCRF: 
FPLV: 
GCP: 
GEP: 
GPP: 
GVP: 
ICF: 
ICH: 
IDS: 
IEC: 
INN: 
IRB: 
Angiotensin-Conve1ting-Enzyme 
Adverse Drug Reaction 
Adverse Event 
Angiotensin Receptor Blocker 
Angiotensin II receptor Type 1 
Body Mass Index 
Blood Pressure 
Competent Authority 
Case Report Form 
Contract Research Organisation 
Cuniculum Vitae 
Distolic Blood Pressure 
Data Management Plan 
Drug Safety Officer 
Ethics Committee 
electronic Case Rep01t Form 
First Patient Last Visit (end of enrollment) 
Good Clinical Practice 
Good Epidemiologycal Practice 
Good Pharmacoepidemiology Practices 
Good Phaimacovigilance Practices 
Informed Consent Form 
International Conference on Harmonisation 
International Drug Safety 
Independent Ethics Committee 
International Nonproprietary Name 
Institutional Review Board 
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HTN: 
Hype11ension 
LEC: 
Local Ethics Committee 
LPL V: 
Last Patient Last Visit 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NIS: 
Non-interventional study 
pCRF: 
paper Case Rep011 Form 
PP AR: 
Peroxisome Proliferator-Activated Receptors 
PSUR: 
Periodic Safety Update Repo11 
QA: 
Qality Asurance 
RK: 
the Republic of Kazakhstan 
RAAS: 
Renin-Angiotensin-Aldosteron System 
RF: 
the Russian Federation 
SAP: 
Statistical Analysis Plan 
SADR: 
Serious Adverse Drug Reaction 
SAE: 
Serious Adverse Event 
SBP: 
Sistolic Blood Pressure 
SD: 
Standrad Deviation 
SDV: 
Source Data Verification 
SPC: 
Summary of Product Characteristics 
WHO: 
World Health Organization 
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4.2 Definition of Terms 
According to guidelines of the Russian Ministry of Health for the management of HTN, 
[ 6] protocols of the Republic of Kazakhstan on clinical diagnosis and treatment of 
hypertension and protocol on the management of patients with type II diabetes [7,9]: 
Target Blood Pressure (BP) -, target BP for all categories of patients is <140/90 mm 
Hg, except of patients with diabetes in whom target BP is <140/85 mm Hg. 
Target Distolic Blood Pressure (DBP) - , target DBP for all categories of patients is 
<90 mm Hg, expect of patients with diabetes in whom target BP is <85 mm Hg 
Target Sistolic Blood Pressure (SBP) - , target SBP for all categories of patients is 
<140mmHg 
BP response - decrease of SBP~ 20 mm Hg or decrease of DBP~l 0 mm Hg 
Overweight - elevation of body mass index (BMI) is from 25 to 30 
Obesity - elevation of BMI > 30 [8, 9]. Obesity is divided for 3 classes according to 
severity. 
Class of obesity 
BMI 
Obesity class 1 
30-34,9 
Obesity class 2 
35-39,9 
Obesity class 3 
BMI~40 
Metabolic syndrome - according to the definition of the Russian Ministry of Health for the 
management of HTN [6], metabolic syndrome is diagnosed in the presence of main criterion and 2 
any additional criteria listed below: 
Main Criterion 
Men 
Women 
waist circumference 
~94cm 
~80cm 
Additional Criteria 
Men 
Women 
low-density lipoprotein 
>3.0 mmol/l 
>3.0 mmol/l 
cholesterol 
high-density lipoprotein 
<1.0 mmol/L 
<1.2 mmol/L 
cholesterol 
triglycerides 
>1.7 mmol/L 
>1.7 mmol/L 
impaired glucose tolerance 
post-load plasma glucose 7.8 
post-load plasma glucose 7.8 
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(post-load plasma glucose) 
- 11 .0 mmol/L 
- 11.0 mmol/L 
fasting glucose 
6.1 - 7.0 mmol/l 
6.1 - 7.0 mmol/l 
5 Introduction 
5.1 Disease background 
Hypertension (HTN) is the established main risk factor of cardiovascular diseases, leading 
to the progressive impairment of its target organs: herut, kidneys, brain and vessels [6, 12]. High 
blood pressw-e (BP) is the leading global risk factor for mortality in the world. According to the 
epidemiological data, about 44% of Russian population is hypertonic [13]. Among them only 23% 
of patients achieve BP goals on antihype1tensive treatment [13]. 
According to official statistics the prevalence of arterial hype1tension in Kazakhstan in 
2008 was 35% [14.]. Moreover, surveys showed that just 1 in 4 respondents diagnosed with high 
blood pressure were taking medication daily in 2010 [15]. Thus, the problem of diagnostic and 
tr·eatment of HTN in Russia and Kazakhstan is the matter of high significance. 
The special concern is necessary of treatment ofHTN patients with overweight and obesity. 
The frequency of such combination is very high. According to World Health Organization data, in 
2008 35% of people ~20 years old were overweight and 11 % were obese (overweight was define 
as body mass index (BMI) >25kg/m2; obesity - as BMI>30 kg/m2) [16]. Among patients with 
HTN prevalence of overweight is about 39%, of obesity is as high as about 52% [17]. 
Situation with BP control among patients with metabolic syndrome and diabetes mellitus is 
even worse. Epidemiological data suggest that target BP is achieved only in 64% with HTN and 
metabolic syndrome and in 61 % of patients with diabetes [14]. Local observational studies in 
Russia reveal that 13% of patients with unconh·olled HTN have diabetes [15]. Trial REGATAa-
PRIMA revealed, that as many as 61 % of patients with uncontrolled BP have metabolic syndrome 
[20]. 
5.2 Drug background 
5.2.1 Drug description 
Edarbi® (Azilsartan medoxomil) is the new angiotensin II receptor type 1 (A Tl) blocker 
(ARB). Azilsartan has a number of specific characteristics. It is structurally similar to candesaitan 
except that it beai·s a 5-oxo-1,2,4-oxadiazolemoiety in place of the tetrazole ring. Fmther it has a 
carboxyl group at the 7-position of the benzimidazole ring, which is believed to result in 
insmmountable receptor antagonism. 
Trade name: Edarbi® 
International Non-proprietary Name (INN): azilsaitan medoxomil 
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Azilsmedox-5008 
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Pharmacotherapeutic group: Angiotensin II antagonists. 
Pharmaceutical form: tablets 40 and 80 mg. 
Composition: 
1 tablet 40 mg contains: 
version 2.4 09-Jan-2019 
Active substance: azilsartan medoxomil potassium 42.68 mg conesponding to azilsaitan 
medoxomil 40 mg. Excipients: mannitol 95,63 mg, fumaric acid 2 mg, sodium hydroxide 0,69 
mg, hydroxypropylcellulose 5,4 mg, croscarmellose sodium 13,8 mg, cellulose microcrystalline 
18 mg, magnesium stearate 1,8 mg. 
1 tablet 80 mg contains: 
Active substance: azilsa1tan medoxomil potassium 85.36 mg cmTesponding to azilsrutan 
medoxomil 80 mg. Excipients: mannitol 191,26 mg, fumaric acid 4 mg, sodium hydroxide 1,38 
mg, hydroxypropylcellulose 10,8 mg, croscarmellose sodium 27,6 mg, cellulose microcrystalline 
36 mg, magnesium stearate 3,6 mg.ATC code: C09CA09 
Description 
Tablets 40 mg: from white to nearly white round biconvex tablets, debossed "ASL" on one 
side and "40" on the other. 
Tablets 80 mg: from white to nearly white round biconvex tablets, debossed "ASL" on one 
side and "80" on the other. 
5.2.2 Summary of trials and studies 
Azilsartan medoxomil has shown more potent blockage of A Tl receptors in vitro than 
several other comparable ARBs and the ability to remain tightly bound to A Tl receptors for very 
long periods of time after drug washout [21]. These pharmacological chru·acteristics result in 
significant advantages of Azilsa1tan medoxomil in BP control. In direct comparative studies with 
over antihypertensive drugs Azilsaitan medoxomil was more effective in decreasing BP than 
ARBs olmesartan [22] and valsartan [23]. 
The subanalysis of data pooled from Azilsaitan medoxomil studies revealed, that Azilsaitan 
medoxomil lowers systolic BP more effectively than olmesartan and valsartan at their maximally 
approved doses in patients with diabetes and prediabetes [24]. 
Besides its significant effect on the BP Azilsartan has demonstrated several positive 
pleiotropic effects. On the preclinical studies on animal models Azilsaitan increased the insulin 
sensitivity and the glucose tolerance [25], decrease the concentration of glucose and free fatty 
acids in the blood , decrease the adipose tissue weight and the size of adipocites increase the 
expression of adiponectin and PP AR-- receptors [26]. 
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These data indicates that Azilsartan medoxomil could be effective in long-term treatment of 
patients with HTN and improving the prognosis not only due to decrease of BP, but also due to its 
beneficial metabolic effects 
5.3 The study rationale 
Reaching the target BP in HTN patients with overweight and obesity is highly complicated 
[6] It is partially related with the fact that some pathological processes involved in obesity lead to 
BP elevation [11 ]. According to the epidemiological studies, the percentage of HTN patients with 
ove1weight who reach BP goals is as low as 22% and of HTN patients with obesity - as low as 
15% [17]. Clinical studies conducted in Russia revealed that among patients with uncontrolled BP 
the incidence of overweight is 56% [18], of obesity - 63% [27]. In addition, epidemiological 
sh1dies highlighted, that patients with overweight and obesity have significantly higher risk of 
cardiovascular complications, that individuals with normal weight [28]. 
Thus, although there are many effective antihypertensive drugs available, treatment of 
patients with HTN and overweight or obesity still is the unsolved problem [6]. Reaching the BP 
goals and improvement of prognosis in such patients require the new, highly effective antiHTN 
medications. 
The new angiotensin receptor blocker (ARB), azilsaiian medoxomil, opens new 
opportunities in the treatment of HTN [20-22]. Particularly, it may be effective in patients with 
HTN and overweight or obesity, which have difficulties in BP control and high risk of 
cardiovascular complications. So, the assessment of efficacy of azilsartan medoxomil in treatment 
of HTN patients with overweight or obesity in routine clinical practice is a matter of significant 
interest. 
6 
Study Objective(s) and outcomes 
6.1 Study objectives 
Primary objective: 
-
To evaluate the effect of Edarbi® on clinic systolic blood pressure (SBP) among HTN 
patients with overweight or obesity (V 4). 
Secondary objectives: 
-
To evaluate the effect of Edarbi® on clinic diastolic blood pressure (DBP) among HTN 
patients with overweight or obesity (V4); 
-
To evaluate the prop01iion of overweight or obese patients who respond to Edarbi® therapy 
(defined as decrease of SBP2'.: 20 mm Hg or decrease ofDBP2'.:10 mm Hg) (V4); 
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To evaluate the prop01iion of overweight or obese patients who achieved target BP 
(defined as SBP<140 and DBP<90mm Hg) (V4); 
-
To evaluate the effect of Edarbi® on clinic SBP among HTN patients with overweight or 
obesity in subgroups of patients: BMI (overweight, obese), impaired glucose tolerance, 
metabolic syndrome, diabetes mellitus (V 4); 
-
To evaluate the effect of Edarbi® on clinic DBP among HTN patients with overweight or 
obesity in subgroups of patients: BMI (overweight, obese), impaired glucose tolerance, 
metabolic syndrome, diabetes mellitus (V 4); 
-
To evaluate the proportion of overweight or obese patients who achieve target BP 
(SBP<140 mm Hg, DBP<90 mm Hg) in subgroups of patients: BMI (overweight, obese), 
impaired glucose tolerance, metabolic syndrome, diabetes mellitus (V4). 
Safety Objective: 
-
To describe AE characteristics. 
Exploratory objectives: 
-
-
-
-
-
-
-
-
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Primary outcome: 
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Change from baseline in clinic SBP on Edarbi® therapy (Time Frame: Baseline and V4). 
Secondary outcomes: 
-
Change from baseline in clinic DBP on Edarbi® therapy (Time Frame: Baseline and V4); 
-
Propo1tion (%) of patients who respond to Edarbi® therapy (defined as decrease of SBP2: 
20 mm Hg or decrease ofDBP2:10 mm Hg; Time Frame: Baseline and V4); 
-
Propmtion (%)of patients who achieve target BP <140 mm Hg (defined as SBP<140 and 
DBP<90mm Hg) (Time Frame: Baseline and V4); 
-
Changes from baseline in clinic SBP in subgroups of patients: BMI (overweight, obese), 
impaired glucose tolerance, metabolic syndrome, diabetes mellitus (Time Frame: 
Baseline and V4); 
-
Changes from baseline in clinic DBP in subgroups of patients: overweight, obese (stages 
I-III), impaired glucose tolerance (yes, no), metabolic syndrome (yes, no), diabetes 
mellitus (yes, no) (Time Frame: Baseline and V4); 
-
Propmtion (%)of patients who achieve target BP (SBP<140 mm Hg, DBP<90 mm Hg) in 
subgroups of patients: overweight, obese (stages I-III), impaired glucose tolerance (yes, 
no), metabolic syndrome (yes, no), diabetes m.ellitus (yes, no) (Time Frame: Baseline and 
V4). 
Safety Outcome: 
-
Incidence and type of adverse events. 
Exploratmy outcomes: 
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7 
Study Administrative Structure 
Contact and responsibilities of all patties contributing to the study, including all 
investigators, are detailed below. 
The sponsor is responsible for all study-related activities including study set-up activities 
and study documentation development. The responsible CRO for specific study-related activities 
will perform these activities in full or in pa1tnership with the sponsor. 
7.1 Steering Committee 
The Steering Committee serves to provide overall supervision of the study activities across 
the study. The Steering Committee is responsible for composing and evaluating the 
research/scientific/medical questions and issues; guiding and coordinating; maintaining open and 
active communication about the goals, process, and findings of the Study; compiling and editing 
the final Study Rep01t and study publication. 
The members of the Steering Committee are the following. 
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7 .2 Study Sites 
The study is planned to be conducted in approximately 80 investigational sites from the Russian 
Federation and about 10 investigational sites in the Republic of Kazakhstan. 
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The study sites will be selected according to following criteria: 
-
out-patient clinics, 
-
availability of cardiologist specialists in out-patient clinics, 
-
significant patient flow with essential hype1tension (the sites should treat at least 350 
patients with hypeitension per year). 
The Sponsor/responsible CRO will keep a record of the individuals responsible for each 
participating Study Site, the Investigators. The chosen Investigators must have qualifications and 
expertise directly related to the Study. 
7.3 Sponsor Personnel 
Takeda will keep a record of all relevant sponsor personnel. 
Name and address of the Sponsor: 
Takeda Pharmaceutical LLC 
2, bld. 1, Usacheva str., Moscow 
119048, Russian Federation 
Phone: + 7 495 933 5511 
Fax: 
+ 7 495 502 1625 
Name, position, address and telephone 
of specialist who is responsible for 
preparation of the protocol 
Name and position of person who 
responsible 
for 
coordinating 
management of the non-interventional 
study 
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Name, position, address and telephone 
of healthcare professional who is 
responsible for the study, signs the 
protocol and protocol amendments on 
behalf of the Sponsor 
Name and position of specialist who is 
responsible for drug safety on behalf 
of the Sponsor 
Name and position of specialist who is 
responsible for drug safety on behalf 
of the Sponsor in the Republic of 
Kazakhstan 
Name and position of specialist who is 
medical responsible on behalf of the 
Sponsor 
m 
the 
Repablic 
of 
Kazakhstan 
 
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7.4. Contract Research Organisation (CRO) 
Summary of tasks delegated to the CRO: 
-
The study documentation development (project management plan, data management plan 
etc), 
-
Study implementation and initiation, study conducting and study close-out, 
-
Data management, 
-
Project management, 
-
Statistical analysis, including the statistical analysis plan, 
-
Study report development 
Every task has more detailed description in the Takeda-CRO contract. 
The CRO will keep a record of all involved CRO personnel (e.g. CVs of monitors and data 
manager involved in the study as well as CV and other confirming documentation of the persons 
who are responsible for database constructing and all the medical operations). 
Name, address and telephone of the 
Contract Research Organization: 
Name and position of person who 
responsible for 
coordinating management of the 
study and for drug safety on behalf 
of the CRO 
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Name and position of person who 
responsible for data management on 
behalf of the CRO: 
Name and position of specialist who 
is responsible for statistical strategy 
and analysis of the study on behalf of 
the CRO: 
Name and position of specialist who 
is responsible for quality assurance 
and quality control on behalf of the 
CRO: 
7.5 Essential Documents 
Study Protocol 
The following essential documents must be received by the Sponsor before the study is 
initiated at a site: 
• Written agreement between Takeda and CRO; 
• Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the investigator; 
• Patient Info1mation Sheet and Informed Consent Form in local language (notified to I 
approved by Independent Ethics Committees (IECs) I Institutional Review Boards (IRBs) as 
locally required); 
• Written IEC I IRB approval I vote according to local regulations; 
• 
Authority notification according to local regulations. 
8 Ethics 
This study is an observational study where the existence of the study has no impact on the 
patient except for collection of infmmed consent to use of the patient's data. 
8.1 Ethical conduct of the Study 
This study is a non-interventional study where there is no assignment of a patient to a 
particular therapeutic strategy, and no additional diagnostic or monitoring process is required for 
participation or during the study [5]. Epidemiological methods shall be used for the analysis of the 
collected data [5]. All the activities during the study to be perfo1med according to the ethical rules 
and considerations, described in the Declaration of Helsinki (2013, Fortraleza) [1]. 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki, Good Pharmacoepidemiology Practices (GPP), ISPE GPP guideline, 
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Good Epidemiological Practice requirements and any local regulations [I -5]. Special attention 
will be paid to data protection. 
Takeda/the responsible CRO will ensure that the protocol, any amendments and the Patient 
Information Sheet/Informed Consent Form are submitted to the relevant Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) according to local requirements. 
Takeda as the Sponsor is responsible for meeting the ICH requirement for yearly updates to 
the IECs/IRBs, if applicable. 
8.2 Independent Ethics Committee I Institutional Review Board and Authorities 
(IEC/ IRB) 
According to applicable regulations, the responsible CRO or the Investigators will: 
• notify or obtain approval from the relevant IEC/IRB of the protocol, any amendments 
and the Patient Information Sheet I Informed Consent Form 
The responsible CRO or the Investigator will submit required documents to the IEC I 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 responsible CRO will supply relevant documents for submission to the 
Independent Ethic Committee for the protocol's review and approval. This protocol, amendments 
to the protocol, the informed consent form, and other documents required by all applicable laws 
and regulations, must be submitted to a central IEC for approval. The IRB's or IEC's written 
approval of the protocol and patient informed consent must be obtained and submitted to the 
sponsor or the responsible Contract Research Organisation before start of the study. Documented 
approval from central IECs will be obtained for all participating investigational sites (principle 
investigators) prior to the study start. 
If necessary, the Sponsor will get prolongation, change or resumption of approval by IEC. 
IEC should submit to the Sponsor, at its request, the list of the members of IEC taking part in 
voting and the confomation that IEC is organized and is conducting its activities in conformity 
with the principles of ICH GCP, the principles stated in the Helsinki declaration, the applicable 
legislation and normative documents. 
The Sponsor/responsible CRO will keep an updated list of all submission and approval dates 
of all documents submitted to the IEC I IRB and will provide the Investigators with a copy of this 
list prior to the study start. 
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8.3 Local Ethics Committee (LEC) 
This non-interventional study will be submitted to Local Ethics Committees (LECs) upon 
the regulations of the paiticipated countries LEC should also approve all amendments to the 
protocol. 
If necessary, investigator should get prolongation, change or resumption of approval by 
LEC. LEC should submit to the Sponsor, at its request, the list of the members of EC/LEC taking 
pait in voting and the confirmation that EC/LEC is organized and is conducting its activities in 
conformity with the principles of ICH GCP, the principles stated in the Helsinki declaration, the 
applicable legislation and normative documents. When necessai·y, an extension, amendment or 
renewal of the LEC approval must be obtained and also forwarded to the Sponsor. 
8.4 Authorities approval 
Non-interventional (observational) studies are not covered by the definition of the «clinical 
trials» stated in the Directive 2001/20/EC [5]. In this connection for conduction of the present 
study, a written approval of IEC and (if necessary) of LECs of the sites of NIS to be with the 
ethical principles ofNISs and protection of rights of the patients taking pa1t in it. 
Authorities approval in the Russian Federation 
There is no need in permission of other competent authorities (CA) of the Russian 
Federation for conduction of the present NIS. 
The Sponsor will send required documents to the CA and/or other national or regional 
authorities for their notification. The Sponsor will keep an updated list of submission and 
notification dates and a copy of all documents submitted. 
Authorities approval in the Republic Kazakhstan 
The Sponsor or responsible CRO on behalf on Sponsor will send all the required documents 
to the CA. In case of a positive conclusion, expe1ts appointed by CA notify the customer of the 
possibility provide the documents to the Commission on Ethics for the ethical evaluation of 
material. After getting an approval from the Commission on Ethics expe1ts notify the CA, then 
CA makes the decision on whether to approve the conduct of the study or not. The Sponsor will 
keep an updated list of submission and notification dates and a copy of all documents submitted 
[33]. 
8.5 Patient Information Sheet and Informed Consent Form 
The investigator must have the IEC/IRB written approval/favourable opinion of the written 
Informed Consent Form and any other written info1mation to be provided to patients/legal 
representatives prior to the beginning of the observation. 
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Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and will be in accordance with all applicable laws and regulations. 
The informed consent form and patient information sheet describe disclosures of the patient's 
personal and personal health information for purposes of conducting the study. The informed 
consent form and the patient information sheet fmther explain the nature of the study, its 
objectives, and potential risks and benefits, as well as the date informed consent is given. 
In the event the patient is not capable of rendering adequate written informed consent, then 
the patient's legally acceptable representative may provide such consent for the patient in 
accordance with applicable laws and regulations. 
The informed consent form will detail the requirements of the patient and the fact that 
he/she is free to withdraw at any time without giving a reason and without prejudice to his or her 
further medical care. The patient information sheet and info1med consent form must be written in 
a language fully comprehensible to the prospective patient. 
The patient must agree that Sponsor personnel, their representatives or IEC/IRB or CA 
personnel (national or other) may require direct access to the patient's data I personal records 
which were collected, processed and stored in an anonymous form. The patient must agree that 
his I her data will be processed and stored in an anonymous form for evaluation of this study and 
any later overviews. Data may also be transfened in anonymous form to third pa1ties, e.g. other 
companies or authorities, which may be located in other countries with potentially different 
regulations for data. 
The patient/legal representative 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 (for details, please see the section 9.4.). 
For details, see the Patient Inf01mation Sheet and Informed Consent Form. 
8.6 Signing of Informed Consent Form 
The investigator must give the patient/legal representative oral and written information 
about the study in a form that the patient/legal representative can understand, and obtain the 
patient's/legal representative's written consent before collection of identifiable patient information 
(hereinafter referred to as personal data). 
Before consenting, the patient/legal representative must be left with ample time to: (1) 
inquire about details of the study, (2) decide whether or not to paiticipate in the study and (3) 
consider and to pose questions. Since the study is observational the consent only concerns the data 
collection per see and is not consent to any interventional procedure or treatment. 
If the patient/legal representative determines he or she will pa1ticipate in the study, then the 
informed consent foim must be signed and dated by the appropriate person, at the time of consent 
and prior to the patient entering into the study. The patients/legal representatives should be 
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instructed to sign using their legal names, not nicknames, using blue or black ballpoint ink. The 
investigator must also sign and date the informed consent form at the time of consent and prior to 
patient entering into the study. 
The original, signed Informed Consent Fmms must be kept on the Site. Copies of the signed 
info1med consent form and patient information sheet shall be given to the patient. 
8. 7 Patient identification 
The Patient Information Sheet and Informed Consent Fo1m will explain that study data will 
be stored in an paper or electronic CRF (pCRF/eCRF) and computer database, maintaining 
confidentiality. Patients in this database will be identified by unique central patient identification 
code (patient number). 
This code is only used for study purposes. After informed consent is signed every patient is 
given an identification code. The patient code consists of: 
-
study ID number (MACS-2014-100633), 
-
patient number; patient will be given as a four-digit figure attributed to the patient (0001, 
0002, 0003 ... etc). 
Sites which will choose the paper type of CRF will get an amount of paper CRF with patient 
identification code preprinted. The Investigator will sign a fmm where numbers of CRFs will be 
denoted for his/her pa1ticular site. Sites which will choose the electronic type of CRF will amount 
of identification codes via database. 
For the duration of the study and afterwards, only Investigator is able to identify the patient 
based on the identification code. The Investigator must keep a Patient Identification List of all 
patients that have signed the informed consent, including patient number, full patient' name, date 
ofbiith and date of Informed Consent signing (see section 8.9). 
Authorized representative of a regulatory authority may require direct access to pa1ts of the 
trial site records relevant to the study, including patients' medical records for data verification 
purposes. 
8.8 Patient insurance 
In this study, data on routine treatment of patients in daily practice are analyzed with the 
help of epidemiological methods, and treatment including diagnosis and monitoring of therapy 
follows exclusively routine daily practice. Cunent medical daily practice is observed, and for the 
patient no risks beyond regular therapy exist - there is no additional hazard arising from study 
paiticipation. As no study related risks exist, there is no need to protect the patient additionally by 
a patient insurance. The general regulations of medical law and the professional indemnity 
insurance of the physicians and, respectively, the institutions involved provide sufficient 
protection for both patient and physician. 
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No study medication will be provided to participants. Thus, product insurance is covered by 
the existing product liability. 
8.9 Confidential and non-disclosure of personal data 
The sponsor and responsible CRO affirm and uphold the principle of the patient's right to 
protection against invasion of privacy. The personal data of the NIS participants will be kept and 
processed with observance of the provisions of the RF federal law No. 152 "On personal data" 
and law of the Republic of Kazakhstan "On personal data and their protection" [25, 34]. 
Throughout this study, a patient's source data will only be linked to the study database or 
documentation via a unique identification number (see Section 8.7). 
The necessary personal data of the patients (for example, demographic parameters) will be 
gathered solely for achieving the objectives of the NIS, envisaged by its design and the minimal 
volume. Names, addresses, numbers of medical records/ambulatory record will not be entered into 
CRF. No documentation identifying the patients will be disclosed. 
The patients' names will not be disclosed to the sponsor. If the patient's name is mentioned 
in a document, such name should be deleted before submission of the copy/original of the 
document to the sponsor/responsible CRO. The results of the NIS kept in the electron form, 
should be stored in accordance with the laws of information protection. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to pe1mit its monitor or designee's monitor, representatives from 
any competent authority, the sponsor's designated auditors, and the appropriate IRBs and IECs to 
review the patient's original medical records (source data or documents), including, but not 
limited to, laboratory test result repmis, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a patient's study paiiicipation. Before inclusion in the NIS, 
the patient will be acquainted with the terms and conditions of confidentiality of using his/her 
personal data, including the necessity of access to them of the monitor and other authorized 
persons of the Sponsor. These terms and conditions will be presented in the information for 
patient. The patient will be included into the NIS only after getting acquainted with the above-
mentioned information and signing of the Informed Consent Form. 
Copies of any patient source documents that are provided to the sponsor must have ce1iain 
personally identifiable information removed (i.g. patient name, address, and other identifier fields 
not collected on the CRF). 
The investigator will keep the list of the patients' names (Patient Identification List) so that 
to use it if the patients' primary documentation is needed. If SADR is repmied, the representative 
of the regulatory authorities can ask for additional explanations. In this case the Sponsor is 
prohibited to contact the patient directly. All additional inf01mation will be presented by the 
investigator. 
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9 
Study Design and Plan 
9.1 Overall study design 
This is an international, prospective, multicentre, non-interventional, observational study. 
This study is a 'non-interventional study' as defined in Directive 2001/20/EC [5] and will 
follow the guidelines for GPP and GVP [3,4]. This means that: 
• the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms 
of the marketing authorisation; 
• the assignment of a patient to a particular therapeutic strategy is not decided in advance by 
the study protocol but falls within current practice; 
• the prescription of the medicine is clearly separated from the decision to include the patient 
in the study; 
• no additional diagnostic or monitoring procedures shall be applied to the patients; 
• epidemiological methods shall be used for the analysis of collected data. 
9.2 Study Schedule 
Milestone 
Planned Date 
Planned Start of the study 
May, 2016 
Planned End of the emolment (LPFV) 
October, 2017 
Planned End of the patient observation (LPL V) 
April, 2018 
Planned End of the study (end of data collection) 
May, 2018 
Final study report 
August, 2018 
Due to the observational design, patient visits to the refening physician are not pre-specified 
by the study protocol, but will follow usual clinical practice. All patient-care decisions, including 
diagnostic and therapeutic interventions, will be made by and conducted at the discretion of the 
participating study physicians according to their clinical judgment and the local standard of 
medical care. 
Start of the study is defined as the date of the start of data collection (first patient signed 
ICF for data collection). 
End of the enrolment (Last Patient First Visit) is defined as the date when the last patient 
signs ICF and enrolled in the study. 
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End of the patient observation (Last Patient Last Visit) is defined as the last date when 
the patients are observed in the scope of the study. 
End of study (end of data collection) is defined as the date when the last data point is 
collected. Up to this date all the CRFs should be completed and all the data clarifications (queries) 
should be done. 
The Sponsor will ensure that End-of-Study notification is submitted to the concerned 
authorities and IEC/IRB. The Sponsor will ensure that results are posted on "clinicaltrials.gov" 
and as required by local authorities. 
The study is considered to be completed after the database is closed, the final statistical 
analysis is performed and the study report is written. The study report will be signed within 12 
months after the collection of the last data point. 
9.3 Discussion of Study Design 
The primary study objective is to estimate antihypertensive effect of Edarbi® therapy on 
blood pressure in patients with overweight or obesity in routine clinical practice of HTN treatment 
in the Russian Federation. So the non-interventional study design was chosen as it helps to obtain 
data in routine clinical practice. 
Non-interventional principles defined in Directive 2001/20/EC [5] permits to estimate "real 
life" conditions. Besides non-interventional studies help to analyze big sample sizes without 
special selection and screening within routine clinical practice. Thus, non-interventional design 
allows attaining the objective of the study. 
Non-interventional study design has number of limitations. It doesn't suppose 
randomization or blinding, so no control group will be used. Other limitations of this study are the 
absence of control arm and comparator, less well defined population, compared with controlled 
clinical trials. But this limitation is not critical as there are direct comparisons of Edarbi® with 
commonly used angiotensin-conve1ting-enzyme (ACE) inhibitors (ramipril) and ARB (valsartan, 
candesartan and olmesartan). Besides comparators are not used in the study due to the defined in 
the protocol study objectives and outcomes. 
The population that is planned to include in the study supposed to be heterogeneous in terms 
of clinical characteristics. It is planned to avoid this bias by subgroup analysis, including patients 
with overweight obesity, metabolic syndrome and diabetes mellitus. 
9.4 The Study Population 
The patients will be treated m accordance with local routine clinical practice. Patient 
eligibility is determined according to the following inclusion and exclusion criteria. Patients 
should be included in the study only once. 
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Investigator should consult with appropriate approved local SmPC of Edarbi® before 
including patients into the study and get acquainted with the info1mation about dosage and method 
of administration of the drug, duration of treatment, special warnings and precautions regarding 
the use. The approved local SmPC Edarbi® will be included into the documentation on the study. 
Approximately 1916 patients should be included into the study in accordance with the 
inclusion/exclusion criteria below. 
9.4.1 
Criteria inclusion 
Every eligible patient at participating investigational sites must meet the following criteria: 
1. Male and female patients ~ 18 years of age with HTN 1-2 grade* 
2. Patients with: 
o Newly diagnosed arterial HTN or 
o inadequately controlled previously prescribed monotherapy with RAAS blocker or 
o inadequately controlled previously prescribed combination therapy with RAAS 
blocker + diuretic or RAAS blocker + calcium antagonist. 
3. The physician decides to prescribe Edarbi® 
o as monotherapy or 
o as a part of combination therapy including diuretics or calcium antagonists; 
4. Overweight or obesity of any degree (body mass index> 25 kg/m2); 
5. Is capable of understanding the written informed consent, provides signed and written 
informed consent, and agrees to comply with protocol requirements. In case the patient is 
blind or unable to read, informed consent will also be witnessed. 
* in accordance with guidelines of the Russian Ministry of Health for the management of HTN [6] 
and Kazakh protocol on clinical diagnosis and treatment of hypertension (2013) [7]. 
9.4.2 Criteria exclusion 
Any patient who meets any of the following criteria will not be qualified for entry into the 
study: 
1. Confomed secondary HTN; 
2. Contraindications for Edarbi® of respective approved local SmPC of Edarbi®; 
3. Any reasons of medical and non-medical character, which in the opinion of the 
physician can prevent patient paiticipation in the study. 
4. Is an employee or family member of the investigator or study site personnel. 
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5. Is currently paiticipating in a clinical trial. Participation in non-interventional registries 
is permitted. 
6. Vulnerable patients who are unable to understand information about study or those who 
depend on investigator. 
9.4.3 Justification for criteria inclusion and exclusion 
The criteria are set to ensure a patient population that will enable the investigation of the set 
objectives. 
Results of azilsa1tan clinical trials suggest that this drug provides potent and fast 
antihypertensive effect, so it could be effective in newly diagnosed HTN patients in achieving BP 
goals. Comparative studies of azilsartan with ACE (Ramipril) and ARBs (valsaitan, candesartan, 
olmesaitan) have shown the superior efficacy of Edai·bi® over comparators. Thus, azilsartan could 
be effective in patients with insufficient BP control on other RAAS blockers in monotherapy or 
combination therapy. So, inclusion criteria ai·e designed to provide the inclusion of patients with 
either newly diagnosed HTN or with poorly controlled BP on mono- or combination therapy, 
including RAAS blockers. 
Cml'ent approach of administration of combination therapy with RAAS in routine clinical 
practice in the Russian Federation suggest the addition of calcium channel blockers or diuretics. 
These types of combinations also ai·e specified as reasonable in current Russian guidelines on 
HTN treatment and Kazakh protocol on clinical diagnosis and treatment of hype1tension (6, 7]. 
So these types of combination therapy are defined in inclusion criteria. 
As this is non-interventional observational study, we don't restrict exclusion criteria 
artificially. According to ethical rules, all patients must write informed consent before enrolling. 
Data enoneously collected from patient for which written consent is not available, will not be 
included in or will be deleted from the database. 
Exclusion criteria are just based on contraindication approved local SmPC of Edarbi® and 
routine practice. Exclusion criteria were designed to prevent inclusion of patients who cannot 
receive Edarbi® therapy for medical reasons (due to contraindications or secondary HTN). 
9.4.4 Patient selection and procedure for avoiding of selection bias 
In order to reduce selection bias, each patient who ai·e planned to treat of arterial HTN by 
Edai·bi® has to be documented in an anonymous patient log file (independent of prescribed 
treatment and signing of the Informed Consent Form) in a consecutive manner at each site. 
Eligible patients who receive Edarbi® must be emolled consecutively into the study and 
documented in the case report form. No eligible Edarbi®patient must be skipped. In case a patient 
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is not eligible (e.g. no informed consent signed), the reason for non-eligibility must be 
documented in the patient log file. 
9.4.5 Discontinuation/withdrawal of patients from the study 
9.4.5.1. Criteria for Discontinuation or Withdrawal of a patient 
Patients may be discontinued from study or study drug at any time, at the discretion of the 
investigator. Specific reasons for discontinuing a patient from the study are: 
1. Voluntary withdrawal of informed consent in patient's request or at the request of patient's 
legally acceptable representative. 
The patient (or patient's legally acceptable representative) wishes to withdraw from the 
study. The reason for withdrawal, if provided, should be recorded in the CRF. Note: All attempts 
should be made to determine the underlying reason for the withdrawal and, where possible, the 
primary underlying reason should be recorded (ie, withdrawal due to an AE or lack of efficacy 
should not be recorded in the "voluntary withdrawal" category). 
2. Development of exclusion criteria or other safety reasons (not a AE or SAE) during the 
study. 
3. Adverse Events (AE)/ Serious Adverse Events (SAE), including Patient's death 
The patient has experienced an AE or SAE that requires early termination because patient is 
unwilling to continue because of the AE or SAE or continuation of patients' visit to the clinic is 
impossible or any other occurrence which can be happened. 
4. Protocol deviations, inconect emolment of the patient. The investigator and the sponsor 
will decide whether there is a deviation from the protocol. 
5. Lost for observation within the framework of the study. The patient did not return to the 
clinic and attempts to contact the patient were unsuccessful. 
6. Study termination. Sponsor decision or regulatory authorities' requirement about cessation 
of the study. 
7. Pregnancy. The patient is found to be pregnant. 
Note: If the patient is found to be pregnant, the patient must be withdrawn immediately. 
8. Other (specify) 
If the patient is lost for observation within the framework of the study that is, it is 
impossible to conduct the final visit; the investigator must do its best to get in touch with the 
patients for getting full information and clarifying the reasons of the loss of contact. Premature 
end of HTN treatment by Edarbi® automatically means end of data collection. 
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Details for the premature termination of the study/sites as a whole are provided in section 
9 .6 (Premature termination or Suspension of Study or lnvestigational Site). 
9.4.5.2. Procedures for Discontinuation or Withdrawal of a patient 
There are no special procedures of discontinuation of patients. The investigator may 
terminate a patient's study participation at any time during the study when the patient meets the 
study termination criteria described above in Section 9 .4 .4 .1. In addition, patient/legal 
representative may discontinue participation in the study without giving a reason at any time 
during the study. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the patient's 
medical records. The patients who prematurely withdrew from the study are not replaced with 
new ones, and their data will be included into the final analysis. In case if investigator loses 
contact with the patient during the study observation, the investigator may contact with the patient 
directly or through the other health care professionals who observe this patient in routine practice. 
In that case pait of CRF "End of observation" can be filled in basing on data received via e-
mails/calls. 
9.5 The study plan (plan of observation) 
A physician makes the decision to prescribe Edarbi® to a patient. Afterwards the physician 
evaluates inclusion/exclusion criteria and offers the patient participation in the observational study. 
The investigator gives the patient necessary information about the study and asks the patient 
to read the Patient Information Sheet and Informed Consent Form. If the patient agrees to 
participate in the study then the patient and the investigator sign the Inform Consent Form and the 
investigator includes the patient in the study. 
During participation in the study patients are observed according to the local routine 
practice. The assignment of a particular therapeutic strategy to the patient including all diagnostic 
procedures is decided in accordance with Russian guidelines "Diagnostics and treatment of 
hypertension" (2010) and Kazakh protocol on clinical diagnosis and treatment of hypertension 
(2013) [ 6, 7] and local routine practice. The patients would tal<:e Edarbi® according to local SmPC. 
Due to the non-interventional study design it's not possible to appoint exact times for the 
study visits, although it is expected that the period of observation will be approximately 6 months. 
The frequency of the visits will be assigned by each physician according to their routine practice. 
It is anticipated that the patients will visit their physician every 3 months and more often at the 
beginning until the patient achieves target blood pressure. Information for the study will be 
collected from 4 patients' visits to the physician: 
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• Visit 1 (Baseline visit): is carried out after the physician made the decision to prescribe 
medication and the patient signed the Informed Consent Form. Baseline visit is the visit when the 
patient was prescribed appropriate medication. 
• Visit 2 (Observational visit): assessment of blood pressure dynamics, data collection is 
performed approximately one month after therapy beginning 
• Visit 3 (Observational visit): assessment of blood pressure dynamics, data collection is 
performed approximately 3 months after therapy beginning 
• Visit 4 (Final observational visit): assessment of therapy effectiveness. Data collection is 
perf01med approximately 6 months after therapy beginning 
Last visit can occur later than 6 months after baseline but not more than 7 months total. 
Conditions when the special form "End of observation" should be filled in earlier than 
patient passes 6 months are described in the Section 10.5. 
Scheme 1. The observational study schematic 
The physician 
takes a 
decision of 
Edarbi~ 
admi nistration 
G 
··- ··---··-·1 
ICF signed i 
by the 
l 
patient ! 
E!~.!ll® therapy: treatment tactics 
····-··-···--·--··---; 
V1 
Baseline visit 
(inclusion) 
Start of Edarbi•:ID 
thera'PY' 
V2 
Observational 
Visit 
Blood Pressure I 
dynamic I 
assessment 
7
·='-"0'~.-:~~11~-~•·1·~,~------............. lJ 
approximately after I 
1 month fromthe 
start of Edarbi 
; 
therapy 
i 
.......................................................... .! 
V3 
Observational 
Visit 
Blood Pressure ! 
dynamic 
I 
assessment j 
.:::.·.-::.-::.""::"::.-:=:::.:::::::;.·::."::..<>:::::::.·:::::.".·:;.·::.l 
Data collection 
i 
approximately after ! 
3 month fromthe i 
start of Eclarbi 
! 
therapy 
i 
.................................................... ! 
V4 
Final 
Observational 
visit 
Blood Pressure ·1 
dynamic 
i 
assessment J 
--·--
·1 
Data collection I 
approximately after 6 
month from the 
i 
start of Edarbi 
I 
therapy 
i 
9.6. Premature Termination or Suspension of Study or Investigational Site 
The study will be completed as planned unless appearing of situation which will require 
temporary suspension or early termination of the study. 
The sponsor has the right to close the study with serving a preliminary written notice to 
investigators and hospitals. The sponsor has the right to unilaterally stop at any time emollment of 
patients and I or gathering of data in the study with serving a preliminary written notice thereof on 
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the Investigator indicating the date of stop of enrollment. The sponsor should ensure that 
notification about premature termination or suspension of the study is submitted to the concerned 
authorities and IEC. 
The investigator has the right to stop recruitment at any time with serving a preliminary 
written notice to the Sponsor/responsible CRO. 
In case of premature closure of the site/termination of the study, all completed and also 
unused (including the unused pages of paitially completed CRFs) CRFs and all documentation 
forms (except documentation that has to remain stored at site) must be returned to the Sponsor, 
even unused ones. Study material may be destroyed only with permission of the Sponsor. 
10 Conduct 
10.1. Data source 
Data collection should be staited only after Informed Consent Form is signed by the 
investigator and patient. A unique patient identification number (patient number) will be assigned 
to each patient at the time that inf01med consent is obtained; this patient number will be used 
throughout the study. Source data will include medical records or other sources of information 
(e.g. laboratory tests forms, validated copies of medical summaries given by other specialists etc.). 
10.2. Data collection overview 
The documentation of study data will be reported by the attending physician via paper or 
electronic case report form (CRF). 
Term 
Baseline 
Observational 
0 bservational 
Final 
visit 
0 bservational 
visit (V2) 
visit (V3) 
(Vl) 
visit (V4) 
Inclusion/exclusion criteria 
x 
Signed Inf01med consent form 
x 
Date of visit 
x 
x 
x 
x 
Demographic information 
x 
Medical history (incl. risk 
factors, prior diseases, prior 
x 
HTN therapy etc) 
Body Mass Index (BMI) 
x 
x 
x 
x 
Physical examination and vital 
x 
x 
x 
x 
signs* 
HTN therapy (drugs, doses) 
x 
x 
x 
x 
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Laboratory tests and instrumental 
x 
x 
exams* 
Concurrent medical conditions 
x 
Concomitant medication 
x 
Adverse events 
x 
version 2.4 09-Jan-2019 
x 
x 
x 
x 
x 
x 
* All examinations (physical examination and vital signs, laboratory tests and instrumental exams) 
are done in accordance with clinical routine practice and physician's decision. Instrumental exams are 
measurement of blood pressure, hard rate, ECG, 24-hour ambulatory blood pressure monitoring. 
All 
examinations should be registered in the CRF only if they are done in routine practice. 
10.3. Data collected on the Baseline visit 
Baseline visit is a visit after physician makes a decision to prescribe Edarbi® for HTN 
treatment. It means that investigator inform patient about the study only after taking decision 
about strategy of HTN treatment. 
etc) 
Data to be collected: 
• Date of visit (day, month, year) 
• Date of Informed consent form signing (day, month, year) 
• Compliance with Inclusion/exclusion criteria 
• Demographic information: sex, date of birth, ethnicity, region of residence (city, town 
• Medical history: 
-
History of HTN 
o Duration of HTN/first diagnosed 
o Presence of HTN target organ damage 
Risk factors of cardiovascular disease (smoking, dyslipidaemia, glucose intolerance, 
obesity, abdominal obesity, family history of cardiovascular disease,) 
-
Cardiovascular diseases history: 
o established cardiovascular diseases (coronary aitery disease, chronic heart failure, 
arrhythmias, peripheral aitery diseases, ischemic hea1t disease etc.) 
o history of cardiovascular events (myocardial infai·ction, stroke, etc.) 
-
Alcohol use 
• Diagnose of HTN: grade, stage, risk. 
• Physical examination and vital signs: height (cm), weight (kg), waist circumference (cm), 
body mass index, systolic and diastolic blood pressure (position, time, values), heart rate, physical 
inactivity 
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previous HNT-treatment (if applicable), 
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-
reason(s) for discontinuation of previous HNT-treatment (if applicable), 
-
monotherapy/combination treatment, 
-
Edarbi® dosage regimen, 
-
other HTN co-medications: INN, trade name, dosage regimen (if applicable). 
• Laboratory data (last available measurements, if done within routine practice): 
-
total cholesterol, 
-
triglycerides, 
-
low-density lipoproteins, 
-
high-density lipoproteins, 
-
blood glucose, 
-
serum creatinine, 
-
urea, 
-
glycated haemoglobin 
• Concurrent medical conditions (diabetes mellitus, chronic kidney disease, chronic 
obstructive pulmonary disease, etc.) 
• Concomitant medication: INN, trade name, dosage regimen (single and total daily dose), 
duration of treatment, indication for administration 
• Adverse events: seriousness, severity, causality, start and stop dates, action, outcomes 
10.4. Data collected on the Observational visits 2, 3 and 4 
Data to be collected: 
• Date of visit (day, month, year) 
• Diagnose of HTN: grade, stage, risk. 
• Physical examination and vital signs: height (cm), weight (kg), waist circumference (cm), 
body mass index, systolic and diastolic blood pressure (position, time, values), hea1t rate 
• HTN treatment: 
-
monotherapy/combination treatment, 
-
Edarbi® dosage regimen, 
-
other HTN co-medications: INN, trade name, dosage regimen. 
• Laboratory data (last available measurements, if done within routine practice): 
-
total cholesterol 
-
triglycerides, 
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low-density lipoproteins, 
-
high-density lipoproteins, 
-
blood glucose, 
-
serum creatinine, 
-
urea, 
-
glycated haemoglobin. 
• Concomitant diseases 
version 2.4 09-Jan-2019 
• Concomitant medication: INN, trade name, dosage regimen (single and total daily dose), 
duration of treatment, indication for administration 
• Adverse events: seriousness, severity, causality, staii and stop dates, action, outcomes 
10.5. Data collected on the End of observation 
The end of observation in this study should be documented when: 
Voluntary withdrawal of informed consent in patient's request or at the request of 
patient's legally acceptable representative; 
-
Development of exclusion criteria or other safety reasons (not a AE or SAE) during 
the study; 
Adverse Events (AE)/ Serious Adverse Events (SAE) that requires early termination 
because patient is unwilling to continue because of the AE or SAE or continuation 
of patients' visit to the clinic is impossible or any other occurrence which can be 
happened; 
-
Lost for observation within the framework of the study. The patient did not return to 
the clinic and attempts to contact the patient were unsuccessful; 
-
Patient's death; 
-
Study termination. Sponsor decision or regulatory authorities' requirement about 
cessation of the study; 
-
Pregnancy; 
-
Premature end of HTN treatment by Edarbi®, 
End ofHTN treatment by Edarbi®, 
In case if one of described above events become, investigator should fill m the last 
appropriate Observational visit Form and the "End of observation" Form. 
The following data on the CRF titled "End of Observation" should be documented: 
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visit): 
• Diagnose of HTN and cardiovascular diseases (changes in comparison with Baseline 
HTN target organ damage, 
-
risk factors of cardiovascular diseases, 
-
cardiovascular diseases. 
• HNT treatment: 
-
Date of the last Edarbi® intake or prolongation of Edarbi® treatment, 
Reason(s) for discontinuation of Edarbi ®treatment, 
planned HTN treatment (if applicable) (INN, trade name, dosage regimen (single and 
total daily dose), 
-
assessment of Edarbi® treatment by investigator (very satisfied, satisfied, neutral, 
unsatisfied, very unsatisfied), 
-
assessment of HTN treatment by investigator (very satisfied, satisfied, neutral, 
unsatisfied, very unsatisfied). 
• Reason(s) for discontinuation of observation 
For patients who will discontinue observation in this study for any reason but continue 
treatment with Edarbi®, the investigator needs to rep01t that therapy with Edarbi® will be 
continued on the appropriate CRF entitled "End of Observation". 
10.6. Treatments to be documented in the study 
All medications should be administered according to approved local SmPCs. 
10.6.1. Documentation of the study medication 
Due to non-interventional design of the study, the decision about pa1ticular HTN treatment 
strategy to the patient is taken by attending physician. Treatment of interest is Edarbi®. The study 
medication is not provided by the sponsor. 
Edarbi® treatments will be registered in the CRF The following information about Edarbi® 
treatment will be collected: 
-
strut date of Edarbi®, 
end date of Edarbi® treatment or prolongation of Edarbi® treatment, 
single and total dose, dose regimen, 
reason(s) for discontinuation of Edarbi ®treatment (if applicable). 
Edarbi® should be administered according to the official prescribing information (The 
Russian SmPC). The staiting dosage will be 40 mg per day. In case of insufficient efficacy the 
dosage could be increased up to 80 mg per day. 
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In case of combination HTN-treatment all co-medications for HTN treatment should be 
registered in Case Repo1t Form. For every type of co-medication following data should be 
documented: 
-
INN, trade name, 
-
dosage regimen (dose taken), 
-
duration of treatment. 
10.6.3. Prior HTN treatment 
Medication taken before strut of the study is called prior medication. In case the patient 
already underwent HTN treatment during 12 weeks prior to strut ofEdarbi® treatment, details of 
the therapy should be recorded in the CRF. 
10.6.4. Concomitant medication 
Concomitant medication is any drug given in addition to the HTN treatment. These drugs 
may be prescribed by a physician or obtained by the patient over the counter. Concomitant 
medication is not provided by the sponsor. 
The information about concomitant medication can be received both on base of medical 
records and on questions to patients (according to routine practice). During the visits the 
information about changes in the concomitant therapy is recorded. At each study visit, patients will 
be asked whether they have taken any medication other than the study medication (used from 
signing of informed consent through the end of the study). 
All drugs and drug combination for concomitant medication will be registered in CRF. For 
every type of drug there will be documented trade name, INN, dosage regimen (dose taken), 
duration of treatment, indications. 
The ru·ea of interest is on antidyslipidemic and anti diabetic drugs. 
10.6.5. Follow-up HTN treatment 
If a patient withdraws from study due to change of Edarbi® treatment, the follow-up 
prescribed HTN treatment should be documented in the CRF. 
10.6.6. Pregnancy 
If any patient is found to be pregnant during the study she should be withdrawn. The 
pregnancy should be repmted immediately, using an AE repmt form. 
All pregnancies in patient on active study drug will be followed up to final outcome. The 
outcome, including any premature termination, must be reported to the Sponsor. An evaluation of 
child wellness after the biith must be reported to the Sponsor. 
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10.7. Laboratory, instrumental exams, physical examination and vital signs to be 
documented in the study 
All examinations (physical examination and vital signs, laboratory tests and other exams) 
will be performed in accordance with common clinical routine practice, routine practice of a 
particular medical institution. All examinations are solely based on the physician's decision about 
strategy of diagnostics and treatment. 
All examinations should be registered in the CRF only the protocol required lab tests will be 
recorded in the CRFs if they are done in routine practice. The documentation of laboratory and 
instrumental tests will strictly follow clinical practice. The reference ranges for each protocol 
required lab test performed according to routine practice will be collected as well. 
10.8. Body Mass Index (BMI) Calculation 
The BMI is calculated using metric units with the formula provided below: The Takeda 
standard for collecting height is centimeters without decimal places and for weight it is kilograms 
(kg) with 1 decimal place. BMI should be derived as: 
Metric: 
BMI = weight (kg)/height (m)2[ optional] 
Note that although height is reported in centimeters, the formula uses meters for height; 
meters can be dete1mined from centimeters by dividing by 100. Thus, for example, if height=l 76 
cm (1.76 meters) and weight=79.2 kg, then BMI=79.2/l.762=25.56818 kg/m2The values should 
be reported to 1 decimal place by rounding. Thus, in the above example BMI would be reported as 
25.6 kg/m2. As the BMI is used as entry criteria based on >25kg/m2 cut-off point, then this 
determination must be made after rounding. 
10.9. Documentation of Medical history, Concurrent Medical Conditions and 
co morbidities 
Medical history is history of diseases indicated before signing of the Informed Consent 
Form. 
ConcmTent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. 
Comorbidities (concomitant disease) are diseases which occm after start of Edarbi® 
treatment and are not related to the Edarbi® treatment. Comorbidities may include not limited to 
cardiovascular disorders (coronary aiiery disease, peripheral artery disease, cerebrovascular 
disease), diabetes, chronic pulmonary artery disease, chronic kidney disease. The condition (ie, 
diagnosis) should be described. 
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Risk factors are conditions which increase probability of cardiovascular disease in patients 
with HTN at the moment of signing ICF. Risk factors are described in accordance with Russian 
guidelines "Diagnostics and treatment of hypertension" (20 I 0) [21]. 
Time of medical event/disease 
Birth to day before ICF signed 
At the moment of ICF signing 
At the moment of ICF signing 
After ICF signing and sta1t of Edarbi® treatment 
11 Safety Reporting 
11.1 Definitions 
11.1.1. Adverse Event 
How it should be documented 
Medical history 
Risk factors 
Concunent medical conditions 
Adverse Events 
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign ( eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
11.1.2. Additional Points to Consider for AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions underlying disease should not be 
considered AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason. 
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Diagnoses vs signs and symptoms: 
version 2.4 09-Jan-2019 
• 
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unlmown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s). 
Laboratory values and ECG findings: 
• 
Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the 
investigator judges the change to be beyond the range of normal physiologic fluctuation). 
A laboratory re-test and/or continued monitoring of an abnormal value are not considered 
an intervention. In addition, repeated or additional noninvasive testing for verification, 
evaluation or monitoring of an abnormality is not considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should 
be reported appropriately as an AE. 
Pre-existing conditions: 
• 
Pre-existing conditions (present at the time of signing of informed consent) are considered 
concunent medical conditions and should NOT be recorded as AEs. However, if the 
patient experiences a worsening or complication of such a concunent condition, the 
worsening or complication should be recorded as an AE (worsening or complication 
occurs after start of study medication). Investigators should ensure that the event term 
recorded captures the change in the condition ( eg, "worsening of. .. "). 
• If a patient has a pre-existing episodic condition (eg, asthma, epilepsy) any occmTence of 
an episode should only be captured as a AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures 
the change in the condition from Baseline ( eg "worsening of. .. "). 
• If a patient has a degenerative concurrent condition (eg, cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE 
term recorded captures the change in the condition ( eg, "worsening of. .. "). 
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• If the patient experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition ( eg, 
"worsening of ... "). 
Changes in severity of AEs: 
• If the patient experiences changes in severity of an AE, the event should be captured once 
with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be captured appropriately as an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• 
Elective procedures performed where there is no change in the patient's medical condition 
should not be recorded as AEs. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• 
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded 
as an AE. The investigator must make the distinction between exacerbation of pre-existing 
illness and lack of therapeutic efficacy. 
11.1.3. Serious AEs 
A serious AE (SAE) is any AE which results in death, is life tlu·eatening, requires inpatient 
hospitalisation or prolongation of existing hospitalisation, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or bilth defect. 
A serious AE are defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
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2. Is LIFE THREATENING. 
The term "life threatening" refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY /INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an OTHER IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• 
May require intervention to prevent items 1 tlu·ough 5 above. 
• 
May expose the patient to danger, even though the event is not immediately life 
tlu·eatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE List. 
Blood and lymphatic System 
Immune system 
Bone manow failure 
Anaphylaxis 
Disseminated Intravascular Coagulation 
Progressive multifocal 
Haemolytic anaemia 
leukoencephalopathy (PML) 
Thrombotic Tlu·ombocytopenic Purpura 
Transplant rejection 
Cardiovascular System 
Nervous System 
Cardiac anest 
Cerebrovascular accident 
Cardiac failure 
Coma 
Cardiomyopathy acute 
Convulsive seizures 
Malignant hypertension 
Hyperthermia malignant 
Myocardial infarction 
Macular oedema 
Ventricular anhythmias 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Endocrine System 
Musculoskeletal System 
Adrenal crisis 
Rhabdomyolysis 
Gastrointestinal System 
Respiratory System 
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Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
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Acute respiratory failure 
Pulmonary hypettension 
Pulmonary thromboembolism 
Reproductive System 
Abortion 
Uterine perforation 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious, such as imp01tant medical events that might not be immediately 
life-threatening or result in death or hospitalisation but might jeopardise the patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalisation, or development of dependency or 
abuse. 
Any suspected transmission of an infectious agent via a medicinal product is considered a 
serious adverse reaction. 
11.1.4. 
Severity AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
Moderate: 
Severe: 
11.1.5. 
The event is transient and easily tolerated by the patient. 
The event causes the subject discomf01t and intenupts the patient's usual 
activities. 
The event causes considerable interference with the patient's usual activities. 
Causality of AEs 
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The relationship of each AE to study medication will be assessed using the following 
categories: 
Related: 
Not Related: 
11.1.6. 
An AE that follows a reasonable temporal sequence from administration of a 
drug (including the course after withdrawal of the drug), or for which possible 
involvement of the drug cannot be ruled out, although factors other than the 
drug, such as underlying diseases, complications, concomitant drugs and 
concun-ent treatments, may also be responsible. 
An AE that does not follow a reasonable temporal sequence from administration 
of a drug and/or that can reasonably be explained by other factors, such as 
underlying diseases, complications, concomitant drugs and concurrent 
treatments. 
Start and Stop Dates 
The start date of the AE is the date that the first signs/symptoms were noted by the patient 
and/or physician. 
The stop date of the AE is the date at which the patient recovered, the event resolved but 
with sequela or the patient died. If AE is ongoing at the moment of end of observation, it should 
be indicated in the CRF. 
11.1.7. 
Frequency 
AEs ( eg, vomiting) or those which occur repeatedly over a period of consecutive days are 
intermittent. All other events are continuous. 
11.1.8. 
Action Concerning Study Medication 
• Drug withdrawn - a study medication is stopped due to the particular AE. 
• Dose reduced - the dose was reduced due to the particular AE. 
• Dose Increased - the dose was increased due to the particular AE 
• Dose not changed - the particular AE did not require stopping a study medication. 
• Dose Interrupted - the dose was intelTupted due to the particular AE 
• Unknown - only to be used if it has not been possible to determine what action has been 
taken. 
11.1.9. 
Outcomes of AEs 
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• Fatal: The patient died due to the AE. If the patient died due to other circumstances than 
the AE the outcome should be stated as 'Not recovered' or 'Recovering'. The date of death will be 
recorded. 
• Recovered/Resolved: The patient has fully recovered from the event or the condition has 
returned to the level observed at baseline 
• Recovering/Resolving: The event is improving but the patient is still not fully recovered 
• Not Recovered/Not Resolved: The event is ongoing at the time of reporting and the 
patient has still not recovered 
• Recovered with Sequelae/Resolved with Sequelae: As a result of the event, the patient 
suffered persistent and significant disability/incapacity (e.g. became blind, deaf or paralysed). 
• Unknown: If Outcome is not known or not reported. 
11.2. Reporting of Adverse Events 
11.2.1. Legislation for Pharmacovigilance 
Applicable legal base Pharmacovigilance for the Russian Federation is following: 
• Federal law of 12 April 2010 "On the Circulation of Pharmaceuticals" 
• Good Pharmacovigilance Practice of Eurasian Economic Union" (came into force 
May, 06, 2017). 
• Roszdravnadzor order #1071 "On Approval of the Pharmacovigilance Procedure" 
(came into force April, 01, 2017). 
• Order of the Ministry of health care and social development of 26 August 2010 N757n 
"On approval of the procedure for drug safety monitoring, reporting of side effects, serious 
adverse drug reactions, unexpected adverse drug reactions" 
• RF Government statement of 30.06.2004 #323 «On approval of the Federal Service on 
Surveillance in Healthcare» 
• RF Government statement of 15.10.2012 .N!!l043 «On approval of the Federal State 
Supervision in medicine circulation» 
Applicable legal base Pharmacovigilance for the Republic Kazakhstan is following: 
• The Code of Republic of Kazakhstan on people's health and the health system (with 
amendments and additions from 19.05.2015) 
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• Order of the Minister of Health of the Republic of Kazakhstan dated November 19, 2009 
NQ 744 On approval of rules of clinical trials and (or) pharmacological tests of medicines, medical 
devices and medical equipment (with amendments from September 28, 2012) 
• Order No. 421 of the Health and Social Development Minister of the Republic of 
Kazakhstan as of 29 May 2015 On Approval of the Rules for Medicines Pharmacovigilance and 
Monitoring of Adverse Reactions of the Medicines, Medical devices and Medical Equipment 
• Order #9 on amendments to the Order #735 of the Minister of Health of the Republic of 
Kazakhstan from 18 November, 2009 On approval of the rnles for state registration, renewal and 
amendments into the registration dossier of the Medicines, Medical devices and Medical 
Equipment 
11.2.2. AE Reporting Form 
All AEs will be documented in the special AE page of the CRF - "AE reporting form". The 
following information will be documented for each event: 
• event term, 
• start and stop date/ ongoing {and time}, 
• severity, 
• Investigator's opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related), 
• action concerning study medication, 
• outcome of AE, 
• senousness. 
The "AE reporting form" contents all information which is required to the form "Report 
about side effect, adverse drug reaction or lack of expected therapeutic endpoint of drug". 
11.2.3. Collection and reporting of AE 
Any AEs observed during the study and follow-up information on these should be reported 
by the investigator as soon as possible after having knowledge to the Sponsor and/or responsible 
CRO. Start of AEs collection: AEs must be collected from start ofEdarbi® treatment. 
Collection of AEs will commence from the time of the first Edarbi® intake (Baseline visit). 
Routine collection of AEs will continue until Observational visit 4 (Final visit). 
A physician must report all rep01table AEs on the special "AE repo1ting form" provided by 
the Sponsor. The physician should record only one AE per 1 "AE rep01ting form". The physician 
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has to record the diagnosis if available. If no diagnosis is available, the physician should record 
each sign and symptom as separate reports. 
11.2.4. Collection and reporting of SAE and pregnancies 
The physician should rep01t all rep01table SAEs and pregnancies to Takeda 
Pharmacovigilance Drug Safety Officer immediately (within 24 hours) after obtaining 
knowledge of the event by one of the following way: 
-
by email to 
 using the separate "AE repo1ting form", 
-
by fax number:+ 7 (495) 502 16 25 using the separate "AE reporting form". 
If information is not available at the time of the first repo1t becomes available at a later date 
or upon on the sponsor's request, the investigator should complete an additional SAE form and 
provide it by one of mentioned above way immediately within 24 hours of receipt. Copies of any 
relevant data from the hospital notes (eg, ECGs, laboratory tests, discharge summary, postmo1tem 
results) should be sent to the addressee, if requested. 
In any case all SAEs should be followed up until resolution or permanent outcome of the 
event. The timelines and procedure for follow-up rep01ts are the same as those for the initial 
rep01t. 
11.2.5. Safety reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
All safety-related data on study patient collected in the study database or reported to Takeda 
according to the normal procedure for marketed drugs, e.g. serious and non-serious AEs, will be 
summarised in the Non-Interventional Study Rep01t. 
In case of changes in benefit-risk assessment of Edarbi® the Sponsor will also prepare an 
expedited rep01t for safety issues. The investigational site also will forward a copy of all 
expedited reports to their IRB or IEC. 
Specialized safety reporting in the Russian Federation 
The Sponsor is responsible for reporting all ADRs, SADR and pregnancies to the Federal 
Service on Surveillance in Healthcare not later than 15 calendar days from the day when relevant 
information becomes known to the sponsor. 
Periodic Safety Update Rep01t (PSUR) contains drug safety inf01mation obtained from 
spontaneous reports, literature and in clinical trials for a certain rep01ting period. According to the 
Russian legislation PSUR submission periodicity is determined by International Birth Date of a 
drug. PSUR submission time: Every 6 months during first 2 years from International Bi1th Date; 
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Annually during the following 2 years; 
-
Once in three years - thereafter. 
Specialized safety reporting in the Republic Kazakhstan: 
The Investigator informs the Authorized organization, Ethics Committee and the 
Sponsor/responsible CRO about all ADRs not later than 15 calendar days from the day when 
relevant information becomes known. 
Periodic Safety Update Report (PSUR) contains drug safety information obtained from 
spontaneous reports, literature and in clinical trials for a certain reporting period. 
The marketing authorization holder, within the marketing authorization validity period, shall 
provide the authorized organization with the Periodic Safety Repo1t from the date of regish·ation 
in the Republic of Kazakhstan in accordance with the following standard periodicity: 
• once every six months within two years after registration; 
• annually - within the next three years; 
• then - every three years or after receiving a report from the central office (if applicable); 
• in future - upon subsequent medicine re-registration - once in five years; 
• immediately at the authorized organization's request. 
12 Data Quality Control and Assurance 
12.1 Quality Control 
12.1.1. Training of investigators 
Before start of data collection all investigators will be trained on: 
-
the background and objectives of the study, 
-
study procedures, 
-
safety reporting, 
-
ethical regulations, 
-
data entering and database 
-
etc. 
12.1.2. Quality reviews during the study conducting 
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The data quality will be assured by using the following methods of quality review: 
- telephone interview, 
- monitoring in the study sites (the monitoring will consist of two parts: on-site interview 
and verification of the compliance of the data presented in the CRF with the data of the primary 
documentation - source data verification (SDV)). 
Due to non-interventional study design source documents will be partly reviewed for 
verification of data recorded on the CRF. Source documents are defined as original documents, 
data, and records. The investigator and institution guarantee access to source documents by the 
Sponsor or its designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation can be patient to review by the sponsor or 
responsible CRO, including but not limited to the Investigator's Binder, patient medical records, 
informed consent documentation and review of CRF and associated source documents. It is 
important that the investigator and other study personnel are available during the monitoring visits 
and that sufficient time is devoted to the process. The investigator and institution guarantee access 
to source documents by the sponsor or responsible CRO and by the IRB or IEC. 
Due to the non-interventional study design it can be able to conduct quality review only on 
subset of investigational sites and case report forms. Exact extent of quality reviews will be 
defined in the Monitoring Plan. The detailed description of the quality review will be presented in 
the Monitoring Plan, the Data Management Plan (DMP) and Statistical Analysis Plan. 
The investigational sites where telephone interview or monitoring visit will take place will 
be dete1mined randomly. Due to long overall duration of the study several waves of quality 
reviews will be perfo1med. 
12.1.3. Data checks and data queries 
The data from paper CRFs will be doubly entered into the common database by the 
authorized officers of CRO in accordance with the internal standard operational procedures. After 
completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the sponsor 
and responsible CRO and will be answered by investigators. 
Conections to CRF are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant c01Tections should additionally be included. 
12.1.4. Quality Assurance Audits 
The Quality Assurance (QA) unit or out-sourced by the Sponsor agency may audit the study 
to ensure that study procedures comply with the protocol and standard operating procedures, and 
that collected data is correct and complete. 
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12.2. 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 investigator must immediately 
contact to the Sponsor and must make the records available as requested. The Inspector must be 
reminded up front that consent to access to personal data has not been obtained from the 
participants in this study. 
12.3. Data Management 
12.3.1. Data Management Plan 
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. Responsible CRO will 
provide all the data management service including data transfen'ing, data clarification and quality 
control of the process. The data management provider should approve all data formats before the 
data collection tools are made available to the sites. 
The data from paper CRFs will be doubly entered into the common database by the 
authorized officers of CRO in accordance with the internal standard operational procedures. After 
completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by the Sponsor 
and responsible CRO and will be answered by investigators. 
12.3.2. Data privacy 
The sponsor and responsible CRO affirm and uphold the principle of the patient's right to 
protection against invasion of privacy. The personal data of the NIS pa1ticipants will be kept and 
processed with observance of the provisions of the RF federal law No. 152 "On personal data". 
Throughout this study, a patient's source data will only be linked to the study database or 
documentation via a unique identification number (for details, please, see Sections 8.5, 8.6., 8.7., 
8.9). 
If the written info1med consent of a patient is known not to be available in spite of it being 
required, data for this patient is not entered into or is deleted from the database. 
If a patient is included in the study in spite of being treated off-label (not according to the 
local SmPC), data is kept in the database and analysed separately and as part of the overall 
analyses as described in the Statistical Analysis Plan. 
The patients will be identified in the database only by patient identification code (for details, 
please, see the section 8.7) 
12.3.3. Case Report Form (CRF) 
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Both types of CRF - electronic and paper will be used in the study. The decision about type 
of CRF should be taken by investigator before start of ICF signing. 
The sponsor or responsible CRO will supply investigators with paper CRFs if investigator 
chooses the paper type of CRF. The CRF must be completed in Russian. All data are entered 
directly into CRF. The investigator must sign off the complete data set for each patient, 
confirming the collected data. Furthermore, the investigator must retain full responsibility for the 
accuracy and authenticity of all data entered on the CRF. ADR data reported according to section 
11 and data on serious ADRs collected according to section 11.3 should be signed off by 
investigator separately. 
The completed CRFs are the sole prope1ty of the sponsor and should not be made available 
in any fo1m to third parties, except for authorized representatives of appropriate governmental 
health or regulatory authorities, without written permission of the sponsor. 
The study database will be set up and maintained by responsible CRO. 
Paper Case report Form (pCRF) 
Part of the study data will be collected using paper Case Rep01t Form (pCRF). In the 
beginning of the study every site should select type of CRF. Whenever possible, complete data 
sets should be entered. Text field entries and any data collected on paper should be legible and 
follow the requested language standard. 
All paper CRFs must be filled out legibly in black or blue ballpoint ink (use of black ink is 
preferred)/ Data are transcribed directly onto eCRFs. 
Conections to paper CRFs are to be made by making a single-line strikeout of the inc01Tect 
information and writing in the revisions. All corrections must be initiated and dated. Reasons for 
significant corrections should additionally be included. All new additions are to be made with the 
date and signature or seal affixed. 
After the CRFs are transmitted to the sponsor/responsible CRO, any change of, modification 
of or addition to the data on the pCRF should be made by the investigator with use of change and 
modification records of pCRF (Data Clarification Form) provided by the sponsor/responsible 
CRO. Any changes to the data must be signed by the investigator. 
Electronic Case Report Form ( eCRF) 
The sponsor or responsible CRO will supply investigators with access to eCRF. Patient data 
will be entered directly into the database by authorized investigators. The sponsor will make 
arrangements to train investigators in the use of the eCRF. 
12.3.4. Coding of AEs and concomitant medications 
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Adverse events, medical history and concurrent medical conditions are coded with 
MedDRA dictionary (Medical Dictionary for Regulatory Activities). Concomitant Medication is 
coded with WHO Drug Dictionary. 
12.3.5. Record retention 
The investigator agrees to keep the records stipulated in Section 12.3.3 and those documents 
that include (but are not limited to) the study-specific documents, the Patient Identification list, 
medical records, all original signed and dated informed consent forms to enable evaluations or 
audits from regulatory authorities, the sponsor or responsible CRO. The study records should be 
retained until an amount of time specified by applicable regulatory requirements or for a time 
specified in the Study agreement. The investigator should contact and receive written approval 
from the sponsor before disposing of any such documents. 
13 Statistical Methods and Determination of Sample Size 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
section describes the statistical analyses as foreseen at the time of planning the study. Any known 
deviations from the planned analyses, the reason for such deviations and all alternative I additional 
statistical analyses that may be perfmmed as well as the final statistical analysis must be described 
in a revised Statistical Analysis Plan (SAP) before completion of data collection. All later 
deviations and I or alterations will be summarised in the Clinical Study Report. 
13.1 Patient Population 
Due to observational nature of this study patients will not be excluded from analysis based 
on their performance and/or data availability. All obtained data will be summarised after 
procedures of data cleaning and verification. All planned analyses (including descriptive analyses 
and study listings) will be perfo1med for Full Analysis Set of data. 
The following patient's populations will be included into statistical analysis: 
-
Safety population: Patients who have taken at least one dose of Edarbi® after emolling in 
the study (Baseline visit) 
-
All Patients Enrolled population. 
13.2 The study data and Statistical Analysis methods 
This study is observational and epidemiological methods will be employed for data 
analyses. Descriptive analysis will be performed of all collected data except data collected only 
for the purpose of data cleaning, i.e. all data listed in section 9. 
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The primary and secondary outcomes of the study are presented in section 6.2. 
13.2.1. Summary of study data 
All continuous variables will be summarised using the following descriptive statistics: n 
(non-missing sample size), mean, standard deviation, median, 25 percentile, 75 percentile, 
maximum and minimum. The frequency and percentages (based on the non-missing sample size) 
of observed levels will be rep01ted for all categorical measures. For variables marked "binary" 
exact (Clopper-Pearson) 95% confidence intervals will be calculated where appropriate. For 
categorical variables with more than 2 categories 95% confidence intervals will be calculated 
using Goodman's method [8]. 
In general, all data will be listed, s01ted by site and patient, and when appropriate by visit 
number within patient. All summary tables will be structured with a column for each cohort in the 
increasing order and will be annotated with the total population size relevant to that table/dose 
cohort, including any missing observations. 
The baseline visit is defined as the last observations collected prior to administration of the 
study drug. 
Patient Disposition 
Data regarding how many patients reached the vanous stages of the trial, how many 
dropped out, discontinued the treatment and for what reasons (death, AD Rs, treatment failure, 
withdrew consent, lost to follow-up) will be presented for each subgroup and for study in bulk. 
Standard CONSORT diagram describing study patient flow will be provided 
13.2.2. 
Statistical analysis methods 
Primary study outcome - change from baseline in clinic SBP value tot Visit 4 will be 
estimated with 95% confidence interval construction. 
In addition, clinic SBP (DBP) change from baseline will be assessed and evaluated using 
Mixed model repeated measures (MMRM) methodology [30, 31]. The multiple visits for each 
patient will be incorporated as repeated measures within each patient. Visit will be treated as a 
categorical predictor and baseline SBP (DBP) will be included as a covariate. An appropriate 
covariance structure will be selected to provide estimates (Least Square Means) of change from 
Baseline and to perform statistical analysis at Visit 4. The dose-response trend hypothesis test will 
be conducted using the appropriate contrast statement for a linear (ordinal dose) tTend. In addition, 
Least Squares Means, the associated standard errors and 95% confidence intervals will be 
displayed by each individual dose group. 
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Patients who reached target level of SBP (DBP) at visits 2, 3 and 4 will be presented using 
frequencies and percentages for the study population. Patients who respond to therapy at visits 2, 
3 and 4 will also be presented using frequencies and percentages. Secondary and exploratory 
outcomes will be analysed using descriptive statistics and frequencies and percentages as follows: 
-
Changes in systolic BP (SBP) during the treatment with Edarbi® (V2-V3) will be 
calculated and presented in summary tables using descriptive statistics for continuous 
variables; 
-
Changes in diastolic BP (DBP) during the treatment with Edarbi® (V2, V3) will be 
calculated and presented in summary tables using descriptive statistics for continuous 
variables; 
-
Percentage of patients who achieve target SBP<140 mm Hg (V2, V3, V4) will be 
described and presented in summary tables using absolute frequencies and percentages as 
well as 95% confidence intervals, 
-
Percentage of patients who achieve target DBP<90 mm Hg (V2, V3, V4) will be 
described and presented in summary tables using absolute frequencies and percentages as 
well as 95% confidence intervals; 
-
Percentage of patients who respond to Edarbi® therapy (defined as decrease of SBP2: 20 
mm Hg or decrease of DBP2:10 mm Hg; V2, V3, V4) will be described and presented in 
summary tables using absolute frequencies and percentages as well as 95% confidence 
intervals; 
-
Percentage of patients who achieve target BP (defined as SBP<l 40 mm Hg, DBP<90 mm 
Hg; V2, V3, V4) will be described and presented in summary tables using absolute 
frequencies and percentages as well as 95% confidence intervals; 
-
-
-
-
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13.2.3. Analysis of Safety Data 
All safety data will be analysed on the safety population. Prior to analysis, adverse drug 
reactions will be coded using MedDRA. 
Incidence and characteristic of adverse drug reactions will be described and presented in 
summary tables using absolute frequencies and percentages as well as 95% confidence intervals; 
Evaluation of AEs, including the AEs, will consist of the determination of total number of 
AEs, total number of patients with AEs and the number of AEs requiring discontinuation of the 
study treatment. The incidence and severity of all AEs will be summarized by body system. 
Treatment discontinuation due to AEs will be tabulated 
AEs reported in the study as well as AEs repo1ted directly to authorities and to Takeda 
International Drug Safety according to section 11.3 and not captured in the study database will be 
extracted from the overall safety database and the study database and listed or tabulated in the 
final report in the standard way of presenting such data in a Periodic Safety Update Rep01t 
(PSUR). 
13.2.4. Potential study biases 
The study limitations are those inherent to uncontrolled observational studies. Taking into 
account observational and uncontrolled nature of the study, fully evaluating of azilsa1tan 
medoxomil efficacy will not be available. However data regarding blood pressure (SBP and DBP) 
dynamic during and after azilsartan medoxomil titration in real-life practice will be gathered and 
analyzed. The inclusion criteria are those that used when administering azilsaitan medoxomil in 
practice and therefore, the same criteria as those that would have been used if we had performed a 
similar prospective study. This type of experimental design should prevent selection bias that 
could occur when patient emollment is related to the development of the outcome. In prospective 
observational study like this attrition bias is possible, however, in case of early leaving study last 
BP data will be gathered and efficacy will be estimated, these cases will not be excluded from 
efficacy analysis. 
Details of the statistical analyses will be presented in the Statistical Analysis Plan. 
13.2.5. Data handling 
13.2.5.1. Missing data and invalid data 
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Missing data will not be restored. No procedures for missing data pattern assessment and/or 
imputation are pla1med. Outlier detection will be performed during blind data review, using 
modified Z-score( [32] calculation 
"1· = 0.674ti(s; - i) 
. ' 
;\:LAD 
with MAD denoting the median absolute deviation and .r denoting the median. 
Values of modified Z-score > 3 .5 will be considered outliers for univariate data sets that are 
assumed to follow an approximately normal distribution. If the normality assumption for the data 
being tested is not valid, then a determination of outlier using interquartile range and median 
(values more than 1.5 times the interqua1tile range will be considered outliers). Outliers will not 
be excluded from primary analysis en bloc, however, the medical context for each outlier will be 
defined and appropriate action taken. List of outliers flagged and actions taken will be included 
into Statistical Analysis Report. An additional sensitivity analysis will be performed excluding 
outliers. 
13.2.5.2.Multiplicity 
It is plalU1ed to use statistical analysis methods, which incorporates corrections for 
multiplicity. When needed, corrections for multiplicity will be justified and performed according 
to Bonferroni. Overall alpha-level will be controlled and will not exceed 0.05 
13.3 Interim Analyses 
No interim Analysis is plalU1ed in the study 
13.4 Determination of Sample Size 
Sample size was calculated for the primary objective of the study: to estimate the effect of 
Edarbi® treatment on blood pressure for patients with increased weight or obesity. This 
estimation will be conducted with 95% confidence interval construction. Sample size was 
calculated using SAS 9.3 proc power procedure (Confidence Interval for Paired Mean 
Difference) for following parameters (fixed scenario elements): 
Fixed Scenario Elements 
Distribution 
Method 
Alpha 
CI Half-Width 
Standard Deviation 
Correlation 
Nominal Prob(Width) 
Number of Sides 
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Normal 
Exact 
0.05 
1 
17.79 
0.4375 
0.9 
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Azilsmedox-5008 
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Prob Type 
Conditio 
nal 
Where the distribution is assumed to be normal, alpha specifies the level of significance, 
Nominal Prob (Width) specifies the desired probability of obtaining a confidence interval 
half-width less than or equal to the value specified as CI Half-Width. Half-width of the 
desired confidence interval was set to 1 mm Hg. Standard deviation and correlation 
coefficient were estimated by pooling recent studies data [12, 13, 14, 19, 20] for clinic 
Systolic Blood Pressure after at least 6 weeks of antihype1iensive treatment with azilsaiian 
medoxomil. Pooled effect estimation (clinic SBP difference at the end of the treatment from 
baseline SBP value) is -17 .311 with pooled SD of 17. 7887, which c01Tesponds to the 
standardized difference of -0.9731 and coll'elation coefficient of 0.4375. For the denoted 
scenario, it is required to receive data from at least 1437 patients before-after the treatment. 
Computed N Pairs 
Actual 
' Prob(Width) 
0.903 
N 
Pairs 
1437 
Taking into account a possible dropout of 25%, it is recommended to enrol at least 1916 
patients into the study. 
According to the reference studies [24-29], the SD for effect for DBP is less than the SD 
for SBP, so the denoted number of patients will be sufficient for the COll'esponding secondary 
outcomes. 
14 Reports 
A Non-Interventional Study Rep01i based on the results obtained will be prepared and 
submitted to the Sponsor for distribution. The Final Study Repo1i should be available within one 
yeai· from collection of the last data point, and the participating sites should be informed about the 
results when the rep01i is finalised. Composed the study repo1i should be provided to the IEC. 
15 Publications 
15.1 Publication and Disclosure 
During the study, only the sponsor may make study information available to other study 
investigators or to regulatory agencies, except as required by law or regulation. Except as 
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otherwise allowable in the study site agreement, any public disclosure (including publicly 
accessible websites) related to the protocol or study results, other than study recruitment materials 
and/or adve1iisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the study contracts. In the event of any discrepancy between the 
protocol and the study contracts, the study contracts will prevail. 
The sponsor aims to have the results of this study published and acknowledges the right of 
the participating sites to publish results from this study. The sponsor has the right to use the data 
and results for regulatory purposes and for internal presentation within the company and to 
partners 
15.2 Study Registration 
The sponsor aims to have the results of this study published. 
In order to ensure that information on the study reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, the sponsor will, at a minimum register all 
clinical trials and observational studies conducted in patients that it sponsors anywhere in the 
world on ClinicalTrials.gov or other publicly accessible websites before study initiation. The 
sponsor contact info1mation, along with investigator's city, country, and recruiting status will be 
registered and available for public viewing. 
16 Archiving of Study Documentation 
During the course of the study the investigator must as a minimum file the essential 
documents (Section 7.4), the protocol, any amendments, the list of participating patients, the 
written informed consents, the CRFs and the progress reports in the Study Site File. After final 
database lock the investigator must as a minimum store the list of paiiicipating patients and the 
signed Informed Consent Forms on site for 5 yeai·s. The investigator should store additional study 
documentation for a longer period of time as required by any local regulations and/or hospital 
requirement. 
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17 References 
Observational/Non-Interventional 
version 2.4 09-Jan-2019 
Study Protocol 
1. World Medical Association Declaration of Helsinki. Ethical principles for Medical 
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5. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on 
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6. Pocc11H:c1Coe 
Me)J.11u:11ttc1<0e o6mecrno no 
apTepmurI>HOH 
rnrrepToIDIB 
(PMOAf), 
Bcepocc11H:c1<oe Ha~oe o6mecrno I<ap,n:11orroros (BHOK). ,n:11arnocTmca 11 nelfeH11e 
apTep11annHoli rnrrepTeH31111. Pocc11H:c1rne 
pe1<0MeH,n:au;1111 (qernepTI>rn rrepecMOTp ). 
C11cTeMHI>Ie r11rrepTeH3mr 2010; 3: 5-26 
7. "Protocol on clinical diagnosis and treatment of hypertension" of the Republic of 
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8. L.A. Goodman, On simultaneous confidence intervals for multinomial proportions, 
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9. "Clinical protocol on diagnosis and treatment on diabetes mellitus type 2" of the Republic 
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10. PeI<oMeH,n:au;1111 no se.n:emno 6oJibHI>IX c Mern6orr11qecI<11M c11H,n:poMOM. Kn11H11qec1<11e 
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M11H11cTepcrno 
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oc 
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M11tt11cTepcTBO 
3,n:pasooxpaHeHIDI 
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13. ApTepHa.JI.bHaSI 
rnrrepTOHH.sr 
cpeAH 
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25-64 
rreT: 
pacrrpocTpaHeHHOCTb, 
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xapaKTepMCTHI<a 
pe3MCTeHTHOM 
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27. KaprroB 
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ITporpaMMa 
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qrnI<cHpoBaHHOH 
I10JIHO)J;030BOH KOMfoIHal(HH rrepHH.D:Orrpmrn aprnHHHa If m1.n:anaMH.n:a B Jie'leHHH rrnoxo 
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