Conditions: Hypertension
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 301
Healthy volunteers: no

Brief summary:
Study to assess the anti-hypertensive efficacy and safety of the extemporaneous combination of Nebivolol 5 mg in combination with Amlodipine 5 mg or AML 10 mg in lowering the sitting diastolic BP after 8 weeks of treatment inpatients with uncontrolled BP previously treated with Nebivolol (NEB) or Amlodipine (5 mg) monotherapies for at least 4 weeks.

Detailed description:
Approximately 290 patients are planned to be screened to ensure at least 216 patients complete the run-in period and start with the assessment period.

Grade 1 - 2 hypertensive patients \[BP ranging from ≥140 to ≤179 mmHg for Systolic Blood Pressure (SBP) and from ≥90 to ≤109 mmHg for Diastolic Blood Pressure (DBP)\] on treatment with any Beta Blocker (BB) or Calcium Channel Blocker (CCB), including NEB (only 5 mg dosage allowed) or AML (only 5 mg dosage allowed) for at least one month prior to Visit 1 will be screened for eligibility.

Allowed CCBs at screening includes Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine. Patients treated with Amlodipine or Nebivolol in dosages higher than 5 mg/daily will not be eligible.

On the same day of the Screening visit, the eligible patients will enter into a run-in period of 4 weeks after screening, during which:

* Patients receiving NEB 5 mg or AML 5 mg will continue the same therapy for 4 weeks.
* Patients on any other BBs or CCBs will be switched to NEB 5 mg or AML 5 mg. Patients entering this phase in therapy with NEB 5 mg or AML 5 mg should be in a 1:1 ratio.

After 4 weeks (±2 days) of run-in period of monotherapy, the BP will be further assessed (Visit 2). Patients with uncontrolled BP levels (sitting SBP/DBP ≥130/80 mmHg) at Visit 2, with the treatment adherence (ranging between 80% to 120%) and who did tolerate the treatment will enter into the assessment period and will be assigned to the extemporaneous combination of NEB 5 mg and AML 5 mg. Patients with controlled BP levels (sitting SBP/DBP \<130/80 mmHg) and/or who do not tolerate the treatment or have an adherence range below 80% or above 120%, will be withdrawn from the study.

After 4 weeks ±2 days in the assessment period, patients BP will be further evaluated at Visit 3: patients with controlled BP levels (sitting SBP/DBP \<130/80 mmHg) will continue the same extemporaneous combination, while patients with uncontrolled BP levels will be uptitrated from extemporaneous combination NEB/AML 5/5 mg to extemporaneous combination of NEB/AML 5/10 mg for further 4 weeks.

At the end of the assessment period (8 weeks ±4 days), the patients will attend an End of Treatment Visit 4.

To correctly evaluate the additional effect of the combination therapy, the number of patients with uncontrolled BP on NEB or AML monotherapy needs to be balanced at Visit 2. In order to maintain a 1:1 ratio during the assessment period, a cap of 110 patients for each treatment arm (ie. NEB and AML) will be included at Visit 2 in order to maintain a balanced number of uncontrolled patients entering the assessment period for each drug. The evaluation will be done every 50 patients. If the rate of entrance in the assessment period for one of the 2 tested drugs will deviate more than 5%, a corrective measure will be initiated.

Arms:
arm 1: MONOTHERAPY PHASE 4 weeks (Run-in from -4 week to week 0):

patients will be treated with Nebivolol 5mg

COMBINATION THERAPY PHASE 8 weeks (from week 0 to week 8):

uncontrolled patients during Monotherapy Phase will be treated with the extemporaneous combination of Nebivolol 5mg and Amlodipine 5mg for 4 weeks (from week 0 to week 4). Amlodipine 10mg will replace Amlodipine 5mg in uncontrolled patients for further 4 weeks (from week 4 to week 8) while controlled patients with Nebivolol 5mg/Amlodipine 5mg will continue with the same therapy. arm 2: MONOTHERAPY PHASE 4 weeks (Run-in from -4 week to week 0):

patients will be treated with Amlodipine 5mg

COMBINATION THERAPY PHASE 8 weeks (from week 0 to week 8):

uncontrolled patients during Monotherapy Phase will be treated with the extemporaneous combination of Nebivolol 5mg and Amlodipine 5mg for 4 weeks (from week 0 to week 4). Amlodipine 10mg will replace Amlodipine 5mg in uncontrolled patients for further 4 weeks (from week 4 to week 8) while controlled patients with Nebivolol 5mg/Amlodipine 5mg will continue with the same therapy.

Interventions: intervention 1: Nebivolol intervention 2: Amlodipine
Intervention descriptions: intervention 1: Tablets administered orally once daily according instructions provided by Principal Investigator. intervention 2: Tablets of 5mg and 10mg administered orally once daily according instructions provided by Principal Investigator.

Protocol document:
Prot_000.pdf: 
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STATEMENT OF CONFIDENTIALITY 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by law. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied 
to you which is indicated as privileged or confidential. 
CONFIDENTIAL    
       1 
PROTOCOL TITLE 
CLINICAL STUDY PROTOCOL 
Open-laBel, multicenter, multinatiOnal, inTerventional clinical Trial to assess effIcacy 
and safety of the extemporaneous Combination of nEbivoLol and amLodipine in 
grade 1-2 hypertensive patIents versus each monotherapy – BOTTICELLI Study 
Protocol Code 
MEIN/21/AmNe-Hyp/001 
EudraCT - Number
ClinicalTrials.gov - Number 
2021-005077-10
NCT05513937 
Protocol Phase (if 
applicable) 
Phase IV 
Study type and design 
Interventional, multi-center, open-label study 
Protocol Version Number 
Version 1 
Protocol Version Date 
27 September 2021 
Sponsor and address 
Menarini International Operations Luxembourg SA 
Registered Offices: 1, Avenue de la Gare L-1611 
Luxembourg 
Operative Offices: 5D, Rue Eugene Ruppert L-2453 
Luxembourg 
Phone:(+352) 2649761 
Fax: (+352) 26497649 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
STATEMENT OF CONFIDENTIALITY 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by law. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential and may not be 
further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied 
to you which is indicated as privileged or confidential. 
 
 
CONFIDENTIAL                                                                                                                                                2 
Coordinating Investigator 
Professor Massimo Volpe 
Address: Via Di Grottarossa1035 Roma 
Phone: +39 06 33775654 
CRO 
IQVIA 


 
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CONFIDENTIAL                                                                                                                                                3 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
 
N/A 
First Emission 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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CONFIDENTIAL                                                                                                                                                4 
 
TABLE OF CONTENTS 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION .................................................. 3 
TABLE OF CONTENTS ........................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 7 
1 
RESPONSIBILITIES .......................................................................................................... 9 
2 
PROTOCOL SYNOPSIS .................................................................................................. 10 
2.1 
Study Scheme ............................................................................................................. 22 
2.2 
Study Flow Chart ....................................................................................................... 23 
3 
STUDY RATIONALE AND BACKGROUND INFORMATION .................................. 26 
3.1 
Assessment of Potential Risks and Benefits .............................................................. 29 
4 
TRIAL OBJECTIVES AND ENDPOINTS ...................................................................... 30 
5 
STUDY DESIGN .............................................................................................................. 34 
5.1 
Procedures and Study Visits ...................................................................................... 36 
6 
SELECTION OF PATIENTS ........................................................................................... 39 
6.1 
Informed Consent Process ......................................................................................... 39 
6.2 
Inclusion and Exclusion Criteria ................................................................................ 40 
6.2.1 Inclusion Criteria................................................................................................. 41 
6.2.2 Exclusion Criteria ............................................................................................... 41 
6.2.3 Screening Failures ............................................................................................... 43 
7 
STUDY TREATMENT .................................................................................................... 43 
7.1 
Study Treatment Formulation, Appearance, Packaging, and Labelling .................... 44 
7.2 
Study Treatment Distribution and Return/Destruction .............................................. 47 
7.3 
Product Storage and Stability ..................................................................................... 48 
7.4 
Study Product Compliance ......................................................................................... 48 
7.5 
Concomitant Therapy(ies) .......................................................................................... 49 
7.6 
Not permitted medications ......................................................................................... 49 
7.7 
Rescue Medicine ........................................................................................................ 49 
8 
STUDY ASSESSMENT AND PROCEDURES .............................................................. 50 
8.1 
Assessment of Efficacy .............................................................................................. 50 
8.2 
Assessment of Safety ................................................................................................. 50 
8.2.1 Physical Examination .......................................................................................... 51 
8.2.2 Vital Signs ........................................................................................................... 51 
8.2.3 Clinical Laboratory Tests .................................................................................... 51 
8.2.4 Electrocardiograms ............................................................................................. 52 
8.2.5 Urine Pregnancy tests.......................................................................................... 53 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                5 
9 
SAFETY DATA MANAGEMENT .................................................................................. 53 
9.1 
Adverse Event ............................................................................................................ 53 
9.2 
Drug Relationship ...................................................................................................... 53 
9.3 
Adverse Drug Reaction .............................................................................................. 54 
9.4 
Seriousness ................................................................................................................. 55 
9.5 
Adverse Event/Adverse Drug Reaction Intensity ...................................................... 55 
9.6 
Adverse Event/Adverse Drug Reaction Expectedness .............................................. 56 
9.7 
Serious Unexpected Adverse Drug Reaction (SUSAR) ............................................ 56 
9.8 
Individual Case Safety Report (ICSR) ....................................................................... 56 
9.9 
Collection, Recording and Reporting of AEs ............................................................ 56 
9.10 Management of Serious AEs (SAEs) including laboratory abnormalities................. 57 
9.10.1 Reporting Duties of the Investigator ................................................................... 57 
9.10.2 Reporting Duties of the Sponsor ......................................................................... 58 
9.11 Management of Non-serious AEs including laboratory abnormalities ...................... 59 
9.11.1 Reporting Duties of the Investigator ................................................................... 59 
9.12 Management of any laboratory abnormality .............................................................. 59 
9.13 Management of pregnancy exposure cases ................................................................ 59 
10 WITHDRAWAL CRITERIA ........................................................................................... 60 
11 LOST TO FOLLOW-UP .................................................................................................. 62 
12 STATISTIC ....................................................................................................................... 62 
12.1 Statistical Methods (Blinding and Randomization) ................................................... 62 
12.2 Determination of Sample Size ................................................................................... 62 
12.3 Analysis Populations .................................................................................................. 63 
12.4 Analysis Variables ..................................................................................................... 64 
12.5 Statistical Analysis ..................................................................................................... 65 
12.5.1 Descriptive statistics ........................................................................................... 65 
12.5.2 Primary (efficacy) analysis ................................................................................. 65 
12.5.3 Sensitivity analysis .............................................................................................. 66 
12.5.4 Secondary (efficacy) analysis ............................................................................. 66 
12.5.5 Exploratory (efficacy) analysis ........................................................................... 67 
12.5.6 Safety analysis..................................................................................................... 69 
12.5.7 Interim analysis and stopping rules ..................................................................... 69 
12.5.8 Data imputations ................................................................................................. 69 
12.6 Protocol Deviations and Protocol Amendments ........................................................ 69 
12.7 Statistical Analysis Plan ............................................................................................. 70 
13 STUDY DISCONTINUATION AND CLOSURE ........................................................... 70 
14 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ............................................... 71 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                6 
15 QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 71 
15.1 Study Monitoring/Data Quality Control .................................................................... 71 
15.2 Electronic Case Report Forms ................................................................................... 72 
15.3 Quality Assurance ...................................................................................................... 72 
16 ETHICS ASPECTS ........................................................................................................... 72 
16.1 Ethics Committees ..................................................................................................... 72 
16.2 Patient’s Insurance ..................................................................................................... 73 
17 PERSONAL DATA PROTECTION SECTION .............................................................. 73 
17.1 General Principles on Personal Data Compliance ..................................................... 73 
17.2 Acknowledgment ....................................................................................................... 74 
17.3 Data Controllers and Data Processors ........................................................................ 74 
17.4 Duties of the Parties involved in the performance of the study ................................. 75 
17.5 Archiving of the clinical trial master file and code pairing list.................................. 78 
17.6 Information notice on personal data protection and pseudo-anonymization ............. 80 
17.7 Genetic Data ............................................................................................................... 81 
17.8 Transfer of patients’ data outside the European Union .............................................. 81 
17.9 Exercise of patients’ data privacy rights .................................................................... 81 
17.10 Future research ........................................................................................................... 82 
18 DATA HANDLING AND RECORDS KEEPING .......................................................... 82 
19 PUBLICATION POLICY AND RESULTS ..................................................................... 83 
20 REFERENCES .................................................................................................................. 85 
21 PROTOCOL APPROVAL PAGE .................................................................................... 87 
22 INVESTIGATOR’S APPROVAL PAGE ........................................................................ 89 
23 APPENDICES ................................................................................................................... 90 
 
 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
DEFINITION 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AEOSI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AML  
Amlodipine  
ATC 
Anatomical Therapeutic Chemical 
BBs 
Beta-Blockers 
BP 
Blood Pressure 
CCBs 
Calcium Channel Blockers 
COVID-19 
Coronavirus Disease 2019 
CRO 
Clinical Research Organization 
CVD 
Cardiovascular disease 
DBP 
Diastolic Blood Pressure 
DPO 
Data Protection Officer 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
eCRF 
Electronic Case Report Form 
ESC 
European Society of Cardiology 
ESH 
European Society of Hypertension 
FPI 
First Patient In 
FSH 
Follicular Stimulating Hormone 
GCP 
Good Clinical Practice 
GLM 
General linear model 
HA 
Health Authorities 
HRT 
Hormonal replacement therapy 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
ICSR 
Individual Case Safety Report 
IMP 
Investigational medicinal product 
IP 
Investigational product 
IT 
Information technology 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                8 
IUD 
Intrauterine Device  
IUS 
Intrauterine hormone-releasing system 
LPO 
Last Patient Out  
mITT 
Modified Intent-to-treat 
NEB 
Nebivolol 
NO 
nitric oxide 
PI 
Principal Investigator 
PP 
Protocol Population 
RCT 
Randomized controlled trial 
SAE 
Serious Adverse Events 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD  
Standard deviation  
SmPC 
Summary of product characteristics 
SOP 
Standard Operative Procedures 
SUSAR 
Serious Unexpected Adverse Drug Reaction 
TMF 
Trial Master File 
UPT 
Urine pregnancy test 
ULN 
Upper Limit of Normal 
WOCBP 
Woman of Childbearing Potential 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                9 
1 
RESPONSIBILITIES 
Sponsor 
Name: Menarini International Operations Luxembourg SA 
Address: 1, Avenue de la Gare L-1611 Luxembourg 
Phone: +352 2649761 
Fax: +352 26497649 
Clinical Trial Coordinator 
Name: Manuella Mendes Martins 
Address: Via dei Sette Santi 1-3, 50131, Firenze 
Phone: 39 055 56809145 
Fax: + 39 055 56809961 
Study Medical Expert (SME) 
Name: Marco Miroddi 
Address: Via dei Sette Santi 1-3, 50131, Firenze 
Phone: +39 055 56809936 
Fax: +39 055 56809710 
Study Drug Safety Manager (SDSM) Name: Jaleh Khabirinejad 
Address: 1 Av. de la Gare, 1611 Luxembourg 
Phone: +352 26497696 
Fax: +352 26497649 
Coordinating Investigator 
Name: Professor Massimo Volpe 
Address: Via Di Grottarossa1035 Roma 
Phone: +39 06 33775654 
Fax: N/A 
CRO 
Name: IQVIA 
Address: 3 Forbury Place, 23 Forbury Road, Reading, RG1 
3JH, United Kingdom 
Statistician 
Name: Aswin Nair 
Address: IQVIA RDS India Pvt Ltd  
World Trade Center Kochi (Brigade), 
7th Floor, Tower A, Info Park SEZ,  
Info Park Phase -1 Campus, Kakkanad - 682030 
Kochi, Kerala – India. 
 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                10 
2 
PROTOCOL SYNOPSIS 
 
Title 
 
 
 
 
Acronym 
 
 
Sponsor Study Code  
Open-laBel, multicenter, multinatiOnal, inTerventional clinical 
Trial to assess effIcacy and safety of the extemporaneous 
Combination of nEbivoLol and amLodipine in grade 1-2 
hypertensive patIents versus each monotherapy 
 
BOTTICELLI Study 
 
 
MEIN/21/AmNe-Hyp/001 
Study product, Dosage 
and Regimen: 
- Investigational Product 
 
- Reference Therapy 
(comparator) 
Extemporaneous combination of nebivolol (NEB) 5 mg tablets 
(Anatomical Therapeutic Chemical [ATC] code: C07AB12) with 
amlodipine (AML) 5 mg (ATC code: C08CA01) tablets or 
amlodipine 
10 mg 
(ATC 
code: 
C08CA01) 
tablets 
 
Each monotherapy: NEB 5 mg and amlodipine (as besylate) 5 mg 
tablets 
Study Type and Design 
This is a Phase IV, interventional, open-label, multicenter, 
multinational study with 2 study periods (a run-in period of 4 weeks 
and an assessment period of 8 weeks).  
Screening Visit 1 (Week -4): Patients with Grade 1 - 2 hypertension 
with systolic blood pressure (SBP) ranging from ≥140 to 
≤179 mmHg and diastolic blood pressure (DBP) ranging from ≥90 
to ≤109 mmHg on treatment with any beta-blockers (BBs) or 
calcium channel blockers (CCBs)c including NEB 5 mg or AML 
5 mg for at least one month prior to Visit 1 will be screened for 
eligibility. 
Run-in period from Visit 1 (Week -4) to Visit 2 (Week 0): On the 
same day of the Screening visit, eligible patients will enter into a 
run-in period after screening, during which: 
• Patients receiving NEB 5 mg or AML 5 mg will continue 
the same therapy for 4 weeks. 
• Patients on any other BBs or CCBsc will be switched to 
NEB 5 mg or AML 5 mg. 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                11 
Patients entering this phase in therapy with NEB 5 mg or AML 
5 mg should be in a 1:1 ratio. 
Assessment period from Visit 2 (Week 0) to Visit 4 (Week 8): After 
4 weeks (±2 days) of run-in period of monotherapy, BP will be 
further assessed at Visit 2. Patients with uncontrolled BP levels 
(sitting SBP/DBP ≥130/80 mmHg) at Visit 2, with the treatment 
adherence (ranging between 80% to 120%) who did tolerate the 
treatment will enter into the assessment period and will be assigned 
to the extemporaneous combination of NEB 5 mg and AML 5 mg. 
Patients 
with 
controlled 
BP 
levels 
(sitting 
SBP/DBP 
<130/80 mmHg) and/or who do not tolerate the treatment or have 
an adherence range below 80% or above 120%, will be withdrawn 
from the study. 
After 4 weeks ±2 days in the assessment period, patients BP will be 
further evaluated at Visit 3: patients with controlled BP levels 
(sitting SBP/DBP <130/80 mmHg) will continue the same 
extemporaneous combination, while patients with uncontrolled BP 
levels will be uptitrated from extemporaneous combination 
NEB/AML 5/5 mg to extemporaneous combination of NEB/AML 
5/10 mg for further 4 weeks. 
At the end of the assessment period (8 weeks ±4 days), Visit 4 will 
take place. To correctly evaluate the additional effect of the 
combination therapy, the number of patients with uncontrolled BP 
on NEB or AML monotherapy needs to be balanced at Visit 2. In 
order to maintain a 1:1 ratio during the assessment period, a cap of 
110 patients for each treatment arm (ie. NEB and AML) will be 
included at Visit 2 in order to maintain a balanced number of 
uncontrolled patients entering the assessment period for each drug. 
The evaluation will be done every 50 patients. If the rate of 
entrance in the assessment period for one of the 2 tested drugs will 
deviate more than 5%, a corrective measure will be initiated: 
according to the enrolment site statistics, one or more sites will be 
informed to enroll a greater number of patients being treated with 
the least represented drug in the assessment period.  


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                12 
A total number of 290 patients will be screened considering 25% of 
drop-out rate, to obtain approximately 216 completed patients at the 
end of the study (Visit 4). 
Phase 
IV 
Objectives 
Primary objective: 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB 5 mg with AML 5 mg 
or AML 10 mg in lowering the sitting DBP between Visit 2 
(Week 0) and Visit 4 (Week 8) in patients with uncontrolled 
BP, previously treated with NEB 5 mg or AML 5 mg 
monotherapies for at least 4 weeks. 
Secondary objectives: 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB 5 mg with AML 5 mg 
or AML 10 mg in lowering sitting SBP between Visit 2 
(Week 0) and Visit 4 (Week 8) in patients with uncontrolled 
BP previously treated with NEB 5 mg or AML 5 mg 
monotherapies for at least 4 weeks. 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB/AML 5/10 mg versus 
extemporaneous combination of NEB/AML 5/5 mg, in 
lowering sitting DBP and SBP between Visit 3 (Week 4) 
and Visit 4 (Week 8) in patients with uncontrolled BP 
previously treated with NEB 5 mg or AML 5 mg 
monotherapies for at least 4 weeks. 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB 5 mg with AML 5 mg 
or AML 10 mg by evaluating the patients who achieve BP 
goal (sitting BP <130/80 mmHg) at Visit 2 (Week 0), at 
Visit 3 (Week 4), and at Visit 4 (Week 8).  
• To assess the compliance to the treatment (percentage of 
actual doses taken versus doses to be taken) at Visit 2 
(Week 0), at Visit 3 (Week 4), and at Visit 4 (Week 8).  
• To evaluate the safety and tolerability of the monotherapies 
(NEB 5 mg and AML 5 mg) and of the extemporaneous 


 
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CONFIDENTIAL                                                                                                                                                13 
combinations (NEB 5 mg and AML 5mg or AML 10 mg) 
after 8 weeks of treatment. 
Exploratory objectives: 
• To assess change in mean sitting DBP and SBP between 
Visit 1 (Week -4) and Visit 2 (Week 0), Visit 3 (Week 4), 
and Visit 4 (Week 8):  
o In the group of patients who were on NEB 5 mg and 
AML 5 mg at Visit 1 and continued to be on the 
same therapies. 
o In the group of patients who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1. 
• To assess the change in mean sitting DBP and SBP between 
Visit 2 (Week 0) and Visit 3 (Week 4) for uncontrolled 
patients at Visit 3 (Week 4). 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB 5 mg with AML 5 mg 
or AML 10 mg by evaluating the number of patients 
achieving the BP goal (sitting BP <130/80 mmHg) at Visit 2 
(Week 0), Visit 3 (Week 4) and Visit 4 (Week 8):  
o In the group of patients who were on NEB 5 mg and 
AML 5 mg at Visit 1 (Week -4) and continued to be 
on the same therapies. 
o In the group of patients who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1 (Week -4). 
• To 
assess 
the 
antihypertensive 
efficacy 
of 
the 
extemporaneous combination of NEB 5 mg with AML 5 mg 
or AML 10 mg by evaluating the number of patients divided 
into subgroups according to the hypertension grade, the 
presence of diabetes and/or of hypercholesterolemia 
achieving the BP goal (sitting BP <130/80 mmHg) at Visit 2 
(Week 0), Visit 3 (Week 4), and Visit 4 (Week 8): 
o In the group of patients who were on NEB 5 mg and 
AML 5 mg at Visit 1 and continued to be on the 
same therapies. 


 
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CONFIDENTIAL                                                                                                                                                14 
o In the group of patients, who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1. 
Endpoints 
Primary endpoint: 
• Change in mean sitting DBP between Visit 2 (Week 0) and 
Visit 4 (Week 8). 
Secondary endpoints: 
• Change in mean sitting SBP between Visit 2 (Week 0) and 
Visit 4 (Week 8). 
• Change in mean sitting DBP and SBP between Visit 3 
(Week 4) and Visit 4 (Week 8) in patients receiving 
extemporaneous combination of NEB/AML 5/5 mg versus 
patients uptitrated to the extemporaneous combination of 
NEB/AML 5/10 mg. 
• Number and proportion of patients achieving the BP goal 
(sitting SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), 
Visit 3 (Week 4), and Visit 4 (Week 8). 
• Adherence to the treatments (% of doses taken/doses to be 
taken) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 
(Week 8). 
• Safety and tolerability of the monotherapies (NEB 5 mg and 
AML 5 mg) and of the extemporaneous combinations (NEB 
5 mg and AML 5mg or AML 10 mg) will be measured by 
incidence, intensity (severity), seriousness of Adverse 
Events during the study period, (screening, run-in period 
and assessment period), relationship to the study treatments, 
Adverse events of special interest, clinically significant 
abnormal change in vital signs, electrocardiogram (only at 
Visit 1 and Visit 4), laboratory parameters (if applicable) at 
Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8). 
Exploratory Endpoints: 
• Change in mean sitting DBP and SBP between Visit 1 
(Week -4) and Visit 2 (Week 0), Visit 3 (Week 4) and 
Visit 4 (Week 8): 
o In the group of patients who were on NEB 5 mg and 


 
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AML 5 mg at Visit 1 and continued to be on the 
same therapies. 
o In the group of patients who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1. 
• Change in mean sitting DBP and SBP for uncontrolled 
patients at Visit 3 (Week 4), between Visit 2 (Week 0) and 
Visit 3 (Week 4). 
• Number and proportion of patients achieving the BP goal 
(sitting SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), 
Visit 3 (Week 4), and Visit 4 (Week 8):  
o In the group of patients who were on NEB 5 mg and 
AML 5 mg at Visit 1 (Week -4) and continued to be 
on the same therapies. 
o In the group of patients who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1 (Week- 4). 
• Number and proportion of patients divided into subgroups 
according to the hypertension grade, the presence of 
diabetes and/or of hypercholesterolemia achieving the BP 
goal (sitting SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), 
Visit 3 (Week 4), and Visit 4 (Week 8): 
o In the group of patients who were on NEB 5 mg and 
AML 5 mg at Visit 1 (Week -4) and continued to be 
on the same therapies. 
o In the group of patients, who switched to NEB 5 mg 
or AML 5 mg from any other BBs or CCBs at 
Visit 1 (Week -4). 
Study Population: 
Patients characteristics 
Number of Patients 
Approximately 290 male or female uncontrolled hypertensive 
patients between ≥18 and <65 years of age, who are on treatment 
with any BBs or CCBs, including NEB (only 5 mg dosage allowed) 
or AML (only 5 mg dosage allowed) for at least one month prior to 
Visit 1, will be screened for eligibility. 
A total number of 290 patients will be screened considering a 
screen failure/drop-out rate of 25%, to obtain approximately 
216 completed patients at the end of the study (Visit 4). 


 
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Inclusion criteria: 
A patient will be considered eligible to be enrolled in the study only 
if he/she meets all the following inclusion criteria: 
1. Male or female patients with Grade 1 - 2 hypertension with 
mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or 
mean sitting DBP ≥90 mmHg and ≤109 mmHg at screening 
(in accordance with the 2018 European Society of 
Cardiology / European Society of Hypertension guidelines 
definition), ≥18 and <65 years of age, on monotherapy 
treatment either with BBs or CCBs for at least 4 weeks 
before Visit 1 (screening). 
2. Patients are able to understand and have freely given written 
informed consent at Screening Visit. 
3. Patients who are able to comply with all study procedures 
and who are available for the duration of the study. 
4. Ability to take oral medication and willing to adhere to the 
drug regimen. 
5. Female patients are eligible to participate if not pregnant, or 
not breastfeeding and if they refrain from donating or 
storing eggs. For females of reproductive potential: use of 
highly effective contraception (eg. method of birth control 
throughout the study period and for 4 weeks after study 
completion defined as a method which results in a failure 
rate of <1% per year) such as: 
o Combined hormonal contraception (estrogen- and 
progestogen-containing) associated with inhibition 
of ovulation (oral, intravaginal, and transdermal). 
o Progestogen-only hormonal contraception associated 
with inhibition of ovulation (oral, injectable, and 
implantable). 
o Intrauterine device. 
o Intrauterine hormone-releasing system. 
o Bilateral tubal occlusion. 
o Vasectomized partner (procedure conducted at least 
2 months before the screening), (provided the 


 
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partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has 
received medical assessment of the surgical success). 
6. A male patient must agree to use contraception during the 
whole study period and for at least 1 week after the last dose 
of study treatment and refrain from donating sperms during 
this period. 
Exclusion criteria: 
Any patient who meets any of the following criteria will not qualify 
for entry into the study: 
1. Patients with significant history of hypersensitivity to 
nebivolol, amlodipine, other BBs or other dihydropyridines, 
or any related products (including excipients of the 
formulations) as outlined in the relevant Investigators 
Brochures, summary of product characteristics12,13 or local 
package inserts for NEB and AML.  
2. Patients with serious disorders (in the opinion of the 
Investigator) which may limit the ability to evaluate the 
efficacy or safety of the tested medications, including 
cerebrovascular, cardiovascular, renal, respiratory, hepatic, 
gastrointestinal, endocrine or metabolic, hematological, or 
oncological, neurological, and psychiatric diseases. The 
same applies for immunocompromised and/or neutropenic 
patients. 
3. Patients having a history of the following conditions within 
the last 6 months: myocardial infarction, unstable angina 
pectoris, 
percutaneous 
coronary 
intervention, 
bypass 
surgery, heart failure, hypertensive encephalopathy, valve 
replacement 
(transcatheter 
aortic 
valve 
implantation, 
mitraclip), cerebrovascular accident (stroke), or transient 
ischemic attack. 
4. Patients with condition of hypotension with SBP <90 mmHg 
and/or DBP <60mmHg. 
5. Acute heart failure, cardiogenic shock, or episodes of heart 
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therapy. 
6. Patients with secondary hypertension of any etiology 
including renal diseases, pheochromocytoma, Cushing’s 
syndrome, hyperaldosteronism, renovascular disease, and 
thyroid disorders. 
7. Patients with a narrowing of the aortic or bicuspid valve, an 
obstruction of cardiac outflow (obstructive, hypertrophic 
cardiomyopathy), obstruction of the outflow tract of the left 
ventricle (eg. high grade aortic stenosis) or symptomatic 
coronary disease. 
8. Patients with severe renal impairment or renal transplant. 
9. Patients with clinically relevant hepatic impairment. 
10. Patients with sick sinus syndrome, including sino-atrial 
block. 
11. Patients with second- or third-degree heart block (without a 
pacemaker). 
12. Patients with history of bronchospasm and bronchial 
asthma.  
13. Patients with untreated pheochromocytoma. 
14. Patients with bradycardia (heart rate <60 bpm; <50 bpm in 
patients already on BBs treatment). 
15. Patient with metabolic acidosis. 
16. Patients with severe peripheral circulatory disturbances. 
17. Participation in another interventional study within the last 
4 weeks before Screening Visit (Visit 1).  
18. Patients with diseases that, in the opinion of the 
Investigator, prevent a careful adherence to the protocol. 
19. Patients using and not suitable for withdrawing the 
prohibited medications prior to the administration of study 
treatment. 
Clinical Sites 
Number of Centers 
Approximately 25 investigational clinical sites 
List of Countries 
Bulgaria, Poland, and Ukraine. 
Study Duration (specify 
different study phases): 
 
This study will last 12 weeks. 
Screening Visit (Visit 1, Week -4): 


 
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First Patient In (FPI) 
Last Patient Out (LPO) 
Grade 1 - 2 hypertensive patients (BP ranging from ≥140 to 
≤179mmHg for SBP and from ≥90 to ≤109 mmHg for DBP) on 
treatment with any BBs or CCBsc, including NEB (only 5 mg 
dosage allowed) or AML (only 5 mg dosage allowed) for at least 
one month prior to Visit 1 will be screened for eligibility. 
Run-in period (4 weeks) from Visit 1 (Week -4) to Visit 2 
(Week 0): 
Eligible patients will enter a 4-week run-in period on the same day 
of the Screening visit. Patients receiving NEB 5 mg or AML 5 mg 
will continue the same therapy, while patients on any other BBs or 
CCBsc will be switched to NEB 5 mg or AML 5 mg, respectively. 
Patients entering this phase of therapy with NEB 5 mg or AML 
5 mg should be in a 1:1 ratio. 
Assessment period (8 weeks) from Visit 2 (Week 0) to Visit 4 
(Week 8): 
• Patients 
having 
uncontrolled 
BP 
(sitting 
SBP/DBP 
≥130/80 mmHg) at Visit 2 will be assigned to the 
extemporaneous combination of NEB 5 mg and AML 5 mg.  
• After 4 weeks ±2 days at Visit 3 the BP will be assessed 
again:  
o In case of controlled BP levels (sitting SBP/DBP 
<130/80 mmHg), patients will continue to be on the 
same extemporaneous combination for next 4 weeks 
±2 days (Visit 4, Week 8).  
o In case of uncontrolled BP levels (sitting SBP/DBP 
≥130/80 mmHg), the AML dose will be uptitrated 
from 5 mg to 10 mg and the patients will receive the 
extemporaneous combination of NEB/AML 5/10 mg 
for next 4 weeks ±2 days (Visit 4, Week 8). 
 
 
End of March 2022 
Beginning of December 2022. 
Patient Study Phases 
Duration 
For patients completing the study, participation will last up to 
12 weeks: 


 
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• 4 weeks of run-in period (monotherapy) 
• 8 weeks of assessment period (extemporaneous 
combination) 
Statistical Assumptions 
The primary endpoint will be assessed before and after assessment 
period at Week 8 by a paired t-test using the modified 
Intent-to-treat population and the Per-Protocol population. Only 
those patients for whom we have DBP assessment results available 
at both Week 4 and Week 8 will be considered. No imputation will 
be performed for missing DBP. 
To test the covariate effects and the effects of interactions between 
covariates on the primary efficacy endpoint (change in mean sitting 
DBP) as well as the first secondary efficacy endpoint (change in 
mean sitting SBP), a repeated measures general linear model 
(GLM) will be proposed. The GLM repeated measures procedure 
provides analysis of variance when the same measurement is made 
several times on each patient. Age, gender, body mass index, and 
baseline DBP will be included in the GLM model as covariates. 
The GLM model will be explained in detail in the Statistical 
Analysis Plan, approved before database lock. 
All the other continuous secondary/exploratory endpoints will be 
assessed across different study visits using a paired t-test or 
independent t-test, as applicable.   
All secondary/exploratory endpoints related to proportion of 
patients achieving the BP goal at Week 4 and Week 8 will be 
analyzed descriptively along with the relative 95% CI to assess if 
there is a significant difference from Week 0 where all patients 
were uncontrolled. 
Sample size: 
A total sample size of 216 patients is required to achieve 90% 
power at a 5% significance level assuming a difference in mean 
DBP from baseline (Visit 2) to 8 weeks (Visit 4) of 4 mmHg and a 
standard deviation for this difference of 10 mmHg. The mean 
change in DBP for the null hypothesis is set equal to 2 mmHg. 


 
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A total number of 290 patients will be screened considering 25% of 
drop-out rate, to obtain approximately 216 completed patients at the 
end of the study (Visit 4). 
 


 
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2.1 
Study Scheme 
 
 
 
Abbreviations: AML = amlodipine; BBs = beta-blocker; CCBs = calcium channel blockers; DBP = diastolic blood pressure; 
NEB = nebivolol, and SBP = systolic blood pressure.  
Note:  
There is no randomization procedure. 
*Allowed CCBs at screening includes Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and 
nisoldipine. 
Patients treated with Amlodipine or Nebivolol in dosages higher than 5 mg/daily will not be eligible. 
Grade 1 - 2 hypertensive patients: Patients with SBP/DBP ranging from ≥140/90 mmHg to ≤179/109 mmHg. 
**Uncontrolled patients with Grade 1 - 2 hypertension: Patient with sitting SBP ≥130 and DBP ≥80 mmHg. Patients with 
Grade 3 (SBP ≥180 or DBP ≥110 mmHg) hypertension will be withdrawn from the study at Visit 2 and Visit 3. 
Controlled patients: Patients with sitting SBP/DBP <130/80 mmHg.  
 


 
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2.2 
Study Flow Chart 
 
 
Week -4 
Visit 1 
Week 0 
Visit 2 
Week 4 
Visit 3 
Week 8/EOT 
Visit 4 
 
Screening + Start of Run-in 
Period 
End of Run-in period and Start of 
Assessment Period 
Assessment Period 
End of Assessment Period 
Informed consent forma 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Medical history 
X 
 
 
 
Prior medications 
X 
 
 
 
Demographic Informationb 
X 
 
 
 
Concurrent diseases and medical conditions 
X 
X 
X 
X 
Monotherapy of NEB 5 mg or AML 5 mg dispensingc 
X 
 
 
 
Extemporaneous combination of NEB/AML 5/5 mg dispensing 
 
X 
Xd 
 
Extemporaneous combination of NEB/AML 5/10 mg dispensing 
 
 
Xe 
 
Study treatment return/accounting (Compliance assessment) 
 
X 
X 
X 
Concomitant medicationsf 
X 
X 
X 
X 
Urine Pregnancy testg 
X 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
Vital signsh 
X 
X 
X 
X 
Laboratory testsi 
X 
 
 
X 
Blood pressure measurement 
X 
X 
X 
X 
ECG 
X 
 
 
X 
AE/SAE assessmentj 
X 
X 
X 
X 


 
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Week -4 
Visit 1 
Week 0 
Visit 2 
Week 4 
Visit 3 
Week 8/EOT 
Visit 4 
 
Screening + Start of Run-in 
Period 
End of Run-in period and Start of 
Assessment Period 
Assessment Period 
End of Assessment Period 
Written instructions for self-blood pressure measurement and patient 
diary provided to patientk 
X 
X 
X 
 
Written instructions for self-blood pressure measurement and patient 
diary returned to sitek 
 
X 
X 
X 
BP device provided to patientk 
X 
 
 
 
BP device returned to sitek 
 
 
 
X 
Abbreviations: AE = adverse event; AML = amlodipine; BBs = beta-blocker; BP = blood pressure; CCBs = calcium channel blockers; COVID-19 = Coronavirus Disease 2019, ECG = electrocardiogram; EOT = end of 
treatment; FSH = follicular stimulating hormone; IP = investigational product; NEB = nebivolol, and SAE = serious adverse event.  
Notes:  
a. Informed consent must be signed prior to any study-related procedure. 
b. Screening patient information will be obtained in accordance with local regulation, including age, sex (with childbearing status of females and menopausal status), height, weight, race, and 
ethnicity. 
c. Patients on NEB 5 mg or AML 5 mg will continue the same therapy for 4 weeks (run-in period). Patients on any other BBs will be assigned to monotherapy with NEB 5 mg and the patients on 
other CCBs (except AML 10 mg) will be assigned to monotherapy with AML 5 mg. The allowed CCBs are: felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, 
and nisoldipine). 
d. Only patients with controlled BP at Visit 3 will receive NEB/AML 5/5 mg for next 4 weeks. 
e. Only patients with uncontrolled BP at Visit 3 will receive NEB/AML 5/10 mg for next 4 weeks. 
f. All concomitant medications ongoing at the time of the consent and any surgery/procedures should be reported. 
g. Pregnancy test (urine): only for females of childbearing potential.  
h. Vital signs will include body temperature, respiratory rate, and pulse rate. 
i. To ensure patient safety, the patients will be contacted over a phone call within 24 hours, in case of any abnormality and clinically relevant laboratory test according to the Investigator’s judgment 
at any visit. 


 
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j. Patients having any ongoing AE/SAE at the end of the treatment will be followed for further 2 weeks via a phone call to check about the status of the AE/SAE. 
k. These procedures are referred to the COVID-19 Appendix (Appendix 2). 
 


 
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3 
STUDY RATIONALE AND BACKGROUND INFORMATION 
Cardiovascular disease (CVD) is a significant source of morbidity and mortality worldwide, 
with approximately 18.6 million deaths in 20191. 
Hypertension is the primary risk factor for CVD. It is also a leading risk factor for all-cause 
mortality and is one of the largest contributors to global disability-adjusted life years. 
Hypertension is among the major contributors of cardiac complications, stroke, heart diseases, 
kidney failure, including premature death and disabilities2. Epidemiological research over the 
past half-century has confirmed that the risk from hypertension is strong, continuous, graded, 
and doubles for each increment of 20 mmHg systolic blood pressure (SBP) or 10 mmHg 
diastolic BP (DBP) in adults3. 
As per the estimation of World Health Organization, globally more than 1.13 billion of people 
are affected with hypertension among which less than 1 in each 5 is under control2. The 
overall prevalence of hypertension in adults is around 30 to 45%4. Elevated BP was the 
leading global contributor to premature death in 2015, accounting for almost 10 million 
deaths and over 200 million disability-adjusted life years5. 
There are two well-established strategies to lower BP: lifestyle interventions and drug 
treatment6. There is strong evidence from clinical trials that antihypertensive therapy reduces 
substantially premature morbidity and mortality. 
A meta-analysis of 123 randomized controlled trials (RCTs) with 613,815 participants 
showed relative risk reductions proportional to the magnitude of the blood pressure reductions 
achieved. Every 10 mmHg reduction in SBP significantly reduced the risk of major CVD 
events (relative risk [RR] 0.80, 95% confidence interval [CI] 0.77-0.83), coronary heart 
disease (0.83, 0.78-0.88), stroke (0.73, 0.68-0.77), and heart failure (0.72, 0.67-0.78), which, 
in the populations studied, led to a significant 13% reduction in all-cause mortality (0.87, 
0.84-0.91). Blood pressure lowering significantly reduces vascular risk across various 
baseline BP levels and comorbidities7.  
A total of 68 RCTs with 245,885 individuals were eligible, of which 47 (153,825 individuals) 
were 'intentional' RCTs. All outcomes were reduced (p <0.001) by BP lowering, stroke (-36% 


 
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[-29, -42]), and heart failure (-43% [-28, -54]) to a greater extent, with smaller reductions for 
coronary events (coronary heart disease [CHD]: -16% [-10, -21]), cardiovascular (-18% [-11, 
-24]), and all-cause mortality (-11% [-5, -16]). Absolute risk reductions were 17 (14, 20) 
strokes, 28 (19, 35) cardiovascular events, and 8 (4, 12) deaths prevented every 1000 patients 
treated for 5 years. Logarithmic risk ratios were related to SBP, DBP, and PP reductions 
(p = 0.001-0.003) for stroke and composite cardiovascular events, but not for CHD8. 
However, for most patients, achieving BP targets is often not possible with a single agent. In 
fact, at least 75% of individuals with hypertension require treatment with at least 
2 antihypertensive drugs in order to achieve BP control9. The most recent European Society 
of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines recommend that, 
when BP-lowering drugs are used, the first objective should be to lower BP to 
<140/90 mmHg in all patients. Provided that the treatment is well tolerated, treated BP values 
should be targeted to 130/80 mmHg or lower in most patients. 
With the emphasis of a BP target in most patients of 130/80 mmHg or lower, majority of 
patients would require a combination therapy. The combination of medications targeting 
multiple mechanisms reduces the heterogeneity of the BP response to initial treatment and 
provides a steeper dose response than is observed with escalating doses of monotherapy. 
Two-drug combinations have shown to be safe and well tolerated6. Patients with hypertension 
are now generally treated with multiple pharmaceutical products, BP is in fact a 
multi-regulated variable depending on many compensating pathways. Consequently, 
combinations of drugs, working through different mechanisms, are required to reduce BP in 
most people with hypertension. Thus, monotherapy is likely to be an inadequate therapy in 
most patients. Indeed, almost all patients in RCTs have required the combinations of drugs to 
control their BP11. 
Nebivolol (a beta-blocker [BB]) and Amlodipine (a calcium channel blocker [CCB]) are 
antihypertensive drugs widely prescribed as monotherapies in clinical practice. Both drugs 
have specific benefit-risk profiles with different mechanism of action.  
Nebivolol is a third-generation lipophilic β-1 receptor-selective blocker with nitric oxide 
(NO)-mediated vasodilatory effects, devoid of intrinsic sympathomimetic effects as well as 


 
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membrane stabilizing activity and α1 receptor blocking properties. Nebivolol is administered 
as the racemate containing equal amounts of the d- and l-enantiomers. The d-isomer is the 
active β-blocking component; the l-isomer is responsible for enhancing production of NO. 
Nebivolol, at the recommended dosage (5 mg once daily) was similarly effective in lowering 
BP compared with other BB (atenolol and bisoprolol), angiotensin-converting enzyme 
inhibitors (lisinopril and enalapril), the angiotensin receptor blocker telmisartan, and calcium 
channel blockers (nifedipine and amlodipine)9. Nebivolol lowers BP by reducing peripheral 
vascular resistance and significantly increases stroke volume with preservation of cardiac 
output and maintains systemic flow and blood flow to target organs. In particular, nebivolol 
has also shown significant reduction in aortic pressure and wave reflection (markers of central 
BP) and improvements in endothelial dysfunction and arterial stiffness in hypertensive 
patients9. The high selectivity of nebivolol is witnessed by its high safety profile in patients 
affected by asthma or chronic obstructive pulmonary disease who are unable to tolerate 
traditional BB. Its antihypertensive efficacy and safety profile have been clearly proven in 
patients affected by chronic kidney diseases. Furthermore, the vasodilating properties of 
nebivolol mediated through endothelial release of NO offer an advantage over other BB in the 
patient with hypertension and erectile dysfunction. Moreover, it does not negatively influence 
glucose or lipid metabolism10. 
Amlodipine belongs to the dihydropyridine class of CCBs7. Amlodipine, like other CCBs, 
acts primarily by inhibiting extracellular calcium influx through cardiac and vascular smooth 
muscle cell membranes; this inhibition is achieved mainly by blockade of L-type ‘voltage 
operated’ calcium channels. Its main site of action is the peripheral vasculature, although it 
also produces vasodilation in coronary vascular beds. In patients with mild to moderate 
essential hypertension, amlodipine had a sustained and gradual onset of antihypertensive 
effect, when assessed by 24-hour ambulatory or intra-arterial BP monitoring7. Since the two 
drugs have distinct modes of action, they are well suited for use as combination therapy. 
Current literature data has shown an additional antihypertensive effect when Nebivolol or 
Amlodipine is added to other antihypertensive treatment10. At the moment, the most studied 
association with nebivolol concerns its combination with hydrochlorothiazide and valsartan9.  


 
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CONFIDENTIAL                                                                                                                                                29 
3.1 
Assessment of Potential Risks and Benefits 
The combination of a beta adrenergic blocker with a CCB is used when monotherapy is not 
fully effective at controlling symptoms In many cases, combination therapy improves rates of 
BP control and requires less time to achieve target BP with equivalent or better tolerability 
than higher-dose monotherapy. Patients with comorbidities may benefit from the effects of 
different antihypertensive medications classes. Approximately, 70% of patients with 
hypertension require 2 or more agents to achieve their target BP7. In a meta-analysis 
published in 2010, Fixed Dose Combinations of antihypertensive agents not only improved 
compliance by 21%, but also allowed for a 50% increase in persistence with therapy10. 
Beyond improving compliance, combination therapy in the setting of hypertension 
management allows for decreased BP variability. Variability in SBP and DBP is associated 
with an increased risk of myocardial infarction and stroke11. 
Using combination therapy could also drive a potential economic advantage, including 
reduced need to switch medications and long-term improvement in control of BP7. 


 
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4 
TRIAL OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
To assess the antihypertensive 
efficacy of the extemporaneous 
combination of nebivolol (NEB) 5 mg 
with amlodipine (AML) 5 mg or AML 
10 mg in lowering the sitting DBP 
between Visit 2 (Week 0) and Visit 4 
(Week 8) in patients with uncontrolled 
BP, previously treated with NEB 5 mg 
or AML 5 mg monotherapies for at 
least 4 weeks. 
Change in mean sitting DBP between 
Visit 2 (Week 0) and Visit 4 
(Week 8). 
The association 
between elevated DBP 
and increased mortality 
risk has been reported 
several times in 
literature especially in 
younger patients14. 
Secondary 
• To assess the antihypertensive 
efficacy of the extemporaneous 
combination of NEB 5 mg with 
AML 5 mg or AML 10 mg in 
lowering sitting SBP between 
Visit 2 (Week 0) and Visit 4 
(Week 8) in patients with 
uncontrolled BP previously treated 
with NEB 5 mg or AML 5 mg 
monotherapies for at least 
4 weeks. 
• Change in mean sitting SBP 
between Visit 2 (Week 0) and 
Visit 4 (Week 8). 
A robust body of 
evidence demonstrated 
that the reduction of 
SBP decrease the risk 
of CV events and 
mortality7. 
• To assess the antihypertensive 
efficacy of the extemporaneous 
combination of NEB/AML 
5/10 mg versus extemporaneous 
combination NEB/AML 5/5 mg, 
in lowering sitting DBP and SBP 
between Visit 3 (Week 4) and 
Visit 4 (Week 8) in patients with 
uncontrolled BP previously treated 
with NEB 5 mg or AML 5 mg 
monotherapies for at least 4 
• Change in mean sitting DBP and 
SBP between Visit 3 (Week 4) 
and 4 (Week 8) in patients 
receiving extemporaneous 
combination of NEB/AML 5/5 
mg versus patients uptitrated to 
the extemporaneous combination 
of NEB/AML 5/10 mg. 
 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
weeks. 
• To assess the antihypertensive 
efficacy of the extemporaneous 
combination of NEB 5 mg with 
AML 5 mg or AML 10 mg by 
evaluating the patients who 
achieve BP goal (sitting BP 
<130/80 mmHg) at Visit 2 (Week 
0), at Visit 3 (Week 4), and at 
Visit 4 (Week 8).  
• Number and proportion of 
patients achieving the BP goal 
(sitting SBP/DBP 
<130/80 mmHg) at Visit 2 (Week 
0), Visit 3 (Week 4) and Visit 4 
(Week 8). 
The proportion of 
patients at target is a 
very important clinical 
indicator of therapeutic 
success. 
• To assess the compliance to the 
treatment (percentage of actual 
doses taken versus doses to be 
taken) at Visit 2 (Week 0), at Visit 
3 (Week 4), and at Visit 4 (Week 
8). 
• Adherence to the treatments (% of 
doses taken/doses to be taken) at 
Visit 2 (Week 0), Visit 3 (Week 
4), and Visit 4 (Week 8). 
Monitoring compliance 
is extremely important 
to better evaluate the 
efficacy and 
tolerability of the 
extemporaneous 
combination. 
• To evaluate the safety and 
tolerability of the monotherapies 
(NEB 5 mg and AML 5 mg) and 
of the extemporaneous 
combinations (NEB 5 mg and 
AML 5mg or AML 10 mg) after 8 
weeks of treatment. 
• Safety and tolerability of the 
monotherapies (NEB 5 mg and 
AML 5 mg) and of the 
extemporaneous combinations 
(NEB 5 mg and AML 5mg or 
AML 10 mg) will be measured by 
incidence, intensity (severity), 
seriousness of Adverse Events 
(AEs) during the study period, 
(screening, run-in period and 
assessment period), relationship 
to the study treatments, Adverse 
events of special interest, 
clinically significant abnormal 
change in vital signs, 
electrocardiogram (ECG) (only at 
Visit 1 and Visit 4), laboratory 
parameters (if applicable) at Visit 
Incidence of adverse 
drug reactions (ADRs), 
AEs, serious adverse 
events (SAEs), vital 
signs, physical 
examination, ECG 
needs to be studied to 
address safety and 
tolerability of the 
extemporaneous 
combination. 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
2 (Week 0), Visit 3 (Week 4), and 
Visit 4 (Week 8). 
Exploratory 
• To assess change in mean sitting 
DBP and SBP between Visit 1 
(Week -4) and Visit 2 (Week 0), 
Visit 3 (Week 4) and Visit 4 
(Week 8):  
o In the group of patients who 
were on NEB 5 mg and AML 5 
mg at Visit 1 and continued to 
be on the same therapies. 
o In the group of patients who 
switched to NEB 5 mg or AML 
5 mg from any other BBs or 
CCBs at Visit 1. 
• Change in mean sitting DBP and 
SBP between Visit 1 (Week -4) 
and Visit 2 (Week 0), Visit 3 
(Week 4) and Visit 4 (Week 8): 
o In the group of patients who 
were on NEB 5 mg and AML 
5 mg at Visit 1 and continued 
to be on the same therapies. 
o In the group of patients who 
switched to NEB 5 mg or 
AML 5 mg from any other 
BBs or CCBs at Visit 1. 
Evaluation of the 
antihypertensive 
efficacy of 
combination therapy in 
the sub-group of 
patients who switched 
from a different BB or 
CCB and in the 
sub-group of patients 
who were on nebivolol 
or on amlodipine at the 
inclusion in the study. 
• To assess the change in mean 
sitting DBP and SBP between 
Visit 2 (Week 0) and Visit 3 
(Week 4) for uncontrolled patients 
at Visit 3 (Week 4). 
• Change in mean sitting DBP and 
SBP for uncontrolled patients at 
Visit 3 (Week 4), between Visit 2 
(Week 0) and Visit 3 (Week 4). 
To collect and analyze 
data not only in the 
overall population of 
patient but also in 
patients considered 
uncontrolled after 
4 weeks of combined 
therapy. 
• To assess the antihypertensive 
efficacy of the extemporaneous 
combination of NEB 5 mg with 
AML 5 mg or AML 10 mg by 
evaluating the number of patients 
achieving the BP goal (sitting BP 
<130/80 mmHg) at Visit 2 (Week 
0), Visit 3 (Week 4) and Visit 4 
(Week 8):  
o In the group of patients who 
were on NEB 5 mg and AML 5 
• Number and proportion of 
patients achieving the BP goal 
(sitting SBP/DBP 
<130/80 mmHg) at Visit 2 
(Week 0), Visit 3 (Week 4), and 
Visit 4 (Week 8):  
o In the group of patients who 
were on NEB 5 mg and AML 
5 mg at Visit 1 (Week -4) and 
continued to be on the same 
therapies. 
To collect efficacy data 
stratifying the 
population of patients 
on the basis of the 
switching of the 
therapy. 


 
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CONFIDENTIAL                                                                                                                                                33 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
mg at Visit 1 (Week -4) and 
continued to be on the same 
therapies. 
o In the group of patients who 
switched to NEB 5 mg or AML 
5 mg from any other BBs or 
CCBs at Visit 1 (Week -4). 
o In the group of patients who 
switched to NEB 5 mg or 
AML 5 mg from any other 
BBs or CCBs at Visit 1 
(Week- 4). 
• To assess the antihypertensive 
efficacy of the extemporaneous 
combination of NEB 5 mg with 
AML 5 mg or AML 10 mg by 
evaluating the number of patients 
divided into subgroups according 
to their hypertension grade, the 
presence of diabetes and/or of 
hypercholesterolemia achieving 
the BP goal (sitting BP <130/80 
mmHg) at Visit 2 (Week 0), Visit 
3 (Week 4), and Visit 4 (Week 8): 
o In the group of patients who 
were on NEB 5 mg and AML 5 
mg at Visit 1 and continued to 
be on the same therapies. 
o In the group of patients, who 
switched to NEB 5 mg or AML 
5 mg from any other BBs or 
CCBs at Visit 1. 
• Number and proportion of 
patients divided into subgroups 
according to the hypertension 
grade, the presence of diabetes 
and/or of hypercholesterolemia 
achieving the BP goal (sitting 
SBP/DBP <130/80 mmHg) at 
Visit 2 (Week 0), Visit 3 (Week 
4), and Visit 4 (Week 8): 
o In the group of patients who 
were on NEB 5 mg and AML 
5 mg at Visit 1 (Week -4) and 
continued to be on the same 
therapies. 
o In the group of patients, who 
switched to NEB 5 mg or 
AML 5 mg from any other 
BBs or CCBs at Visit 1 
(Week -4). 
To collect efficacy data 
stratifying the 
population of patients 
on the basis of the 
switching of the 
therapy. 


 
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5 
STUDY DESIGN 
This is a Phase IV, interventional, open-label, multicenter, multinational study with 2 study 
periods (a run-in period of 4 weeks and an assessment period of 8 weeks) to assess efficacy 
and safety of the extemporaneous combination of Nebivolol and Amlodipine in Grade 1 - 2 
hypertension patients versus each monotherapy.  
The study will be conducted in approximately 25 investigational clinical sites in Bulgaria, 
Poland, and Ukraine. The total study duration is 12 weeks including a run-in period of 
4 weeks and an assessment period of 8 weeks. 
Screening Visit 1 (Week -4): At Visit 1, after providing the informed consent, patients with 
Grade 1 - 2 hypertension (SBP ranging from ≥140 to ≤179 mmHg and DBP ranging from 
≥90 to ≤109 mmHg) who were on treatment with any BBs or CCBsc including NEB 5 mg or 
AML 5 mg for at least one month prior to Visit 1 will be screened for eligibility. The 
eligibility for Grade 1 - 2 hypertension will be based on the 2018 ESC/ESH guidelines, and 
the BP criteria is defined as mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean 
sitting DBP ≥90 mmHg and ≤109 mmHg. 
Run-in period from Visit 1 (Week -4) to Visit 2 (Week 0): On the same day of the Screening 
visit, the eligible patients will enter into a run-in period of 4 weeks after screening, during 
which: 
• Patients receiving NEB 5 mg or AML 5 mg will continue the same therapy for 
4 weeks. 
• Patients on any other BBs or CCBsc will be switched to NEB 5 mg or AML 5 mg. 
Patients entering this phase in therapy with NEB 5 mg or AML 5 mg should be in a 1:1 ratio. 
Assessment period from Visit 2 (Week 0) to Visit 4 (Week 8): After 4 weeks (±2 days) of 
run-in period of monotherapy, the BP will be further assessed (Visit 2). Patients with 
uncontrolled BP levels (sitting SBP/DBP ≥130/80 mmHg) at Visit 2, with the treatment 
adherence (ranging between 80% to 120%) and who did tolerate the treatment will enter into 
the assessment period and will be assigned to the extemporaneous combination of NEB 5 mg 


 
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and AML 5 mg. Patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg) and/or 
who do not tolerate the treatment or have an adherence range below 80% or above 120%, will 
be withdrawn from the study. 
After 4 weeks ±2 days in the assessment period, patients BP will be further evaluated at 
Visit 3: patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg) will continue 
the same extemporaneous combination, while patients with uncontrolled BP levels will be 
uptitrated from extemporaneous combination NEB/AML 5/5 mg to extemporaneous 
combination of NEB/AML 5/10 mg for further 4 weeks. 
At the end of the assessment period (8 weeks ±4 days), the patients will attend an End of 
Treatment Visit 4. To correctly evaluate the additional effect of the combination therapy, the 
number of patients with uncontrolled BP on NEB or AML monotherapy needs to be balanced 
at Visit 2. In order to maintain a 1:1 ratio during the assessment period, a cap of 110 patients 
for each treatment arm (ie. NEB and AML) will be included at Visit 2 in order to maintain a 
balanced number of uncontrolled patients entering the assessment period for each drug. The 
evaluation will be done every 50 patients. If the rate of entrance in the assessment period for 
one of the 2 tested drugs will deviate more than 5%, a corrective measure will be initiated: 
according to the enrolment site statistics, one or more sites will be informed to enroll a greater 
number of patients being treated with the least represented drug in the assessment period.  
A total number of 290 patients will be screened considering 25% of drop-out rate, to obtain 
approximately 216 completed patients at the end of the study (Visit 4). 
Sitting BP will be measured at all visits before blood sampling. BP will be measured in both 
arms at the Screening visit (Visit 1) in order to detect possible between-arm differences. The 
arm with the higher mean DBP will be used in all subsequent visits for BP assessment. Blood 
pressure measurements should be performed as nearly as possible within the same time frame 
of the day (7:00 to 12:00 a.m.), on the same arm, possibly by the same member of the site 
staff/personnel, and using the same calibrated equipment at each visit. 
Patients should be seated comfortably in a quiet environment for 5 minutes before beginning 
BP measurements. Three BP measurements will be recorded, 1 to 2 minutes apart, and 
additional measurements only if the first two readings differ by >10 mmHg. The mean of the 


 
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three recordings in sitting position will be used as the BP value for that visit. All BP 
measurements during the treatment phase will be performed as through readings (ie. 
24 + 2 hour after the last drug intake). Study medication should be administered/consumed on 
the same time every day during the study; except the days of site visits, when study 
medication should be administered after all assessments mentioned as per study flow chart 
(Section 2.2). At Visit 1 (Week -4) and Visit 4 (Week 8), a 12-lead ECG will be performed. 
Safety (AEs, SAEs) will be measured at all visits. In case of any abnormality of clinically 
relevant safety finding at any of the visits according to the Investigator, the patient will be 
contacted over phone within 24 hours to ensure their safety. Any patient having an ongoing 
AE or SAE at Visit 4, will be followed-up for further 2 weeks over a phone call. 
5.1 
Procedures and Study Visits 
Patients will attend a total of 4 visits during the study. However, due to social restriction 
measures, the patients may not be able to visit the study site. In such cases, the Screening visit 
is a mandatory in-clinic visit and therefore must be performed at the study site. The Principal 
Investigator (PI) remains responsible for reviewing all study-related assessments. 
The patients may not be able to visit the site to perform BP measurement for primary and 
secondary analysis, clinical laboratory tests, vital sign and physical examination, ECG, or 
other assessments required by the study flow chart. In such cases, these assessments will be 
performed by the health care professionals (study staff or qualified designee) at patient’s 
home, if allowed by the country regulations.  
The description of the activities, procedures, and tests to be performed at each visit is detailed 
below: 
1. Screening and Start of Run-in Period (Visit 1, Week -4): 
The following procedures/assessments must be completed during the screening on the same 
day prior to the run-in period (Visit 1): 
• Obtaining informed consent. 
• Checking inclusion and exclusion criteria. 


 
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• Recording of medical history. 
• Recording of prior and concomitant medications. 
• Collection of demographic data. 
• Recording concurrent diseases and medical conditions. 
• Dispensing of antihypertensive treatment with NEB 5 mg or AML 5 mg monotherapy 
and dispensing of tablets for 4 weeks (run-in period) to eligible patients. 
• Dispensing of written instruction for self BP measurement and patient diary. 
• Dispensing of BP device. 
• Physical examination and vital signs. 
• BP measurement. 
• ECG. 
• Laboratory tests (see Section 8.2.3) (a follow-up phone call will be made within 
24 hours in case of any abnormality and clinically relevant results from the laboratory 
tests according to the Investigator).  
• Urine pregnancy test (UPT) (only for female patients). 
• AEs and SAEs assessment. 
• The patients meeting all inclusion criteria and none of the exclusion criteria will enter 
into the run-in period on the same day and will receive monotherapy of NEB 5 mg or 
AML 5 mg: 
o Patients who are already on therapy with NEB 5 mg or AML 5 mg will be 
provided with the same medication ie, NEB 5 mg or AML 5 mg, respectively. 
o Patients taking any other BBs or CCBsc will be provided with NEB 5 mg or 
AML 5 mg. 
2. Start of the Assessment Period (Visit 2, Week 0): 
At the end of the run-in period (treatment with monotherapies for 4 weeks ±2 days), only the 
patients with uncontrolled BP (SBP/DBP >130/80 mmHg), who tolerated the treatment and 
whose adherence to the therapy ranges from 80% to 120%, will enter the 8-week assessment 
period. 
The starting of extemporaneous combination NEB 5 mg/AML 5 mg dosing is noted as 
Week 0. 
The following procedures/assessments must be completed: 


 
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• Recording of concurrent diseases and medical conditions.  
• BP measurement. 
• Compliance assessment by return of NEB and AML tablets (also empty blisters) and 
accountability. 
• Study treatment dispensing (patients will be provided with the extemporaneous 
combination NEB 5 mg/AML 5 mg). 
• Recording of concomitant medications. 
• Physical examination and vital signs.  
• UPT (only for female patients). 
• AEs and SAEs assessment. 
• Dispensing of written instruction for self BP measurement and patient diary. 
• Return of written instruction for self BP measurement and patient diary dispensed at 
Visit 1 to site. 
3. Assessment Period (Visit 3, Week 4): 
During the assessment period, patients with controlled BP at Visit 3 (Week 4) will continue to 
receive NEB/AML 5/5 mg while patients with uncontrolled BP (SBP/DBP >130/80 mmHg) 
will receive the extemporaneous combination NEB 5 mg/AML 10 mg dosing. 
The following procedures/assessments must be completed: 
• Recording of concurrent diseases and medical conditions.  
• BP measurement. 
• Compliance assessment by return of NEB and AML 5 mg tablets (also empty blisters) 
and accountability. 
• Study treatment dispensing (patients will be provided with the extemporaneous 
combination NEB 5 mg/AML 5 mg [in patients with controlled BP] or NEB 
5 mg/AML 10 mg [in patients with uncontrolled BP]). 
• Recording of concomitant medications. 
• Physical examination and vital signs.  
• UPT (only for female patients). 
• AEs and SAEs assessment. 
• Dispensing of written instruction for self BP measurement and patient diary. 
• Return of written instruction for self BP measurement and patient diary dispensed at 
Visit 2 to site. 


 
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4. End of the Assessment Period (Visit 4, Week 8): 
The end of assessment period will be considered as end of 8 week ±4 days treatment with the 
extemporaneous combination NEB 5 mg/AML 5 mg and NEB 5 mg/AML 10 mg. 
The following procedures/assessments must be completed: 
• Recording of concurrent diseases and medical conditions.  
• Recording of concomitant medications. 
• Physical examination and vital signs. 
• BP measurement.  
• ECG. 
• Laboratory tests (a follow-up phone call will be performed within 24 hours in case of 
any abnormality and clinically relevant results from the laboratory tests according to 
the Investigator). 
• UPT (only for female patients). 
• Compliance assessment by study treatment (extemporaneous combination of NEB 
5 mg/AML 5 mg and NEB 5 mg/AML 10 mg) return (also empty blisters) and 
accountability. 
• AE and SAE assessment. In case of any patients having an ongoing AE or SAE at the 
end of the treatment, there will be a follow-up telephone call after 2 weeks to ensure 
patient safety. 
• Return of written instruction for self BP measurement and patient diary dispensed at 
Visit 3 to the site. 
• Return of BP device (dispensed at Visit 1) to the site. 
6 
SELECTION OF PATIENTS 
6.1 
Informed Consent Process 
The patient’s written informed consent to participate in the trial must be obtained before any 
trial-related activities are carried out. Adequate information must therefore be given to the 
patient by the Investigator before informed consent is obtained (a person designated by the 
Investigator may give the information, if permitted by local regulations) The patient’s written, 
dated and signed informed consent shall be obtained to the confidential disclosure, processing 
and transferring necessary documentation of the patient’s health and personal data to the 


 
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Clinical Research Organization (CRO), Sponsor and its Affiliates, the competent Health 
Authorities (HA) and any other institutions, as legally required and in accordance with the 
local applicable privacy laws (for the Privacy information to be reported on the informed 
consent form [ICF] refer to Section 17). 
The institution and the Investigator have the responsibility to duly inform patients about 
personal data processing and the relevant applicable privacy rights before their participation 
into the study. 
After being duly informed and interviewed by the Investigator, the patient freely has to date 
and sign the ICF before being enrolled into the study and before undergoing any study 
procedure. The Investigator must store the original of the signed ICF in the Investigator’s 
File, and the patient will be provided with a copy of it. If a protocol amendment would affect 
the terms of the ICF, it will be revised to reflect the protocol change and submitted to HA and 
Ethics Committee (EC) for approval. The Investigator will ensure that this new consent form 
is signed by all patients subsequently entered in the study and those currently in the study, if 
affected by the amendment. 
Initial informed consent signature must be provided at site. Should the patient need to re-
consent if permitted by investigative site procedures and local regulations, in case of social 
restrictions (Coronavirus Disease-2019 [COVID-19] pandemic), the ICF can be mailed to the 
patient. The patient can sign the consent form at home and mail it to the study site. 
Alternatively, the PI or designee can visit the patient at home to present the changes to the 
study and obtain their signature on the ICF at the patient’s home. If the patient has any 
questions about the changes to the study prior to providing their signature, they will be 
provided with an opportunity to discuss these questions with the PI or designee. After having 
obtained the consent, a copy of the signed consent must be shared with the patient. 
6.2 
Inclusion and Exclusion Criteria 
A patient will be considered eligible to be enrolled in the study only if he/she meets all of the 
inclusion criteria and none of the exclusion criteria. 


 
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6.2.1 Inclusion Criteria 
A patient will be considered eligible for inclusion in the study only if all of the following 
criteria are met: 
1. Male or female patients with Grade 1 - 2 hypertension with mean sitting SBP 
≥140 mmHg and ≤179 mmHg and/or mean sitting DBP ≥90 mmHg and ≤109 mmHg 
at screening (in accordance with the 2018 ESC/ESH guidelines definition), ≥18 and 
<65 years of age, on monotherapy treatment either with BBs or CCBs for at least 4 
weeks before Visit 1 (screening). 
2. Patients are able to understand and have freely given written informed consent at 
Screening Visit. 
3. Patients who are able to comply with all study procedures and who are available for 
the duration of the study. 
4. Ability to take oral medication and willing to adhere to the drug regimen. 
5. Female patients are eligible to participate if not pregnant, or not breastfeeding and if 
they refrain from donating or storing eggs. For females of reproductive potential: use 
of highly effective contraception (eg. method of birth control throughout the study 
period and for 4 weeks after study completion defined as a method which results in a 
failure rate of <1% per year) such as: 
o Combined hormonal contraception (estrogen- and progestogen-containing) 
associated with inhibition of ovulation (oral, intravaginal, and transdermal). 
o Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, and implantable). 
o Intrauterine device. 
o Intrauterine hormone-releasing system. 
o Bilateral tubal occlusion. 
o Vasectomized partner (procedure conducted at least 2 months before the 
screening), (provided the partner is the sole sexual partner of the trial patient 
and that the vasectomized partner has received medical assessment of the 
surgical success). 
6. A male patient must agree to use contraception during the whole study period and for 
at least 1 week after the last dose of study treatment and refrain from donating sperms 
during this period. 
6.2.2 Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the study: 


 
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CONFIDENTIAL                                                                                                                                                42 
1. Significant history of hypersensitivity to nebivolol, amlodipine, other BBs or other 
dihydropyridines, or any related products (including excipients of the formulations)as 
outlined in the relevant Investigators Brochures, summary of product characteristics 
(SmPC)12,13 or local package inserts for NEB and AML.  
2. Patients with serious disorders (in the opinion of the Investigator) which may limit the 
ability to evaluate the efficacy or safety of the tested medications, including 
cerebrovascular, 
cardiovascular, 
renal, 
respiratory, 
hepatic, 
gastrointestinal, 
endocrine/or metabolic, hematological, or oncological, neurological, and psychiatric 
diseases. The same applies for immunocompromised and/or neutropenic patients. 
3. Patients having a history of the following conditions within the last 6 months: 
myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, 
bypass surgery, heart failure, hypertensive encephalopathy, valve replacement 
(transcatheter aortic valve implantation, mitraclip), cerebrovascular accident (stroke), 
or transient ischemic attack.  
4. Patients with condition of hypotension with SBP <90 mmHg and/or DBP <60mmHg. 
5. Acute heart failure, cardiogenic shock or episodes of heart failure decompensation 
requiring intravenous inotropic therapy. 
6. Patients with secondary hypertension of any etiology including renal diseases, 
pheochromocytoma, Cushing’s syndrome, hyperaldosteronism, renovascular disease, 
thyroid disorders. 
7. Patients with a narrowing of the aortic or bicuspid valve, an obstruction of cardiac 
outflow (obstructive, hypertrophic cardiomyopathy), obstruction of the outflow tract 
of the left ventricle (eg. high grade aortic stenosis) or symptomatic coronary disease. 
8. Patients with severe renal impairment or renal transplant.  
9. Patients with clinically relevant hepatic impairment. 
10. Patients with sick sinus syndrome, including sino-atrial block. 
11. Patients with second- or third-degree heart block (without a pacemaker). 
12. Patients with history of bronchospasm and bronchial asthma.  
13. Patients with untreated pheochromocytoma.  
14. Patients with bradycardia (heart rate <60 bpm; <50 bpm in patients already on BBs 
treatment). 
15. Patient with metabolic acidosis. 
16. Patients with severe peripheral circulatory disturbances. 
17. Participation in another interventional study within the last 4 weeks before screening 
(Visit 1). 
18. Patients with diseases that, in the opinion of the Investigator, prevent a careful 
adherence to the protocol. 


 
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19. Patients using and not suitable for withdrawing the prohibited medications prior to the 
administration of study treatment. 
6.2.3 Screening Failures 
Screening failures are defined as patients who consent to participate in the clinical trial but do 
not meet one or more eligibility criteria required for participation in this trial during the 
screening procedures (Visit 1). Subjects who sign the ICF but do not start trial treatment for 
any reason will be considered Clinical Screening Failures. There will be no rescreening of 
screening failure patients in this study. 
7 
STUDY TREATMENT 
The following study treatment are administered during: 
• Run-in period (Visit 1 to Visit 2): NEB 5 mg tablets or AML 5 mg tablets in patients 
who were already receiving NEB 5 mg or AML 5 mg or who were on any other BBs 
or CCBsc, respectively prior to enrolment into the study. 
• Assessment period (Visit 2 to Visit 3): Extemporaneous combination of NEB 5 mg 
and AML 5 mg in patients with uncontrolled BP at Visit 2. 
• Assessment period (Visit 3 to Visit 4): Extemporaneous combination of NEB 5 mg 
and AML 5 mg in patients with controlled BP at Visit 3 and extemporaneous 
combination of NEB 5 mg and AML 10 mg in patients with uncontrolled BP (sitting 
SBP/DBP >130/80 mmHg, who tolerated the treatment and whose adherence to the 
therapies ranges from 80% to 120%) at Visit 2. 
Details on the study design is provided in Section 5. 
Further details on study treatment is provided below in Table 7.1. 


 
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Table 7.1 
Study Treatment Details 
Study Treatment Name: 
Nebivolol  
Marketing Authorisation Holder: A. 
Menarini Industrie Farmaceutiche 
Riunite srl, Via Sette Santi n. 3, 50131 
Florence 
Amlodipine Besylate 
Marketing Authorisation Holder: EG 
S.p.A. Via Pavia, 6 - 20136 Milano 
(MAH) 
Dosage Formulation: 
Tablet 
Tablet 
Unit Dose Strength(s)/Dosage 
Level(s): 
5 mg once daily 
5 mg/10 mg once daily 
Route of Administration:  
Oral 
Oral 
Dosing Instructions*: 
1 tablet of study medication will be 
administered with a glass of water once 
daily 
1 tablet of study medication will be 
administered with a glass of water once 
daily 
Packaging and Labelling: 
Study medication will be provided in a 
polyvinyl chloride (PVC)/Aluminum 
blister 
Study medication will be provided in a 
Aluminum/PVC/polyethylene (PE)/ 
polyvinylidene chloride (PVDC) blister 
Storage Conditions:  
All study treatment must be stored in 
its original packaging and kept in a 
secure area (in a dry place and 
protected from light and in accordance 
with the label’s instructions) with 
access limited to the Investigator and 
authorized site staff. No other special 
precautions are needed.  
All study treatment must be stored in its 
original packaging and kept in a secure 
area (in a dry place and protected from 
light and in accordance with the label’s 
instructions) with access limited to the 
Investigator and authorized site staff. No 
other special precautions are needed. 
*The patients will take the monotherapy tablets or the extemporaneous combination of NEB and AML in the 
morning between 6 am to 10 am except on the visit days. On the visit days, the patients will take the 
monotherapy tablets or the extemporaneous combination of NEB and AML after the study assessments. It is 
important to keep the medication intake on the same time every day throughout the study period. NO restriction 
will be there concerning food intake and both the monotherapies, or the extemporaneous combination can be 
given with or without meals. 
7.1 
Study Treatment Formulation, Appearance, Packaging, and Labelling 
Study treatment dosage form, strength, formulation: 
Nebivolol 5 mg: NEB 5 mg is white, round, cross-scored tablet with one-sided dividing cross 
score. The tablet can be divided in equal quarters. 
Amlodipine besylate 5 mg: AML 5 mg is white, round tablet. 


 
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Amlodipine besylate 10 mg: AML 10 mg is white, round tablet with a score line on one side. 
A tablet may be divided into two equal doses. 
Study treatment manufacturing: 
The NEB 5 mg tablets and AML 5/10 mg tablets will be sourced as authorized European 
Union (EU)-marketed products from a commercial supplier in the European market. 
Marketing authorization holders are reported in relative SmPC.12,13 
Study treatment packaging and labelling: 
The study treatment packaging and labelling operations for Clinical Trials are performed by 
manufacturer: A. Menarini Manufacturing Logistics and Services S.R.L. (Menarini Group), 
Via Sette Santi, 3 50131-Florence (Italy). 
The study treatment packaging and labelling operations will be performed in compliance with 
all applicable regulatory requirements and Good Manufacturing Practice guidelines, as well as 
any additional national requirement and Standard Operative Procedures (SOPs). 
The label wording will be in the local language for each country and will report the contents 
of the boxes and the instructions on how to administer and store the study medication. 
Study treatment packaging description: 
Both NEB 5 mg and AML 5/10 mg will be provided in dedicated treatment. Patient Kits to be 
dispensed at Visit 1 (beginning of the run-in period) and at Visit 2 (start of the assessment 
period) and Visit 3. 
The Kits are labelled with labels of different colours, in order to facilitate the recognition and 
distribution of study treatments. 


 
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Visit 1 (Run-in Period): 
• NEB 5 mg: each trial participant is provided with one Patient Kit with nebivolol 5 mg 
42 tablets (3 blisters with 14 tablets). 
• AML 5 mg: each trial participant is provided with one Patient Kit with amlodipine 
5 mg 42 tablets (3 blisters with 14 tablets). 
Trial participant must be instructed by Investigator or designee to take one tablet of nebivolol 
5 mg or amlodipine 5 mg, according to Study Protocol. 
Visit 2 (Beginning of Assessment Period): 
Each trial participant is provided with one Patient Kit made up by: 
• NEB 5 mg: one box containing nebivolol 5 mg 42 tablets (3 blisters with 14 tablets). 
• AML 5 mg: one box containing amlodipine 5 mg 42 tablets (3 blisters with 14 tablets). 
The two boxes are then sealed together into a transparent plastic film in order to realize the 
treatment Patient Kit. 
Trial participant must be carefully instructed by Investigator or designee to take 
simultaneously (at the same time): nebivolol 5 mg as one white round cross-scored tablet and 
amlodipine 5 mg as one white, round tablet, according to Study Protocol. 
Visit 3 (Assessment Period): 
Participants with controlled BP are provided with one Patient Kit made up by: 
• NEB 5 mg: one box containing nebivolol 5 mg 42 tablets (3 blisters with 14 tablets). 
• AML 5 mg: one box containing amlodipine 5 mg 42 tablets (3 blisters with 14 tablets). 
The two boxes are then sealed together into a transparent plastic film in order to realize the 
treatment Patient Kit. 


 
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Trial participant must be carefully instructed by Investigator or designee to take 
simultaneously (at the same time): nebivolol 5 mg as one white round cross-scored tablet and 
amlodipine 5 mg as one white, round tablet, according to Study Protocol. 
Participants with uncontrolled BP are provided with one treatment Patient Kit made up by: 
• NEB 5 mg: one box containing nebivolol 5 mg 42 tablets (3 blisters with 14 tablets). 
• AML 10 mg: one box containing amlodipine 10 mg 42 tablets (3 blisters with 
14 tablets). 
The two boxes are then sealed together into a transparent plastic film in order to realize the 
treatment Patient Kit. 
Trial participant must be carefully instructed by Investigator or designee to take 
simultaneously (at the same time): nebivolol 5 mg as one white round cross-scored, tablet and 
amlodipine 10 mg as one white, round tablet (with one break on one side), according to Study 
Protocol. 
7.2 
Study Treatment Distribution and Return/Destruction 
The PI will be responsible for the management of all study medications to be used for the 
clinical trial.  
An inventory will be maintained by the PI (or designee) to include a signed account of all 
medications received, dispensed to, and returned by each patient at the planned visits.  
An explanation will be given for any discrepancies.  
At the conclusion of the study, the Drug Accountability Form will be completed after a final 
medication supply inventory. 
All supplied (used or unused) study treatment must be accounted for and provided with 
relative return documentation duly filled in, signed, and dated as appropriate.  
Any discrepancy (if any) must be investigated and satisfactorily explained.  


 
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Destruction of study medications will be carried out by manufacturer after written 
authorization of the Sponsor. 
The following paragraph is applicable for all study visits (Visits 2, 3, and 4) except Visit 1 
(screening): 
Due to social restriction measures, the patient may not be able to reach the study site. In such 
cases, the study treatment will not be dispensed to the patients at the site. Instead, the study 
treatment may be distributed to the patients’ home at the times defined in the study flow chart 
by the designated site staff or by a distributor independent from, and acting on behalf of the 
Sponsor in line with national law or temporary national emergency measures. Patients will be 
informed and trained on the new dispensing procedures. Patients will be instructed to keep 
unused/partially used study treatment, which will be collected by the designated site staff on 
the earliest possible time or agreed with the patient to return to site via courier. 
7.3 
Product Storage and Stability 
Nebivolol 5 mg tablets do not require any special storage precautions.  
Amlodipine 5/10 mg tablets: must be stored in the original package in order to protect against 
the light. 
7.4 
Study Product Compliance 
Compliance with study treatment will be assessed at Visit 2 for monotherapy and Visit 3 and 
Visit 4 for the combination therapy. The PI must instruct patients to return the medications at 
each visit. The amount of study medication taken by the patient will be derived by counting 
the number of tablets in the blister returned and will be recorded in the source document and 
in the electronic case report form (eCRF). 
Adherence to treatment will be measured through treatment compliance which will be 
calculated by using the below formula: 
 × 100 


 
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A patient who has taken at least 80% and no more than 120% of the required study 
medication intake since the last visit will be considered as compliant. 
7.5 
Concomitant Therapy(ies) 
Any medication that the patient was receiving at the time of enrolment, and the other regular 
or occasional use of any concomitant medication during the study will be recorded in the 
source documents and in the eCRF. Whenever possible, without jeopardizing the patients 
care, study patients should remain on the same concomitant medication at a stable dose 
throughout the study. In order to facilitate recording of medication history, patients will be 
asked to bring their medication, preferably in their original packaging. 
7.6 
Not permitted medications 
The following drugs modifying BP, even if used for other indications, are considered 
Prohibited medications and the patients will not be permitted to use these medications from 
screening until the end of treatment:   
Blood pressure modifying drugs including  
• Alpha receptor blockers and agonists. 
• Beta receptor blockers and agonists. 
• Calcium antagonists. 
• Angiotensin converting enzyme inhibitors. 
• Diuretics. 
• Centrally acting antihypertensive (eg. clonidine, methyldopa, guanfacine). 
• Reserpine. 
• Moxonidine. 
• Chronic nitrate treatment (eg. isosorbide dinitrate or isosorbide mononitrate). 
• Phosphodiesterase inhibitor and angiotensin II receptor blockers. 
Moreover, special attention should be paid to contraindicated/not-recommended drugs as per 
Nebivolol and Amlodipine SmPCs, in particular the CYP3A4 inductors and inhibitors. 
7.7 
Rescue Medicine 
Not applicable. 


 
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8 
STUDY ASSESSMENT AND PROCEDURES 
8.1 
Assessment of Efficacy 
The efficacy variable is to assess the antihypertensive effect of the extemporaneous 
combination of NEB (5 mg)/AML (5 mg/10 mg) in patients with Grade 1 - 2 hypertension 
versus each monotherapy after 8 weeks of treatment. Data for this variable will be collected 
from BP measurements. 
BP measurements: 
Sitting BP will be measured at all visits. Blood pressure will be measured in both arms at the 
Screening visit (Visit 1) in order to detect possible between-arm differences. The arm with the 
higher mean DBP will be identified at screening and will be used in all subsequent visits for 
BP monitoring. Blood pressure measurements should be performed as nearly as possible at 
the same time of the day (between 7:00 a.m to 12:00 noon), on the same arm, possibly by the 
same site personnel, and using the same calibrated equipment at each visit. 
Patients should be seated comfortably in a quiet environment for 5 minutes before beginning 
BP measurements. Three BP measurements will be recorded, 1 to 2 minutes apart, and 
additional measurements only if the first two readings differ by >10 mmHg. The mean of the 
three recordings in sitting position will be used as the BP value for that visit. All BP 
measurements during the treatment phase will be performed as through readings (ie. 
24 + 2 hour after the last study medication intake). Study medication should be 
administered/consumed on the same time every day during the study; except the days of site 
visits, when study medication should be administered after all assessments mentioned as per 
study flow chart (Section 2.2). At Visit 1 (Week -4) and Visit 4 (Week 8), a 12-lead ECG will 
be performed. 
8.2 
Assessment of Safety 
Safety will be assessed through collection of treatment-emergent AEs, SAEs, AEs of special 
interest (AEOSI)-that start after the first dose of study treatment (analyzed in terms of 
incidence, severity, seriousness, and treatment causality), and physical examination (body 


 
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weight and height), vital signs, BP, and heart rate. Safety assessments will be performed at 
time points as described in Section 2.2.  
8.2.1 Physical Examination 
Physical examination will be performed according to the local practice. Physical examination 
will consist of the following body systems: eyes, ears, nose, throat, cardiovascular system, 
respiratory system, gastrointestinal system, dermatologic system, extremities, musculoskeletal 
system, nervous system, and lymph nodes. Height and weight will also be recorded at 
screening. Any new finding, or worsening of a previous finding, should be reported as a new 
AE. 
8.2.2 Vital Signs 
Vital signs will include body temperature (tympanic measurement), respiratory rate (breaths 
per minute), sitting BP (see Section 8.1), and pulse rate (beats per minute). All BP 
measurements will be performed after at least 10 minutes of rest; in sitting position in 
triplicate (spaced by at least 1 minute), and once in standing position. The mean of the 3 BP 
readings in sitting position will be recorded on the source documents and in the eCRF. Blood 
pressure and pulse measurements will be assessed with a completely automated device. 
8.2.3 Clinical Laboratory Tests 
All samples will be collected in accordance with standard laboratory procedures. The 
maximum volume of blood is approximately 40 mL, which will be the total blood collected 
during the study (Visit 1 and Visit 4). 
A follow-up phone call after Visit 1 and Visit 4 will be performed within 24 hours only in 
case of clinically significant abnormality laboratory tests according to the Investigator 
judgment. 
The local laboratory will perform laboratory tests for hematology and serum chemistry. The 
results of laboratory tests will be returned to the Investigator, who is responsible for 
reviewing and filing these results. 


 
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The following hematology and serum chemistry laboratory tests will be performed at Visit 1 
(Week -4) and Visit 4 (Week 8): 
Hematology 
Serum Chemistry 
Red blood cell 
White blood cell 
Hemoglobin 
Hematocrit 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Platelets 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils absolute  
Lymphocytes absolute 
Monocytes absolute  
Eosinophils absolute 
Basophils absolute 
International Normalized Ratio (INR) 
ALT 
Albumin 
Alkaline phosphatase 
AST  
Direct bilirubin 
Total bilirubin 
Total protein 
Creatinine 
estimated Glomerular Filtration Rate (eGFR) 
Blood urea nitrogen 
Creatine kinase 
Gamma-glutamyl transferase 
Triglycerides 
Cholesterol 
High- and low-density lipoprotein 
Chloride 
Blood glucose 
Potassium 
Lactate dehydrogenase (LDH) 
Uric acid 
Prothrombin Time (PT) 
Partial Thromboplastin Time (PTT) 
Note: Patients with an abnormal renal function (creatinine clearance <30 mL/min) and/or abnormal liver enzyme parameters 
(alanine aminotransferase [ALT] or aspartate aminotransferase [AST] level of >2.5 × upper limit of normal [ULN] or 
total bilirubin level >1.5 × ULN) will be withdrawn from treatment and study. 
8.2.4 Electrocardiograms 
A single 12-lead resting ECG will be recorded after the patient has been in supine position for 
at least 5 minutes to calculate the heart rate and measure PR, QRS, QT, and QTc intervals. 
The results will be recorded in the eCRF. A trained clinical site physician will perform the 
clinical assessment of each 12-lead ECG. Additional 12-lead ECGs will be performed if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of ECGs is required. 


 
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8.2.5 Urine Pregnancy tests 
Urine pregnancy tests (when appropriate) will be performed at Visit 1, 2, 3, and 4, by 
determination of the urine β human chorionic gonadotropine, using locally available 
commercial dipsticks. Unscheduled re-tests can be performed as required according to the 
Investigator’s judgment. 
9 
SAFETY DATA MANAGEMENT 
9.1 
Adverse Event 
An AE is defined as any untoward medical occurrence in a patient or clinical trial patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
9.2 
Drug Relationship 
The causal relationship between an AE and study treatments will be judged according to the 
following categories: 
Certain: The AE occurs in a plausible time relation to the administration of the drug and 
cannot be explained by a concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (dechallenge) should be clinically plausible. The event must be 
definitive pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary. 
Probable: The AE occurs in a reasonable time relation to the administration of the drug, it is 
unlikely to be attributed to a concurrent disease or other drugs or chemicals and it follows a 
clinically reasonable response on withdrawal (dechallenge). Rechallenge information (AE 
reappearance after drug reintroduction) is not required to fulfill this definition. 


 
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Possible: The AE occurs with a reasonable time relation to the administration of the drug, but 
it could also be explained by a concurrent disease or other drugs or chemicals. Information on 
drug withdrawal (dechallenge) may be lacking or unclear. 
Unassessable: The relationship cannot be judged, because of the information is insufficient or 
contradictory and cannot be supplemented or verified. 
Unlikely: A causal relationship cannot be definitively ruled out, but: other drugs, chemicals, 
or underlying disease provide plausible explanations and/or the temporal relation to the 
administration of the drug makes a causal relation improbable. 
Not Related: Any of the following are present: 
• Existence of a clear alternative explanation, and/or 
• Unreasonable temporal relationship between Drug and Event, and/or 
• Non-plausibility. 
9.3 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is any untoward and unintended response to an 
investigational medicinal product (IMP) related to any dose administered. 
The definition implies a reasonable possibility of a causal relationship between the event and 
the IMP. This means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
An ADR is considered any AE for which the relationship is considered as: 
• Certain 
• Probable 
• Possible 
• Unassessable 
An AE is not considered as ADR when the relationship is judged as: 
• Unlikely 


 
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• Not related 
9.4 
Seriousness 
An AE/ADR is considered serious when: 
• Results in death 
• Is life-threatening 
Note: Life-threatening is considered any AE in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect. 
• Is another medically important condition that may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed above. Any suspected 
transmission of an infectious agent via a medicinal product is considered serious and 
should be assessed under the category of medically important events in the absence of 
other seriousness criteria. 
An AE/ADR is considered non-serious when it does not fulfill the conditions for the 
definition of SAE/ADR. 
9.5 
Adverse Event/Adverse Drug Reaction Intensity 
The intensity level of a serious or a non-serious AE or ADR is attributed according to the 
following definitions: 
Mild: does not interfere with routine activities; in case of laboratory tests, when there is a 
mild abnormality. 
Moderate: interferes with the routine activities; in case of laboratory tests, when there is a 
moderate abnormality. 


 
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Severe: makes it impossible to perform routine activities; in case of laboratory tests, when 
there is a significant abnormality. 
9.6 
Adverse Event/Adverse Drug Reaction Expectedness 
An AE/ADR is considered unexpected when the nature, severity, or outcome of the AE/ADR 
is not consistent with the information provided in the Reference Safety Document (SmPC). 
9.7 
Serious Unexpected Adverse Drug Reaction (SUSAR) 
Any SAE judged by the Investigator or the Sponsor as drug-related (see Section 9.3) and 
considered as unexpected qualifies as a SUSAR. 
Serious Unexpected Adverse Drug Reactions are subject to expedited reporting, as specified 
in Section 9.10, as having a “Reasonable Possibility” of relationship with the IMP. 
9.8 
Individual Case Safety Report (ICSR) 
Format and content provided to describe one or several AEs or a disease experience that occur 
to an individual patient at a particular point of time. 
9.9 
Collection, Recording and Reporting of AEs 
At each visit the Investigator will collect and assess any subjective or objective AE occurred 
to each patient after his/her signature of the informed consent. 
Any laboratory test abnormality (newly occurring after the study treatment administration or 
worsening of previously known abnormalities) that the Investigator considers as clinically 
relevant: ie. values significantly above or under normal range or which require an intervention 
or diagnostic tests or may result in the study treatment discontinuation will be reported as an 
AE. 
Any AE(s) communicated by the patient or by the patient’s relatives or delegates through 
phone calls, letters or e-mails will also be collected and assessed. 
The Investigator shall record on the respective eCRF AE recording pages/AE form any 
recognized AE identifying an ICSR, both serious and non-serious, whether or not thought to 


 
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SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                57 
be drug-related, observed in or reported by the patient (or relatives/delegates), specifying the 
judgment on the causal relationship with the study treatment. 
Any available information and diagnostic measure (laboratory and instrumental tests, 
procedures, etc.) shall be recorded in and/or attached to the concerned eCRF pages/sections. 
The Investigator is also expected to record any AE which is ongoing at the last treatment dose 
and a follow-up phone call will be made after 2 weeks from the last study visit. The 
Investigator is expected to follow-up until the outcome of the AE has been determined. 
The Investigator must report all the collected information on any ICSR including seriousness 
(whether or not thought to be related to the investigational drug), providing the concerned 
eCRF AE pages by alert e-mail, after the first knowledge of the occurrence of the case, to: 
CRO Pharmacovigilance Officer: Will be reported through CRO’s Pharmacovigilance group 
(AmNe_SO@IQVIA.com) for which its details will be provided via study guidelines. 
The eCRF pages concerning IMP, medical history, concomitant medication, and laboratory 
tests should also be sent to the Sponsor by e-mail. 
9.10 Management of Serious AEs (SAEs) including laboratory abnormalities 
9.10.1 Reporting Duties of the Investigator 
If the Investigator becomes aware of a SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical trial in a patient 
treated by him or her, the Investigator shall, without undue delay, report the SAE to the 
Sponsor. 
The Investigator must report all the collected information on any serious ICSR (whether or 
not thought to be related to the investigational drug), as specified above, no later than 
24 hours after the first knowledge of the occurrence of the case. 
Any further information and supporting documentation that become available (copies of 
laboratory reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                58 
provided no later than 24 hours after the knowledge, by the Investigator to the CRO by alert 
e-mail, to be forwarded to the Sponsor. 
The Investigator must also comply with the local applicable obligation(s) on the reporting of 
ADRs to the local concerned Regulatory Authority/EC. 
9.10.2 Reporting Duties of the Sponsor 
The Sponsor shall ensure that all relevant information about any SUSAR, is expeditiously 
reported to the competent authorities and ECs as required, with these deadlines after the first 
knowledge, intended as the day when the CRO receives the notification of the SUSAR: 
• Fatal and life-threatening unexpected cases, no later than 7 days. 
• Other unexpected serious cases, no later than 15 days. 
The Sponsor shall ensure that all relevant information and supporting documentation that 
subsequently becomes available, is also expeditiously reported as follow-up information 
according to the above-mentioned deadlines. 
Furthermore, the following safety issues will be subjected to expedited management for the 
identification of possible necessary actions: 
• SAEs associated with the trial procedures. 
• Potential clinically significant findings emerging from non-clinical studies. 
• An anticipated end or suspension for safety reasons of another trial with the same 
study treatment. 
When appropriate and applicable the Sponsor will arrange the adequate information to be 
communicated to the Investigators. 
For trials in high morbidity and/or mortality disease, where efficacy endpoint could also be 
serious unexpected ADR or when a fatal or other serious outcome is the primary efficacy 
endpoint, agreement with competent authority will be reached to treat SAE as disease-related 
and not subjected to expedited reporting. 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                59 
9.11 Management of Non-serious AEs including laboratory abnormalities 
9.11.1 Reporting Duties of the Investigator 
The Investigator must report all the collected information on any non-serious AE ICSR 
(whether or not thought to be related to the investigational drug), as specified above, no later 
than 5 calendar days after the first knowledge of the occurrence of the case. 
Any further information and supporting documentation that become available (copies of 
laboratory reports, tests, procedures, etc.) shall be provided no later than 24 hours after the 
Investigator first becomes aware, to the CRO by e-mail or fax, to be forwarded to the 
Sponsor. 
9.12 Management of any laboratory abnormality 
Any laboratory test abnormality which occurs after IMP administration and is considered by 
the Investigator as an AE, is to be managed as above detailed (refer to Section 9.9). However, 
all “out of range” values should be collected and reviewed periodically (modality to be 
established) by the CRO and the Sponsor. 
9.13 Management of pregnancy exposure cases 
The Investigator is expected to record in the provided form any case of pregnancy exposure 
occurring in a female patient or in a male patient’s partner the treatment and follow-up 
periods, sending it within 5 days after being made aware of the pregnancy, to the CRO by 
e-mail or fax, to be forwarded to the Sponsor. 
The Investigator is requested to follow each case of pregnancy exposure until the outcome. 
If the pregnancy results in an abnormal outcome, this will be recorded in the eCRF as a SAE 
and managed as above described. 
Eligibility of a woman of childbearing potential (WOCBP) will be considered as described in 
Section 6.2.1. A woman is considered fertile following menarche and until becoming 
postmenopausal unless permanently sterile as described below. 


 
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Women in the following categories are not considered WOCBP if: 
• Premenarchal 
• Premenopausal female with one of the following: 
o Documented hysterectomy. 
o Documented bilateral salpingectomy. 
o Documented bilateral oophorectomy. 
Note: Documentation can come from the study site personnel’s review of the patient’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female: A postmenopausal state is defined as no menses for 
12 months without an alternative medical cause. A high follicle stimulating hormone 
(FSH) level to 30 mIU/mL or higher may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. Females on HRT and whose menopausal status is in doubt will be 
required to use one of the non-estrogen hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment. 
10 WITHDRAWAL CRITERIA 
Withdrawal of monotherapies or the study treatment 
Withdrawal from the monotherapies or study treatment refers to any patient who does not 
receive the complete course, ie. when no further planned dose is administered from the date of 
withdrawal. A patient withdrawn from the monotherapies or study treatment may continue 
further study procedures (safety) planned in the Study Protocol, as deemed appropriate by the 
Investigator once the safety of the patient is recovered/reassured. 
A patient’s study treatment or monotherapies may be discontinued for any of the reasons 
below. In addition to the scheduled visits, patient who have been withdrawn from study 
treatment or monotherapies may also undergo additional medical follow-up at the discretion 
of the Investigator. 


 
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CONFIDENTIAL                                                                                                                                                61 
• Any AE, which required treatment termination according to the Investigator's 
judgment. 
• Clinically significant intercurrent illness or laboratory results which could compromise 
the safety of the patient or the scientific value of the study. 
• Investigator deems it to be in the best interest of the patient to discontinue. 
• Requirement to use prohibited medication that could compromise the safety of the 
patient or the scientific value of the study. 
Withdrawal of patient from the study 
The patient may withdraw from the study at any time without explanation, without losing the 
right to future medical care. The participation of the patient may, at any moment, be 
terminated by the Investigator, if considered appropriate. 
A patient can be withdrawn during the study for any of the following reasons: 
• Any AE, which required treatment and study termination for the patient according to 
the Investigator’s judgment. 
• Abnormal renal function or liver enzyme parameters as described in Section 8.2.3. 
• Patient becomes pregnant during the study. 
• Request of the patient (without giving any reason). 
• Investigator deems it to be in the best interest of the patient to discontinue. 
• Failure to adequately comply with the dosing, evaluations, or other requirements of the 
study. 
• If the patient meets an exclusion criterion (newly developed or not previously 
recognized) that precludes further study participation. 
• Use of any prohibited medication that in the opinion of the Investigator or Sponsor 
necessitates the patient being withdrawn. 
The reason for the withdrawal of study treatment, or withdrawal from the study must be well 
documented in the source documents and in the eCRF page and should capture the date and 
the specific underlying reason for discontinuation of study treatment or patient 
discontinuation/withdrawal. 


 
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2.0, CURRENT 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                62 
Patients who discontinue from the study early will be asked, anyway, to complete all the 
assessments of Visit 4. Patients may discontinue the study treatment, but remain in the study 
for follow-up, especially for safety study endpoints (if applicable). 
If a patient has been discontinued/withdrawn due to an AE, the Investigator must immediately 
notify the relevant pharmacovigilance contact (see Section 9.9) and should be followed-up 
until the AE is resolved or the Investigator deems further observations or examinations as no 
longer medically indicated. 
11 LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she fails to return for the scheduled visits 
and is unable to be contacted by the study site staff.  
The site will attempt to contact the patient and reschedule the missed visit and counsel the 
patient on the importance of maintaining the assigned visit schedule and ascertain if the 
patient wishes to and/or should continue in the study. 
Before a patient is deemed lost to follow-up, the Investigator or designee will make every 
effort to regain contact with the patient. These contact attempts should be documented in the 
patient’s medical record or study file. 
12 STATISTIC 
12.1 Statistical Methods (Blinding and Randomization) 
This is an open-label study. In this study all the patients will receive monotherapy in the 
run-in period and combination therapy in the study assessment period. No randomization will 
be required. 
12.2 Determination of Sample Size 
Considering a screen failure and a drop-out rate of 25% from Visit 1 to Visit 4 (End of 
Treatment), the number of patients to be screened are 290. Two-hundred and sixteen patients 
with uncontrolled hypertension, are planned to be included at screening in the assessment 
period lasting for 8 weeks. A total sample size of 216 patients is required to achieve 90% 


 
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Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                63 
power at 5% significance level assuming a difference in mean DBP from baseline to 8 weeks 
of 4 mmHg and a standard deviation (SD) for this difference of 10 mmHg. The mean change 
in DBP for null hypothesis is set at 2 mmHg. 
12.3 Analysis Populations 
In this study, 4 types of analysis population will be used. 
• Enrolled population: Patients who are enrolled into the study (ie. signed ICF and met 
the eligibility criteria) and may or may not receive the study treatment 
(extemporaneous combination). 
• Modified Intent-to-Treat (mITT) population: Patients who are in the Enrolled 
population and receive at least one dose of study treatment (combination therapy) and 
have at least baseline and Week 8 assessments with primary efficacy data. 
• Safety population: Patients who are in the Enrolled population and receive at least 
one dose of study treatment (ie. monotherapy and/or combination therapy). 
• Per-Protocol (PP) population: All patients included in the Safety population who do 
not have any major protocol deviations that could affect the analyses. 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                64 
12.4 Analysis Variables 
Analysis of Variables and Populations Used 
Efficacy 
 
Analysis Variables 
Population Used 
Primary 
efficacy 
Change in mean sitting DBP between Visit 2 (Week 0) and Visit 4 (Week 8). 
mITT population, PP 
population 
Secondary 
efficacy 
Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8). 
mITT population, PP 
Population 
 
• 
Change in mean sitting DBP and SBP between Visit 3 (Week 4) and 4 
(Week 8) in patients under extemporaneous combination of 
NEB/AML 5/5 mg versus patients uptitrated to the extemporaneous 
combination of NEB/AML 5/10 mg. 
• 
Number and proportion of patients achieving the BP goal (sitting 
SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and 
Visit 4 (Week 8). 
mITT population 
 
• 
Adherence to the treatments (% of doses taken/ doses to be taken) at 
Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8). 
Enrolled population, 
Safety population 
 
• 
Safety and tolerability of the monotherapies (NEB 5 mg and AML 
5 mg) and of the extemporaneous combination (NEB 5 mg and AML 
5mg or AML 10 mg). 
Safety population 
Exploratory 
efficacy 
• 
Change in mean sitting DBP and SBP between Visit 1 (Week -4) and 
Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8): 
o 
in the group of patients who were on NEB 5 mg and AML 
5 mg at Visit 1 and continued on the same therapies. 
o 
in the group of patients who switched to NEB 5 mg or AML 
5 mg from any other BBs or CCBs at Visit 1. 
• 
Change in mean sitting DBP and SBP for uncontrolled patients at 
Visit 3 (Week 4), between Visit 2 (Week 0) and Visit 3 (Week 4).  
• 
Number and proportion of patients achieving the BP goal (sitting 
SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and 
Visit 4 (Week 8):  
o 
in the group of patients who were on NEB 5 mg and AML 
5 mg at Visit 1 (Week -4) and continued on the same therapies.  
o 
in the group of patients who switched to NEB 5 mg or AML 
5 mg from any other BBs or CCBs at Visit 1 (Week -4).   
• 
Number and proportion of patients divided into subgroups according 
Enrolled Population 


 
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CONFIDENTIAL                                                                                                                                                65 
to the hypertension grade, the presence of diabetes and/or of 
hypercholesterolemia achieving the BP goal (sitting SBP/DBP 
<130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 
(Week 8): 
o 
in the group of patients who were on NEB 5 mg and AML 
5 mg at Visit 1 (Week -4) and continued on the same therapies.  
o 
in the group of patients, who switched to NEB 5 mg or AML 
5 mg from any other BBs or CCBs at Visit 1 (Week -4). 
Safety  
Incidence, intensity (severity), seriousness of AEs during the study period, 
(screening, run-in period and assessment period), relationship to the study 
treatments, AEOSIs, abnormal/unexpected change in vital signs, ECG (only 
at Visit 1 and Visit 4), Laboratory parameters (if applicable), and use of 
concomitant medications at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 
(Week 8). 
Safety population 
Abbreviations: AE = adverse event; AEOSI = adverse event of special interest; AML = Amlodipine; BB = beta-blocker; BP = blood 
pressure; CCB = calcium channel blocker; DBP = diastolic blood pressure; ECG = electrocardiogram; mITT = modified 
Intent-to-treat; NEB = nebivolol; PP = per-protocol; and SBP = systolic blood pressure. 
12.5 Statistical Analysis 
12.5.1 Descriptive statistics 
Patient disposition, demographics and baseline characteristics will be summarized for 
monotherapy and combination therapy. Medical history will be summarized only for 
monotherapy. Prior and concomitant medications will be summarized for combination 
therapy (NEB + AML).  
Continuous variables will be summarized using the number of non-missing observations, 
mean, SD, minimum, median, and maximum values. Categorical variables will be presented 
with the number of non-missing observations and column percentages (n, %). 
12.5.2 Primary (efficacy) analysis 
The primary efficacy analysis will be conducted on the mITT population. The results will be 
interpreted for the same population.   
The primary endpoint is the change in mean sitting DBP between Visit 2 (Week 0) and Visit 4 
(Week 8). 


 
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The statistical hypothesis will be defined as below: 
H0: There is no change in the sitting DBP prior or post combination therapy. 
H1: There is a difference in the sitting DBP prior or post combination therapy. 
The above hypothesis will be tested as following: 
• Change from baseline in sitting DBP from prior and post combination therapy will be 
tested using paired t-test. The p-value obtained from the paired t-test will be presented. 
• Assumption of Normality will be investigated using Wilk-Shapiro test. If the data is 
found to be non-Normal, the paired t-test will be replaced by Wilcoxon signed rank 
test. 
• The primary endpoint will be summarized descriptively using n, mean, median, SD, 
Q1, Q3, minimum, and maximum. 
Additionally, a repeated measure general linear model (GLM) will be performed on the 
primary efficacy endpoint (change in mean sitting DBP) to test the covariate effects and the 
effects of interactions between the covariates. Age, gender, body mass index, and baseline 
DBP will be included in the GLM model as covariates. The GLM model will be explained in 
detail in the Statistical Analysis Plan (SAP), approved before database lock. 
12.5.3 Sensitivity analysis 
The primary analyses will be conducted using the PP population.  
The PP population will be used to assess the robustness of the results obtained using the mITT 
population. 
12.5.4 Secondary (efficacy) analysis 
Secondary efficacy variables will be summarized in a descriptive manner using both the 
mITT as well as the PP population. 
• Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8). 


 
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Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                67 
• Change in mean sitting DBP and SBP between Visit 3 (Week 4) and Visit 4 (Week 8) 
in patients under extemporaneous combination of NEB/AML 5/5 mg versus patients 
uptitrated to the extemporaneous combination of NEB/AML 5/10 mg. 
• Number and proportion of patients achieving the BP goal (sitting SBP/DBP 
<130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8). 
Change in sitting BP between visits will be compared using paired t-test. The p-value 
obtained from the paired t-test will be presented. Assumption of Normality will be 
investigated using Wilk-Shapiro test. If the data is found to be non-Normal, the paired t-test 
will be replaced by Wilcoxon signed rank test. 
Similar to the primary end point, the secondary end point of change in SBP between Visit 2 
and Visit 4 will be analyzed using a repeated measures GLM. The same covariates as used in 
the primary analysis will be used for this analysis. 
Change in sitting SBP and DBP between patients under extemporaneous combination of 
NEB/AML 5/5 mg versus patients uptitrated to the extemporaneous combination of 
NEB/AML 5/10 mg will be compared using independent samples t-test. If the data is found to 
be non-Normal, the independent samples t-test will be replaced by Wilcoxon rank-sum test. 
The secondary endpoints will also be presented in a descriptive manner using n, mean, 
median, SD, Q1, Q3, minimum, and maximum. 
The number of patients achieving the BP goal (sitting BP <130/80 mmHg) will be 
summarized for Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8) along with 
percentage and 95% CI. A p-value using McNemar’s test will be presented to compare the 
proportion of patients achieving the BP goal (sitting BP ≤130/80 mmHg) between Visit 2 and 
Visit 3, Visit 2 and Visit 4 and, Visit 3 and Visit 4. 
12.5.5 Exploratory (efficacy) analysis 
Exploratory efficacy variables will be summarized in a descriptive manner using enrolled 
population for Visits 1, 2, 3 and 4. 
• Change in mean sitting DBP and SBP between Visit 1 (Week -4) and Visit 2 
(Week 0), Visit 3 (Week 4) and Visit 4 (Week 8): 


 
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CONFIDENTIAL                                                                                                                                                68 
o In the group of patients who were on NEB 5 mg and AML 5 mg at Visit 1 
(Week -4) and continued to be on the same therapies. 
o In the group of patients who switched to NEB 5 mg or AML 5 mg from any 
other BBs or CCBs at Visit 1 (Week -4). 
• To assess change in mean sitting DBP and SBP, for uncontrolled patients at Visit 3 
(Week 4), between Visit 2 (Week 0) and Visit 3 (Week 4). 
• Number and proportion of patients achieving the BP goal (sitting BP <130/80 mmHg) 
at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8):  
o In the group of patients who were on NEB 5 mg and AML 5 mg at Visit 1 
(Week -4) and continued to be on the same therapies. 
o In the group of patients who switched to NEB 5 mg or AML 5 mg from any 
other BBs or CCBs at Visit 1 (Week -4).   
• Number and proportion of patients divided into subgroups according to the 
hypertension grade, the presence of diabetes and/or of hypercholesterolemia achieving 
the BP goal (sitting BP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4), and 
Visit 4 (Week 8). 
o In the group of patients who were on NEB 5 mg and AML 5 mg at Visit 1 
(Week -4) and continued to be on the same therapies. 
o In the group of patients, who switched to NEB 5 mg or AML 5 mg from any 
other BBs or CCBs at Visit 1. 
Change in sitting DBP and SBP between visits will be using paired t-test. The p-value 
obtained from the paired t-test will be presented. Assumption of Normality will be 
investigated using Wilk-Shapiro test. If the data is found to be non-Normal, the paired t-test 
will be replaced by Wilcoxon signed rank test. 
The exploratory endpoints will also be presented in a descriptive manner using n, mean, 
median, SD, Q1, Q3, minimum, and maximum. 
The number of patients achieving BP goal (sitting BP <130/80 mmHg) will be summarized 
for Visits 2, 3, and 4, along with percentage. A p-value using McNemar’s test will be 
presented to compare the proportion of patients achieving the BP goal (sitting BP 
≤130/80 mmHg) between Visit 2 and Visit 3, Visit 2 and Visit 4, and Visit 3 and Visit 4. 


 
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CONFIDENTIAL                                                                                                                                                69 
12.5.6 Safety analysis 
Safety analysis will be based on the safety population.  
Adverse events recorded during the study will be mapped to a system organ class and 
preferred term using the current Medical Dictionary for Regulatory Activities. Treatment-
emergent adverse events are defined as new AEs that occur on or after the date/time of the 
first administration of study medication or worsen if an AE started prior to the start of first 
administration of study medication. 
Summaries will be provided for treatment-emergent adverse event related AEs, SAEs, AEs 
based on their severity, deaths, and AEs leading to discontinuation from study. 
Laboratory, ECG, Physical examination, and Vital signs data will be summarized by each 
visit for absolute values as well as change from baseline. The number of normal, abnormal 
not clinically significant and abnormal clinically significant values on each parameter will be 
summarized for ECG and Physical examination using shift tables. 
12.5.7 Interim analysis and stopping rules 
Not applicable. 
12.5.8 Data imputations 
All analyses will be performed on observed data. Missing data will not be imputed for this 
study. 
12.6 Protocol Deviations and Protocol Amendments 
No deviations from the protocol should be initiated without prior approval by EC/HA of a 
protocol amendment according to applicable Regulations, except in case of emergency or 
when the change involves only logistical or administrative aspects of the trial. 
Any deviation from the protocol, SOPs, Good Clinical Practice (GCP) and applicable 
Regulatory Requirements should be immediately reported to the Sponsor. 


 
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Changes in the Study Protocol will require a protocol amendment. Such amendments will be 
agreed upon and approved in writing by all signatories of the protocol. 
If amendments are substantial, ie. are likely to have an impact on the safety of the patients, or 
to change the interpretation of the scientific documents in support of the conduct of the study, 
or if they are otherwise significant, the ECs and the country authorities (CAs) in the 
participating countries have to approve these amendments before implementation, according 
to applicable Regulatory Requirements. 
Changes which have no significant impact on medical or scientific validity of the study will 
be agreed upon and approved in writing by all signatories of the protocol and the EC/CA will 
be notified of this protocol amendment. 
Any substantial amendments of the protocol will be integrated in an updated Study Protocol. 
The PI must ensure full compliance with the updated Study Protocol. 
12.7 Statistical Analysis Plan 
This study is an open-label study and SAP will be finalized prior to database lock. However, 
in case of any protocol amendment or any modification which may not affect the integrity of 
data or primary analysis but may lead to modification of SAP version, will be finalized prior 
to database lock. The SAP will describe in detail study endpoints and statistical analyses, 
including the analysis of the primary as well as additional endpoints. In case changes to the 
original primary endpoint or of the original primary analyses occurs during the study, these 
changes will be the subject of a substantial protocol amendment. 
All statistical analyses not prespecified and run after database lock will be considered 
additional/exploratory analyses. 
13 STUDY DISCONTINUATION AND CLOSURE 
In case this study gets temporarily suspended or prematurely terminated, written notification, 
documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study patients, Investigators, ECs, Sponsor and Regulatory 
Authorities with the reason(s) for the termination or suspension. 


 
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The study patients will be contacted by the PI (or a designee), as applicable, and be informed 
of changes to study visit schedule. 
Adequate measures will be taken to ensure the safety of the patients. 
14 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must permit study-related monitoring, audits, EC review, and regulatory 
authorities’ inspections and provide direct access to source data/documents. The 
Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study site patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Source 
documents are filed at the Investigator’s study site. 
15 QUALITY CONTROL AND QUALITY ASSURANCE 
15.1 Study Monitoring/Data Quality Control 
Site monitoring is conducted to ensure that the rights and well-being of trial patients are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Council for Harmonisation (ICH)-GCP, and with applicable regulatory 
requirement(s). 
The Investigator will be contacted by the study monitor on a regular basis. The monitor will 
have the responsibility of reviewing the ongoing study with the Investigator to verify 
adherence to the protocol and to deal with any problems. 
The Investigator agrees to allow access to all study materials/source documents needed for the 
proper review of study conduct. The Investigator agrees to assist the monitor in resolving any 
problem that may be detected during the monitoring visit or data cleaning process. 


 
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15.2 Electronic Case Report Forms 
Data collected during the study will be recorded in the eCRF. Data reported on the eCRF have 
to be consistent with the source documents. The Investigator must ensure the accuracy, the 
completeness and the consistency of the data entered in the eCRF. 
On the eCRF, patients will be identified by the patient number/code, assigned at the Screening 
Visit. The patient number/code will be a number composed of numeric values. 
During the conduct of the clinical part of the study, the eCRF must be available and 
up-to-date, so that it always reflects the latest observations on the respective patient. 
The Investigator will be responsible for entering study data into the eCRF in accordance to 
the eCRF user guidelines. 
15.3 Quality Assurance 
All clinical activities conducted under this protocol is subject to GCP regulations. This 
includes audits/inspections by the Sponsor, and/or by national/international HA 
representatives at any time. Principal Investigators must agree to the inspection of the study 
site, facilities, and of study-related records by the HA representatives and/or by the Sponsor, 
and/or its delegates, which must be performed in accordance with national laws concerning 
personal data protection. 
16 ETHICS ASPECTS 
This study will be carried out in compliance with the Study Protocol, the recommendations on 
biomedical research on human subjects of the Declaration of Helsinki, ICH-GCP Guidelines, 
EU-Directives and Regulations (EU REG) (where applicable) and national requirements of 
the participating countries. 
16.1 Ethics Committees 
Before starting the study in a study site, Study Protocol and relevant documentation (Patient 
information leaflet, ICF, the Investigator’s Brochure and other documents, according to 


 
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National Regulations) must be submitted to and approved by the EC and the HAs of the 
participating countries. 
In addition, all local national legal requirements for the conduct of a clinical study have to be 
followed. Any amendment to the protocol will be submitted to the ECs and HAs before 
implementation. 
Furthermore, the HAs and ECs of the participating countries will be informed about the study 
start, the end of the study, or the premature study termination as appropriate and within the 
requested time period. 
16.2 Patient’s Insurance 
For patients participating in the study, Sponsor will issue an insurance policy in accordance 
with local regulatory requirements. 
Details on the insurance company, the insurance number and conditions will be made 
available to patients in the ICF and/or provided as a separate document, in accordance with 
national requirements. The insurance policy will be submitted for approval to the ECs along 
with the other study documents. 
A copy of the insurance certificate will be provided to each Investigator and will be filed in 
the Investigator’s File at the sites and in the study’s Trial Master File (TMF). 
The Investigator must notify to Sponsor immediately upon notice of any claims or lawsuits. 
17 PERSONAL DATA PROTECTION SECTION 
17.1 General Principles on Personal Data Compliance 
All clinical trial information shall be recorded, processed, handled, and stored in such a way 
that it can be accurately reported, interpreted and verified; at the same time, the 
confidentiality of records and of the personal data of the patients shall remain protected in 
accordance with the applicable law on personal data protection such as the EU General Data 
Protection Regulation 679/2016 and the EU Regulation on clinical trials on medicinal 
products for human use 536/2014.  


 
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This section defines the appropriate technical and organizational measures that shall be 
implemented to protect information and personal data processed against unauthorized or 
unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss as well 
as to assure the fulfilment of patients’ privacy rights.  
17.2 Acknowledgment 
The Site, the PI, the local Laboratory, the CRO as well as their appointed staff and service 
providers acknowledge that: (a) the performance of the study will imply processing of 
sensitive personal data; (b) personal data processing is regulated by the applicable European 
(ie. the EU General Data Protection Regulation 679/2016 and the EU Regulation on clinical 
trials on medicinal products for human use 536/2014) and local laws (ie. the laws of the 
country where the study is conducted) as well as by the Sponsor’s national legislation.  
In particular, it is hereby acknowledged that being the Sponsor a company incorporated under 
Italian law, it has to mandatorily comply with Italian legal provisions on data protection: 
therefore the site, the PI, the local laboratory, the CRO shall cooperate with the Sponsor to 
allow the fulfilment of such obligations; (c) strict compliance with the applicable data 
protection laws and this section of the protocol is deemed by the Sponsor as an essential 
condition of collaboration with the site, the PI, the local laboratory, and the CRO. 
17.3 Data Controllers and Data Processors 
The Sponsor, the site, the PI, and the CRO acknowledges that according to the applicable 
privacy laws, the Sponsor and the site will act as independent data controllers while the CRO 
and the PI will act as data processors respectively of the Sponsor and of site. Before the 
beginning of the study, the site will instruct in writing the PI as its data processor*. However, 
if specific local laws or regulations mandate a different definition of the privacy roles, the 
Sponsor, the site, the PI, and the CRO will implement the relevant legal instruments (eg. if 
pursuant to the local laws the Site is a data processor of the Sponsor, a Data Processing 
Agreement will be finalized; if pursuant to the local laws Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalized).  
* for clinical trials where the PIs are the owners of the Site, this provision may not apply. In such cases, the PI might be 
considered as a Data Controller. 


 
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17.4 Duties of the Parties involved in the performance of the study 
Collection and use of patients’ personal data including their biological samples, will be 
carried out in full respect of the provisions of the information notices submitted to patients, as 
well as the privacy rights, the fundamental freedoms and the dignity of data patients. All the 
parties involved in this study undertake to adopt adequate measures to warrant that data will 
always be processed securely and in compliance with privacy laws. The site, the PI, the 
Sponsor, the CRO, and the local laboratory as well as their appointed staff and service 
providers, each in its respective remit and within the limits of their specific role in the study, 
shall implement the following safety measures (physical, logical, organizational, technical, 
electronic, Information Technology [IT] etc.) to ensure adequate protection of the personal 
data of the patients involved in the study. In particular: 
(i) 
DATA SAFETY: 
The site and/or the PI shall adopt all the necessary measures to prevent or minimize the risks 
of theft, fire, flooding, partial or total loss, accidental disclosure or illegal/unauthorized access 
to patient’s data or Sponsor’s proprietary confidential information; to this extent, before the 
beginning of the study, the Site and/or the PI shall ensure that the actual measures they have 
implemented are fit-for purpose and law-compliant, and in particular:  
• The patient diary must be handed in person by the patient. In case the patient is not 
able to hand over the diary personally, collection must be carried out by a secure 
courier, which will collect the diary and deliver it in the hands of the PI or authorized 
staff (ordinary postal mail is prohibited). The patient diary must not include the 
patient’s name but only patient code. 
• In order to minimize the risk of unauthorized access and theft, the hardware on which 
patients’ personal data are stored shall be placed in a restricted-access area, accessible 
only to those individuals who need to retrieve the patients’ personal data included in 
the database for professional purposes; the same safeguards shall be put in place for 
non-electronic databases; 
• Any electronic database containing the patients’ personal data shall be 
password-protected by means of a strong password. Systems shall be set so that 
passwords must be updated at least every three months and feature at least 8 
characters, with upper-case and lower-case recognition, containing at least 3 "special" 


 
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characters, such as upper-case letters [A-Z], lower-case letters [a-z], numbers [0-9], 
symbols [!, #, $, etc.] or other special characters [Á, ë, ö etc.]. Passwords shall not 
include elements which may easily be associated with the assignee or information 
regarding him/her, such as name and year of birth (eg. “johnbrown80”) or easily 
predictable strings of characters (eg. “qwerty”, “12345”, “admin”, “user”, etc.); 
• Adequate cryptographic protection measures shall be put in place for data “at rest” and 
“in transit” (these include, eg. file system or database cryptography, or any other 
equivalent IT measure which renders data unintelligible to those who are not 
authorized to access them); 
• High level security measures shall be implemented also on the files or databases which 
contain the “key” to match the patients’ personal data (ie. name, surname, etc.) with 
their respective “Patient IDs” (as defined at point (iv) below); 
• Backup processes and other measures that ensure rapid restoration of business-critical 
systems shall be implemented; 
• Updated Antivirus and firewall programs shall be installed on the IT devices. 
The site shall, regularly test and update the measures listed above.  
The site shall, upon request from the Sponsor and/or the CRO, provide detailed written 
information about the measures listed above.  
The CRO shall ensure that the selected sites for the study have implemented the above listed 
measures. 
(ii) 
TRANSMISSION OF DATA:  
All the parties that transfer data through internet and/or to the centralized database(s) used to 
process study data or to generate statistical analyses shall implement secure protocols based 
on cryptographic standards which make data unintelligible to unauthorized individuals. 
(iii) 
SECURITY OF THE CENTRALIZED DATA BASE 
The centralized database held by the Sponsor shall have the following safeguards in place: 
• Appropriate authentication methods, which differentiate between different users 
according to their respective roles so as to ensure that access to a specific set of 


 
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patients' data is permitted exclusively to those for whom access to such data is 
essential in the context of their work for the study. 
• Appropriate measures to ensure that the authentication credentials are periodically 
updated (ie. password change). 
(iv) 
PSEUDONYMIZATION 
All personal data that may allow identification of the patients involved in the study shall be 
adequately dissociated from the other data pertaining to the study (“pseudo-anonymization” 
process). The PI shall adequately dissociate the identification data of patients from the data 
pertaining to the study by linking results to a an alphanumerical code [“Patient ID”], whose 
format shall not make it possible to identify the patient directly or indirectly, so as to ensure 
that only anonymous data are transmitted to the Sponsor, the centralized laboratory and/or the 
CRO. The site/PI shall securely store a separate list (eg. identification log) with the 
identification code, together with all signed informed consents, in accordance with the 
security measures as defined above. 
(v) 
SAMPLE STORAGE 
As outlined below, samples shall only be stored for as long as strictly necessary for the 
study’s performance and should be destroyed after the analysis. Biological samples and any 
other examination (eg. X-ray, ECG) shall bear Patient ID, and in no case will they bear other 
information that may lead to the direct or indirect identification of the patient, especially 
when, in accordance with this protocol, samples shall be forwarded and shared outside the 
clinical site (eg. in case of centralized reading or local laboratory analysis). 
(vi) 
TRAINING 
The parties shall ensure that any personnel involved in the study have received proper training 
on data protection issues. All actions related to the implementation of the afore mentioned 
measures shall be provided by the Sponsor, the site and/or the CRO to the competent 
authorities (including data protection authorities) and ECs if and when requested. If such 
authorities or the Sponsor consider the implementation of the afore mentioned measures 
insufficient to guarantee an adequate level of protection of the patients’ personal data, the site, 


 
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the PI, the CRO, and the centralized laboratory undertake to adopt all the necessary activities 
to overcome such remarks to assure the full compliance with the data protection laws. 
17.5 Archiving of the clinical trial master file and code pairing list 
Unless other EU laws require archiving for a longer period, the study site and the PI shall 
archive the content of the clinical TMF, including the relevant patients’ personal data, for at 
least 25 years after the end of the clinical trial. However, medical records shall be archived in 
accordance with the national laws of the country where the study is performed. The patient 
code pairing list (ie. the list that where the Patient ID is linked to the patients’ identification 
data such as name and surname), shall be archived care of the PI. 
The content of the clinical TMF shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
Any transfer of ownership of the content of the clinical TMF shall be documented. The new 
owner shall undertake the responsibilities set out in this protocol. The Sponsor appoints Paolo 
Fabrizzi for cloud data within the Sponsors’ organization as responsible person for archives. 
Access to archives shall be restricted to those individuals and delegates. 
Once mandatory data retention time for the clinical TMF has elapsed, the study site/PI shall 
seek the authorization of the Sponsor to destroy the clinical TMF.  
Data Breach 
Data Breach is an incident regarding personal data security and leading to the accidental or 
unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, personal data 
transmitted, stored, or otherwise processed. In particular: destruction of personal data is where 
the data no longer exists, or no longer exists in a form that is of any use to the Site, Sponsor, 
CRO, PI etc., data loss is when the data may still exist, but the Site, Sponsor, CRO, PI etc. has 
lost control or access to it, or no longer has it in its possession; damage is where personal data 
has been altered, corrupted, or is no longer complete; data unavailability is where, following a 
data incident (such as a network outage, a natural or manmade disaster, etc.), personal data 
become temporarily inaccessible to the Site, Sponsor, CRO, PI etc. 


 
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Anomalous Event is an event that is not part of the standard operational scope of an 
infrastructure, network or service and which affects, or is likely to affect, personal data; this 
may include theft or loss of IT devices and other physical events (eg. an unauthorized access 
to a locked storage room containing paper files with personal data), and/or electronic/IT 
anomalies (eg. cyber-attacks, default or hacking of cloud services), which may in any way 
entail loss, unavailability, alteration, theft, copy or dissemination of personal data.  
Whoever becomes aware in any way of an Anomalous Event and/or of a Data Breach (see 
definitions above) affecting the patients’ personal data and/or personal data collected in the 
context of the study, shall, as appropriate, immediately (and in any case no later than 24 hours 
from the knowledge of an Anomalous Event and/or of a Data Breach) inform the Clinical 
Operations Director, the Sponsor’s Data Protection Officer (DPO), the Site and the CRO 
(CRO responsible persons for Data Breach incidents management) and shall provide the 
following information: 
1. Anomalous Event/Data Breach Type (eg. data loss, unauthorized access, loss of 
company device, etc.). 
2. Person or source that first reported the Anomalous Event/Data Breach. 
3. Date and Time when the person who first reported the Anomalous Event/Data Breach 
became aware of it. 
4. Anomalous Event/Data Breach Date and Time (actual or presumed). 
5. Place (specify if actual or alleged) where the Anomalous Event/Data Breach occurred. 
6. Anomalous Event/Data Breach Description. 
7. Indicate the source of the Anomalous Event/Data Breach (eg. Investigational Product 
source) - (if relevant). 
8. Indicate the affected 
infrastructure/system/application/cloud/software/hardware/database and their location. 
9. List or describe the processing/storage systems affected by the Anomalous Event/Data 
Breach (if relevant). 
10. Number of data patients involved (if known). 
11. Amount of allegedly breached data.  
12. Other relevant information. 
Once all the above information have been provided, the Sponsor and/or the site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal 
data being compromised. 


 
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Then, as appropriate, Sponsor and Site, each one in its respective remit, shall manage the Data 
Breach in accordance with the applicable data protection regulations. 
For Data Breach affecting personal data of patients enrolled within the EU, Sponsor and Site 
autonomously or jointly (depending on the circumstances and their privacy responsibilities as 
defined by the Regulation 679/2016) shall:  
1. Collect the necessary evidence and information. 
2. Categorize the breach. 
3. Determine the risk probability and level to the rights and freedom of the concerned 
patients. 
4. Identify and put in place appropriate remedies to minimize the impact of the Data 
Breach. 
5. Determine the notification and communication duties vis à vis the competent 
supervisory authority and/or the concerned patients. 
17.6 Information notice on personal data protection and pseudo-anonymization 
Prior to patients’ enrolment in the study, the PI and/or the Site (including their personnel) 
shall provide each patient with adequate, law-compliant “information notices and consent 
forms to process personal data” as included in the ICF (or, as the case may be, through a 
separate, specific form) provided by the Sponsor or delegated CRO and shall collect his/her 
written consent to the processing of personal data according to the actual performance 
conditions in which the study is carried out. The PI is responsible to archive the signed ICF in 
accordance with the security measures described above. Among other things, the ICF (or the 
separate form) shall inform patient about: 
1. The applicable data protection legislation. 
2. The kind of data shall be collected during the study listing them in detail or by 
category. 
3. The purpose of data processing (eg. performance of the study, pharmacovigilance) and 
the legal basis. 
4. Whether granting the consent(s) to process personal data is a necessary or an optional 
condition to take part in the study. 
5. The use of data for future scientific researches/secondary use of data (if any). In such a 
case the future scientific purposes/secondary use shall include the future/further 
scientific processing activities/purposes. 


 
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6. The pseudonymization procedure and scope. 
7. Who can access patients’ data and under what circumstances. 
8. The period of data retention/storage as defined in Section 17.4, including the storage 
of the biological sample. 
9. To which entities/countries outside the EU patients’ data will be transmitted (if 
applicable), as per Section 17.5. 
10. Patients’ data protection rights as defined by the EU General Data Protection 
Regulation 679/2016. 
11. Data Controllers/Data Processors and the relevant contact details. 
12. Sponsor’s DPO contacts. 
13. In case of genetic data processing the possible findings, also with regard to unexpected 
findings that might be disclosed on account of the processing of the genetic data. 
17.7 Genetic Data 
Genetic data will not be collected for this study. 
17.8 Transfer of patients’ data outside the European Union 
The study performance entails transferring patients ‘personal data (coded data) outside the 
EU. To this extent, the Sponsor, the site, the PI, the local laboratory, the CRO, undertake to 
export such data in compliance with adequate safeguards/legal basis as required by the 
Regulation 679/2016 including the Commission Decisions, the Standard Contract Clauses, the 
Privacy Shield, and patients’ specific consent. 
17.9 Exercise of patients’ data privacy rights  
Each study patient has the right to contact the Sponsor, the site, the PI, the centralized 
laboratory, the CRO to exercise the rights afforded to the patient by the law, including those 
afforded under articles 15 to 22 of Regulation (EU) 2016/679, namely: knowing whether or 
not any data referring to his/her is being processed in the context of the study; access his/her 
data; verify the data’s content, origin, exactness, location (including, where applicable, the 
non-EU countries where the data might be); obtain a copy of the data including their 
transmission to another entity indicated by the patient; ask that the data are supplemented, 
updated, amended; in the circumstances set forth by the law, ask that the processing of data is 
restricted, that data are anonymized or frozen; oppose to the processing of his/her data for 


 
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legitimate reasons. Each patient has the right to lodge a complaint with his/her local 
supervisory authority and/or to notify to the DPO any use of his/her personal data. Each 
patient is free to withdraw at any time from the study. In such case, each study patient may 
ask the site staff and the PI to destroy/delete his/her personal data (IF APPLICABLE: 
including his/her biological samples, unless they have been permanently anonymized), thus 
preventing any further processing or analysis of his/her data. However, data and results of 
tests that may have been used to determine the results of the study shall not be deleted, to 
avoid altering or impairing altogether the results of the study. If the Site, the PI, the 
centralized laboratory, the CRO receive a request for data privacy rights exercise, the 
concerned recipient shall immediately inform the Sponsor DPO by e-mail at 
dpo@menarini.com. The request shall be fulfilled within the term set forth by the applicable 
privacy laws (normally 30 days). The Sponsor, the site, the PI, the centralized laboratory, and 
the CRO shall implement adequate organizational measures to reply to patients within the 
above-mentioned deadline. 
17.10 Future research 
With patients’ optional and additional consent, the Sponsor and/or the site may use the data 
collected during the course of the study for further medical and scientific research purposes. 
These may include, eg.: retrospective clinical studies; clinical studies pertaining to the 
patients’ pathology/medical condition(s)or similar conditions; studies which compare the data 
of this Study with those from other sources to identify the factors involved in a disease; 
registration of new drugs. 
In the context of these additional research activities, patients’ data will be processed, 
anonymized and transferred abroad, and may be shared with future research partners–in most 
cases this will prevent patient’s identification; however, in the unlikely event patients full 
identity really needs to be disclosed, the same precautions and safeguards as those described 
in this protocol will be implemented. 
18 DATA HANDLING AND RECORDS KEEPING 
Unless other laws require archiving for a longer period, the site and the PI shall archive the 
content of the clinical trial file, including the relevant patients’ personal data, for at least 


 
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25 years after the end of the clinical trial. However, medical records shall be archived in 
accordance with the national laws of the country where the study is performed. 
The Investigator should keep all study-related documents, as specified in ICH E6 (GCP) 
Section 8 and by the applicable regulatory requirement(s), in the Investigator's File. 
The media used to archive the content of the clinical trial file shall be such that the content 
remains complete and legible throughout the period referred to in the first paragraph. Any 
modification to the content of the clinical TMF shall be traceable. 
The content of the Investigator’s File shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. 
The Sponsor must be notified in writing of the name and address of the new custodian. 
19 PUBLICATION POLICY AND RESULTS 
By signing the Study Protocol, the Investigator (and his/her appointed staff) ensures that any 
information and all the study documents provided by the Sponsor will be maintained strictly 
confidential. 
None of this material may be disclosed to any party not directly involved in the study without 
written permission from Sponsor. 
All information concerning the study, the drug as well as data and results of the study are 
confidential and property of the Sponsor. 
The Sponsor will prepare the final report, including the statistical and clinical evaluations, and 
trial results will be posted and made public, according to applicable Regulatory Regulations. 
The Investigator’s agreement and signature will be obtained, and a copy will be provided to 
the Investigator. 


 
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Sponsor reserves the exclusive right to publish and present data and results of the present 
study at scientific meetings, or to submit these clinical trial data to national and international 
Regulatory Authorities. The Investigator may not use the results of this study for publication 
or presentation without written authorization from Sponsor. 


 
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20 REFERENCES 
1. 
Murray et al. Global burden of 87 risk factors in 204 countries and territories, 1990-2019: 
a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 
2020;396:1223–49. 
2. 
A global brief on hypertension. 2013. World Health Organization (WHO). Available at: 
http://www.who.int/cardiovascular_diseases/ 
publications/global_brief_hypertension/en/[Last accessed March 2021]. 
3. 
O’Donnell et al. Cardiovascular risk factors. Insights from Framingham Heart Study Rev 
Esp Cardiol. 2008;61(3):299-310. 
4. 
Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, et al, PURE Study 
Investigators. Prevalence, awareness, treatment, and control of hypertension in rural and 
urban 
communities 
in 
high-, 
middle-, 
and 
low-income 
countries. JAMA. 2013;310:959-68. 
5. 
Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global burden of 
hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 
1990-2015. JAMA. 2017;317:165–82. 
6. 
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 
ESC/ESH guidelines for the management of arterial hypertension: The Task Force for the 
management of arterial hypertension of the European Society of Cardiology and the 
European Society of Hypertension. J Hypertens. 2018;36:1953-2041. 
7. 
Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, et al. Blood 
pressure lowering for prevention of cardiovascular disease and death: a systematic review 
and 
meta-analysis. Lancet. 2016;387 
(10022):957–67. 
doi: 
10.1016/S0140-6736(15)01225-8. Epub 2015 Dec 24. PMID: 26724178. 
8. 
Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome 
incidence in hypertension. Overview, meta-analyses, and meta-regression analyses of 
randomized trials. J Hypertens. 2014;32:2285–95. 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                86 
9. 
Gradman AH, Basile JN, Carter BL, Bakris GL. Combination therapy in hypertension. 
J Clin Hypertens (Greenwich). 2011;13:146‐154. 
10. Cicero et al. A Critical Review of Nebivolol and its Fixed-Dose Combinations in the 
Treatment of Hypertension. Drugs. (2018) 78:1783–1790. 
11. Mensah GA, Bakris G. Treatment and control of high blood pressure in adults. Cardiol 
Clin. 2010;28:609–22. 
12. Summary of product characteristics, Nebivolol. 
13. Summary of product characteristics, Amlodipine. 
14. Taylor BC, Wilt TJ, Welch HG. Impact of diastolic and systolic blood pressure on 
mortality: implications for the definition of "normal". J Gen Intern Med. 
2011;26(7):685-690. doi:10.1007/s11606-011-1660-6. 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                87 
 
21 PROTOCOL APPROVAL PAGE 
Study Title: Open-laBel, multicenter, multinatiOnal, inTerventional clinical Trial to assess 
effIcacy and safety of the extemporaneous Combination of nEbivoLol and amLodipine in 
grade 1-2 hypertensive patIents versus each monotherapy – BOTTICELLI Study 
Code: MEIN/21/AmNe-Hyp/001 
EUDRA-CT number: 2021-005077-10 
 
The signers confirm that they have read and approved the protocol 
 
Study Medical Expert: MARCO MIRODDI 
 
Signature & Date: ____________________________________         29/09/2021 
 
 
Corporate Medical Director: LORENZO MELANI 
 
Signature & Date:                                                                                    29/09/2021 
 
Coordinating Investigator: MASSIMO VOLPE 
 
Signature & Date:   _____/_____/_______ g                                        30/09/2021 
 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                88 
 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                89 
22 INVESTIGATOR’S APPROVAL PAGE 
I understand that all information concerning the product Menarini International Operations 
Luxembourg SA supplied ............................. in connection with this Study Protocol are 
confidential information. This information includes: Study Protocol, Investigator’s Brochure, 
electronic Case Report Form, Other documents 
_________________. 
I understand that any change in this Study Protocol must be approved in writing by Menarini 
International Operations Luxembourg SA and the Coordinating Investigator, submitted to the 
Ethics Committee and HA. 
Authorities before implementation, except where necessary to eliminate apparent immediate 
hazard to patients. 
I confirm that I will conduct the study according to this protocol, the Good Clinical Practice 
(GCP), the Declaration of Helsinki and laws and regulations in the country where the study is 
to be conducted. 
I confirm that I will record and report all adverse events occurring during the study, according 
to this protocol.  
I confirm that I am informed about the need of data records retention, according to current 
regulations and that no data can be destroyed without the written consent of Menarini. 
I confirm that I will transfer adequate ownership of my responsibilities for the trial and will 
inform the Sponsor, in case I retire from my PI role. 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly 
inform the Sponsor and declare it to the competent authorities. 
Principal Investigator: ____________________________________________________ 
 
Signature & Date: _________________________________________________________ 


 
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Protocol Template 
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Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                90 
23 APPENDICES 
Appendix 1: Declaration of Helsinki 
Appendix 2: Management of clinical trial during Pandemic COVID-19 
Since December 2019, an outbreak of respiratory disease caused by a novel coronavirus, first 
detected in Wuhan City, Hubei Province, China, has been detected in nearly all countries of 
the 
world. 
The 
virus 
has 
been 
named 
“severe 
acute 
respiratory 
syndrome 
coronavirus 2 (SARS-CoV-2)” and the disease it causes has been named “Coronavirus 
Disease 2019” (COVID-19). On 08 March 2020, the World Health Organization declared the 
COVID-19 outbreak a global pandemic. 
The COVID-19 public health emergency may impact the conduct of clinical trials of medical 
products. In response to the pandemic, various HA have issued guidelines to maintain the 
integrity of ongoing clinical studies. 
Summary of Changes in Study-
Related Procedures as a Result 
of the COVID-19 Pandemic 
To assure the safety of study patients, maintain compliance with GCP, and 
minimize risks to study integrity, if necessary, the method of assessments 
may be changed at the discretion of the Sponsor. In addition, site visits may 
be replaced with home visits, telephone, or internet-based video-conferencing 
applications. For this study, except in an urgent situation, changes in study 
conduct need to be approved by the Sponsor before being initiated. The 
specific changes to be implemented will be based on the current conditions in 
the country/region and will be reassessed on an ongoing basis. Not all 
countries or all sites in a country may be impacted. Normal procedures, as 
described in this synopsis, will be resumed as soon as possible thereafter. 
This appendix describes the COVID-19 mitigation plans for BOTTICELLI 
study. The following mitigation measures will be implemented in 
study-related procedures as a result of the COVID-19 pandemic. 
Clinical investigators should document in site files and in source documents 
as appropriate how restrictions related to COVID-19 originated changes to 
the study conduct, duration of changes, and which patients were affected by 
such changes. Communications with Sponsor in regard to the implementation 
of the herein described mitigation measures should be documented in the 
source documents. 
Informed consent 
This paragraph is applicable only in case a patient needs to re-consent in 
study participation. Initial informed consent signature must be provided at 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                91 
site during Visit 1 (screening). 
Each patient must be provided with new information that might impact their 
willingness to participate in the study in a timely manner. Should the patient 
need to re-consent if permitted by investigative site procedures and local 
regulations, the informed consent form can be mailed to the patient. 
The patient can sign the consent form at home and mail it to the study site. 
Alternatively, the PI or designee can visit the patient at home to present the 
changes to the study and obtain the informed consent form signature at the 
patient’s home. If the patient has any questions about the changes to the study 
prior to providing their signature, they will be provided with an opportunity 
to discuss these questions with the PI or designee. 
After having obtained the consent, a copy of the signed consent must be sent 
to or stay with the patient. 
Study Treatment Distribution 
and Return 
This paragraph is not applicable for Visit 1 (screening) but only for the 
subsequent visits. 
Due to social restriction measures, the patient may not be able to reach the 
study site. In such cases, the study treatment will not be dispensed to the 
patients at the site. Instead, the study treatment may be distributed to the 
patients’ home at the times defined in the Study flow chart by the designated 
site staff or by a distributor independent from, and acting on behalf of the 
Sponsor in line with national law or temporary national emergency measures. 
Patients will be informed and trained on the new dispensing procedures. 
Patients will be instructed to keep unused study treatment, which will be 
collected by the designated site staff on the earliest possible time or agreed 
with the patient to return to site via courier. 
Study assessment and 
procedures 
The Screening visit is a mandatory in-clinic visit and therefore should be 
performed at the site. The PI continues to be responsible for reviewing all 
study -related assessments. 
The patient may not be able to reach the site to perform blood pressure (BP) 
measurement for primary and secondary analysis, clinical laboratory tests, 
vital sign and physical examination, electrocardiogram (ECG), or other 
assessments required by the study flow chart. In such cases, these 
assessments will be performed by the health care professionals (study staff or 
qualified designee) at patient’s home, if allowed per country regulations.  
Remote Monitoring Visit 
Study monitors may consider ongoing remote data review and remote data 
verification, where applicable and if site agreed with this approach, and if 
allowed per local regulations, to confirm that data entered into the eCRF by 
authorized study site personnel are accurate, complete, and wherever possible 
verifiable from source documents; that the safety and rights of participants 


 
Corporate Medical Department 
Protocol Template 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08 Jan, 2021 
 
Sponsor: Menarini International Operations Luxembourg 
SA 
Study Code: MEIN/21/AmNe-Hyp/001 
Protocol Version_1 of 27/09/2021 
  
 
CONFIDENTIAL                                                                                                                                                92 
are being protected; and that the study is being conducted in accordance with 
the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. The procedures for remote data 
review must be detailed in the monitoring plan.  
Data Quality Assurance 
During the period of travel restrictions or social distancing, the Sponsor may 
implement remote monitoring in place of on-site visits where available and if 
allowed per local regulations, to assure the accuracy and completeness of the 
data captured. Any such monitoring will be performed as per standard IQVIA 
procedures and must documented in the monitoring plan. 
Abbreviations: COVID-19 = Coronavirus Disease 2019; eCRF = electronic case report form; GCP = Good 
Clinical Practice; ICH = International Council for Harmonisation; PI = Principal Investigator. 
 

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PROTOCOL MEIN 21/AmNe-Hyp 001
Statistica! Analysis Pian
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Statistical Analysis Plan
MEIN/21 /AmNe-Hyp/001
Open-laBel, multicenter, multìnatiOnal, inTerventional clinical Trial to assess efficacy and safety
of thè extemporaneous Combination of nEbivoLoI and amLodipine in grade 1-2 hypertensive
patlents versus each monotherapy - BOTTICELLI Study
Author: Aswin Nair
Version Number and Date: Fi al Vl.o, llNov2022
Document: \\ieedc-vnasc01\Biosdata Menarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
Aut or; Aswin Nair Version Number; Final V1.0
Version Date: 11Nov2022
Tempiale No,: CS_TP_BS016 Revision 7 Reference: CS_WI_BS005
Effective Date: 01Nov2021
Copyrig t©2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents ofthis documentare confldential
and proprietary to IQVIA Holdings Ine, and its subsidiaries, Unauthorized use, disclosure or reproduction is stricll  prohibited.
ClinicalTrials.gov - Number - NCT05513937
EudraCT - Number - 2021-005077-10


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Statistical Analysis Plan Signature Page
Statistica! Analysis Pian Final Vl.O (Dated 1 lNov2022) for Protocol MEIN/21/AinNe-Hyp/OOl.
Name
Si nature
Date
(DDMMMYYYY)
A thor:
Aswin Nair
Refer to eSignature
Positioii:
Biostatistician 2
Compa y:
IQVIA
Upon review of this docuinent, thè undersigned approves this version of thè Statistical Analysis
Pian, authorizing that thè content is acceptable for thè reporting of this study.
Name
Si natu e
Date (DDMMMYYYY)
Ap roved By:
Jisho Jose
O  uSl nid  y Jisfv)
09 i f.A jiiwfcvol
November 23, 2022
n d cument
a,»n|3244l MJ$T
Position:
Director, Biostatistics
1  fCmti IS4C<EFC  5«$98E»£66MB5
Comp ny:
IQVIA
Approved By:
Jean Dorothee Muller
Position:
Sr Clin Project M r
Company:
IQVIA
Approved By:
D . Giorgio Reggiardo
.* O cuS rm by ùi iiyo
yfc . . l ffcovof
novembre 22, 2022
T2.7Q?2\
Position:
Biostatistician
FbClF  K46S2 J E  OF 8 AB f E tbC 
Company:
Menarini International Operations- external consultant.
Approved By:
Simone Baldini
DoiuS'gnol  ySIm fìft
n IN
novembre 23, 2022
c9M il d«um«n1o
20221 D  91B WCE. 
Position:
Global Clinical Operations
Company:
Menarini International Operations
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
Author: Aswin Nair Version Number; Final V1.0
Version Date: 11Nov2022
Tempiale No.; CS_TP_BS016 Re ision 7 Reference; CS_WI_BS005
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Modification History
Uniqiie
Identifìer
for this
Version
ate of t è
Document
Version
Author
Si nificant Changes from
Previous Aut orìzed Versio 
Final VI.0
I lNov2022
Aswin Nair
Not Applicable - First Version
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml 22A67778 Biostatistics\Documentation SAP\SAP Menarini ME!N21AmNe-
Hyp001_Final_V1.0
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Version Date: 11 Nov2022
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Statistica! Analysis Pian Page 4 of 39
Table of Contents
1. INTRODUCTION 9
2. STUDY OBJECTIVES AND ESTIMANDS 9
2.1. Primary O jective 9
2.2. Scconda y Objectives       9
2.3. Explor tory O jcctives   10
3. STUDY DESIGN 11
3.1. Gener l Dcsci'iptioii 11
3.2. Schedule ofEvents 12
3.3. Ch nges to Analysis from Protocol 12
4. PLANNED ANALYSES 13
4.1. Fin l A  lysis 13
5. ANALYSIS POPULATION 13
5.1. Enrolied (ENR| Popul tìon 13
5.2. Modificd Intent-to-Treat (mITT) Popiilation 13
5.3. Safety (SAF) Po ulatìon 14
5.4. Per-Protocol (PP) Popul tìon 14
6. GENERAL CONSIDERATIONS 14
6.1. Refe encc Start Date an  Study Day   14
6.2. Baseline     14
6.3. Retes s, Unsche uled Visits  nd   rly Te min tion D t    15
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Versìon Date: 11Nov2022
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6.4. Windowin  Conventions     15
6.5. Statistica! Tests 15
6.6. Common Calcul tions 15
6.7. Software Version 15
7. STATISTICAL CONSEOERATIONS 16
7.1. Adjust ents for Covari tes  nd Factors to be Inclii ed in Analyses 16
7.2. Multicenter Studies 16
7.3. Missing Data 16
7. . Multiple Coniparisons/ Mult  licity   17
7.5. Examination of Subgroups 17
8. OUTPUT PRESENTATIONS   1 
9. DISPOSITION AND WITHDRAWALS 18
9.1. Disposition   18
9.2. Protocol Deviations 18
.3. COVlD-19 IMPACT 18
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 18
10.1. Derivations   19
11. MEDICAL HISTORY AND PROCEDU ES     19
12. CONCUR ENT DISEASE 20
13. PRIOR AND CONCOMITANT MEDICATIONS 20
14. STUDY MEDICATION EXPOSURE 21
14.1. Derivations 21
Document; \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\B ostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
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15. ST DY MEDICATION COMPLIANCE 21
15.1. Derivaflons   21
16. EFFICACY OUTCOMES
22
16.1. Primary Efficacy 22
16.1.1. P imary Efficac  Va iable & Derivation 22
16.1.2. Intercurrenl Event Mandling and Data Imputation fo   rimary Efficacy Variable 22
16.1.3. Primary Anaiysis of P imary Efficacy Va iable 22
16.1.4. Supplementary Anaiysis of Primary Efficacy Variable 23
16.1.5. Sensitivity Anaiysis of P imaiy Efficacy Va iable(s) 23
16.2. Secon ai  Efficac  23
16.2.1. Secondaiy Efficacy Variables & Derivations 23
16.2.2. Anaiysis of Secondary Efficacy Variables 24
16.2.2.3. Nu ber and pro oilion of patients achieving thè B  goal 25
16.3. Ex loratory Efficacy 25
16.3.1. Explo ato y Efficacy Variables & Derivations 25
16.3.2. An iysis of Exploratory Efficacy Variables 26
17.
18.
QUALITY OF LIFE ANALYSIS 
SAFETY OUTCOMES 
26
26
18.1. Adverse Events 
18.1.1. AllTEAEs 
18.1.1.1. Seve ity 
18.1.1.2. Relationship to Study Medication  
18.1.2.  FEAEs Leading to Discontinuation of Study Medication 
18.1.3. Se ious Adverse Events 
18.1.4. Adve se Events Leading lo Death 
...27
..27
..27
..28
..28
..28
18.2.
Dcaths 
18.3.
Laborator  Evaliia ìons 
18.4.
ECG Ev luations 
18.5.
VUal Sì ns 
18. .
Pliysic l Examin tion 
18.7.
Other S fety Assesstnents..,
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19. DATA NOT SUMMARIZED OR PRESENTED 30
20. REFERENCES   32
APPENDIX 1. PROGRAMMING CONVENTIONS FOR O TPUTS 33
APPENDIX 2. PARTIAL DATE CONVENTIONS 37
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List of Abbrevi tions
Abbreviatioii
Terni
AE
Adverse Event
AML
Amlodipine
ATC
Anatomical Therapeutic Chemical
BBs
Beta-Blockers
BP
Blood Pressure
CCBs
Calcium Channel Blockers
COVID-19
Coronavirus Disease 2019
DBP
Diastolic Blood Pressure
DMC
Data Monitorin  Committee
ECG
Electroca dio ram
eCRF
Electronic Case Report Form
ENR
Enrolled
GLM
General linear model
IGF
Informed Consent Form
mITT
Modified Intent-to-treat
NEB
Nebivolol
PP
Per-Protocol
SAE
Serious Adverse Events
SAP
Statistica  Analysis Pian
SBP
Systolic Blood Pressure
SD
Standard Deviation
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
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Version Date: 11Nov2022
Tempiale No.: CS_TP_BS016 Revision 7 Reference: CS_WI_BS005
Effective Date: 01Nov2021
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1. INTRODUCTION
This statistic ! analysis pian (SAP) describes thè rules and conventions to be used in thè
presentation and analysis of efficacy and safety data for Protocol MEIN/21/AmNe-Hyp/OOI. It
describes thè data to be summarized  nd analyzed, including specifics of thè statistica! analyses to
be performed.
This SAP is based on protocol version I.O, dated 27 September 2021.
2. Study Objectives and Estimands
2.1.Primary Objective
The primaiy objective is to assess thè antihypertensive efficacy of thè extemporaneous
combination of nebivolol (NEB) 5 mg with amlodipine (AML) 5 mg or AML 10 mg in lowering
thè sitting DBP faetween Visit 2 (Wee  0) and Visit 4 (Week 8) in patients with uncontrolled BP,
previously treated with NEB 5 mg or AML 5 mg monotherapies for at le st 4 weeks.
2.2.Secondary Objectives
The secondary objectives are
• To assess thè antihypertensive efficacy of thè extemporaneous combination of NEB 5 mg with
AML 5 mg or AML 10 mg in lowering sitting SBP between Visit 2 (Week 0) and Visit 4
(Week 8) in patients with uncontrolled BP previously treated with NEB 5 mg or AML 5 mg
monotherapies for at least 4 weeks.
• To assess thè antihypertensive efficacy ofthe extemporaneous combination ofNEB/AML 5/10
mg versus extemporaneous combination NEB/AML 5/5 mg, in lowering sitting DBP and SBP
between Visit 3 (Week 4) and Visit 4 (Week 8) in patients with uncontrolled BP previously
treated with NEB 5 mg or AML 5 mg monotherapies for at least 4 weeks.
• To assess thè antihypertensive efficacy of thè extemporaneous combination of NEB 5 mg with
AML 5 mg or AML 10 mg by evaluating thè patients who achieve BP goal (sitting BP < 130/80
mmHg) at Visit 2 (Week 0), at Visit 3 (Week 4), and at Visit 4 (Week 8).
• To assess thè compliance to thè treatment (percentage of actual doses taken ve sus doses to be
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Version Date:
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Page 10 of 39
taken) at Visit 2 (Week 0), at Visit 3 (Week 4), and at Visit 4 (Week 8).
• To evaluate thè safety and tolerability of thè monotherapies (NEB 5 mg and AML 5 mg) and
of thè extemporaneous combinations (NEB 5 mg  nd AML 5mg or AML 10 mg) after 8 weeks
of treatment.
2.3.Exploratory Objectives
The exploratory objectives are
• To assess change in mean sittìng DBF and SBP between Visit 1 (Week -4) and Visit 2 (Week
0), Visit 3 (Week 4) and Visit 4 (Week 8):
1. In thè g oup of patients who were on NEB 5 mg and AML 5 mg at Visit I and continued
to be on thè same therapies.
2. In thè group of patients who switched to NEB 5 mg or AML 5 mg from  ny other BBs
or CCBs at Visit I.
• To assess thè change in mean sitting DBF and SBP between Visit 2 (Week 0) and Visit 3
(Week 4) for imcontrolied patients at Visit 3 (Week 4).
• To assess thè antihypertensive efficacy of thè extemporaneous combination of NEB 5 mg with
AML 5 mg or AML 10 mg by evaluating thè number of patients achieving thè BP goal (sitting
BP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8):
1. In thè group of patients who were on NEB 5 mg and AML 5 mg at Visit 1 (Week -4)
and continued to be on thè same therapies.
2. In thè group of patients who switched to NEB 5 mg or AML 5 mg from any other BBs
or CCBs at Visit 1 (Week -4).
• To assess thè antihypertensive efficacy of thè extemporaneous combination of NEB 5 mg with
AML 5 mg or AML 10 mg by evaluating thè number of patients divided into subgroups
ccording to thei  hypeitension g ade, thè presence of diabetes and/or of hypercholesterolemia
achieving thè BP goal (sitting BP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Wee  4), and
Visit 4 (Week 8);
1. In thè group of patients who were on NEB 5 mg and AML 5 mg at Visit 1 and continued
to be on thè same therapies.
2. In thè group of patients, who switched to NEB 5 mg or AML 5 mg from any other BBs
or CCBs at Visit 1.
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Author: Aswìn Nair Version Number: Final VI .0
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3. Study Design
3.1.Gener l Descrìptìoii
This is a Phase IV, interventional, open-Iabel, multicenter, multinational study wìth 2 study periods
(a run-in period of 4 weeks and an assessment period of 8 weeks). Patients with hypertension with
systolic blood pressure (SBP) ranging from >140 to <179 inmHg and diastolic blood p essure
(DBP)  anging from >90 to <109 mmHg on treatment with any beta-biockers (BBs) or c lciu 
channel blockers (CCBs)c inciuding NEB 5 mg or AML 5 mg for at least one  onth prior to Visit
1 will be screened for eligibiiity. Onthe sameday ofthe Screening visit, eligible patients will enter
into a run-in period after screening, during  hich:
• Patients receiving NEB 5 mg or AML 5 mg will continue thè same therapy for 4 weeks.
• Patients on any other BBs or CCBsc will be switched to NEB 5 mg or AML 5 mg.
Patients ente ing this phase in therapy with NEB 5 mg or AML 5 mg shouid be in a 1:1 ratio. After
4 weeks (±2 days) of  un-in period of monotherapy, BP will be further assessed at Visit 2. Patients
with uncont olled BP levels (sitting SBP/DBP >130/80 mmHg) at Visit 2, with thè t eatment
adherence (ranging between 80% to 120%) who did tolerate thè treatment will enter into thè
assessment period and will be assigned to thè extemporaneous combination of  EB 5 mg and
AML 5 mg. Patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg) and/or who do
not tolerate thè treatment or bave an adherence range below 80% or above 120%, will be
withdrawn from thè study. After 4 weeks ±2 days in thè assessment period, patients BP will be
urther evalu ted at Visit 3: patients with controlled BP levels (sitting SBP/DBP <130/80 mmHg)
will continue thè same extemporaneous combination, while patients with uncontrolled BP levels
will be uptit ated from exte poraneous combination NEB/AML 5/5 mg to extemporaneous
combination of NEB/AML 5/10 mg for further 4 weeks. At thè end of thè assessment period (8
weeks ±4 days), Visit 4 will take place. To correctly evaluate thè additional effect of thè
combination therapy, thè number of patients with uncontrolled BP on NEB or AML monotherapy
needs to be balanced at Visit 2. In order to maintain a 1:1  atio during thè assessment period, a cap
of 110 patients for each treatment arm (ie. NEB an  AML) will be included at Visit 2 in order to
maintain a balanced number of uncontrolled patients entering thè assessment period for each drug.
The evaluation will be done every 50 patients. If thè rate of entrance in thè assessment period for
one of thè 2 tested drugs will deviate more than 5%, a corrective measure will be initiated:
according to thè en olment site statistics, one or mo e sites will be informed to en oll a greater
Document; \\ieedc-vnasc01 Biosdata\Menarini\NebAml\ZZA67778 Biostatis ics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
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number of patients being treated with thè least represented drug in thè assessment period. A total
number of290 patients will be screened considering 25% of drop-out rate, to obtain approximately
216 completed patients at thè end of thè study (Visit 4).
3.2.Schediile of Events
Schedule of events can be found in Section 2.2 of thè protocol.
3.3.Ch nges to Analysis from Protocol
• The secondary and ex loratory analysis use McNema  s test to analyze proportion of patients
achieving BP go l (SBP/DBP <130/80 mmHg) between visit 2, visit 3, and visit 4. As per thè
entry criteria to thè combination therapy, oniy those patients with uncontrolled BP (SBP/DBP
> =130/80 mmHg) at visit 2 are eligible. So, thè proportion of patients achieving thè BP goal
at visit 2  ill be always zero. Thus, SAP has been updated with exact McNemar s test instead
of McNe ar’s test when comparing thè counts with respect to visit 2.
• As per protocol, thè definition of Per Protocol Population is  All patients included in thè Safety
population who do not have any major protocol deviations that could affect thè analyses. . In
SAP, this has been updated to,
“The Pe -Protocol (PP) population will contain all patients included in thè Safety population
who do not have any major protocol deviations that could affect thè primary efficacy analyses
and have at least baseline (Week 0) and Week 8 assessments with primary efficacy data .
• As per p otocol, thè definition of ENR Population is “Patients who are enrolied into thè study
(ie. signed IGF and met thè eligibility criteria) and may or may not receive thè study treatment
(extempo aneous combination).  In SAP, this has been updated to,
“The Enrolied (ENR) population will contain all patients who are enrolied into thè study (i.e.
signed IGF and met thè eligibility criteria) and may or may not receive thè study medication
(i.e., monotherapy and/or combination therapy). An enrolied patient who does not meet thè
inclusion/exclusion criteria might be included in thè ENR population as per thè investigato! 
discretion. .
• As per protocol, Gompliance to study medication will be summarized for Enrolied and Safety
populatìons. In SAP, this has been updated to consider thè summary based on SAP and mITT
because Safety population will include monotherapy patients and thus analysis on ENR is not
required.
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostalislics\Documentalion\SAP\SAP_Menarini_MEIN21AmNe-
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Author: Aswin Nair Version Number; Final VI .0
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Tempiale  o,: CS_TP_BS016 Revlsion 7 Reference: CS_WI_BS005
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• As per protocol, expioratory efficacy analyses will be summarized for Enrolled population. In
SAP, this has been updated to include summary based on mITT population as well.
4. Planned Analyses
The following analyses will be performed for this study:
• Final Anaiysis
4.1. Fin l Anaiysis
All final, planned analyses identified in this SAP will be peiformed by IQVIA Biostatistics
following Sponsor Authorization of this Statistica  Anaiysis Pian, Database Lock, Sponsor
Aiithorization of Anaiysis Popiilations.
5. Analysis Population
Agreement and authorization of patients included/excluded frora each analysis pop lation will be
conducted prior to thè database lock of thè study.
5.1. Enrolled [ENR| Population
The Enrolled (ENR) population will contain all patients who are enrolled into thè study (i.e. signed
ICF and met thè eligibility criteria) and may or may not receive thè study medication (i.e.,
monotherapy and/or combination therapy). An en olled patient who does not meet thè
inclusion/exclusion criteria might be included in thè ENR population  s per thè investigator
discretion.
5.2. Modified Intent-to-Treat (mlTT) Popul tion
The Modified Intent-to-Treat (mITT) population will contain all patients who are in thè Enrolled
population, receive at least one dose of combination therapy, and have at least baseline and Week
8 assessments with primary efficacy data.
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778 Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
Aut or: Aswin Nair Version Number: Final VI.0
Version Date; 11No 2022
Tempiale No.: CS_TP_BS016 Revìsion 7 Reference: CS_WI_BS005
Effective Date: 01Nov2021
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5.3.Safet  (SAF) Popiilation
The Safety population  ill contain all patients who are in thè Enrolled population a d receive at
least one dose of study medication (i.e., monotherapy and/or combination therapy).
5.4.Per-ProtocoI (PP) Population
The Per-Protocol (PP) population will contain all patients included in thè Safety population who
do not bave any major protocol deviations that couid affect thè primary efficacy analyses and bave
at least baseline (Week 0) and Week 8 assessments with primary effìcacy data.
6. General Considerations
ó.l.Reference Start Date and Study Day
Study Day will be calculated from thè  eference start date and will be used to show start/stop day
of assessments and events. It will appea  in every listing where an assessment date or event date
appears.
Reference start date is defined as thè day of thè first dose of study (combination therapy) (Visit 2),
(Day 1 is thè day of thè fi st dose of study d ug).
• If thè date of thè event is on o  after thè reference date, then:
• Study Day = (date of event - reference date) + 1.
• If thè date of thè event is prior to thè reference date, then:
• Study Day = (date of event - reference date).
In thè situation where thè event date is partial or missing, Study Day, and any corresponding
durations will appear partial o  missing in thè listings.
6.2.Baseline
Unless otherwise specifie , baseline is defined as thè last non-missing measurement taken same
day o  prior to reference start date (including unscheduied assessments) before first dose of study
medication (i.e., combination therapy). Adverse Events (AEs) and medications commencing on
Document; \\ieedc- nasc01\Biosdata lenarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
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thè reference start d te/time will be considered post-base!ine, unless thè start time of thè AE is
known to be prior to thè first dosing of thè study drug. SInce there is no Lab assessment in Visit 2,
Lab valiies collected at Visit 1 will be considered baseline for Lab data.
Por combination therapy related analysis, thè baseline will be thè measurements that are t  en at
Visit 2 (Week 0). For safety analysis, if thè measurement at visit 2 is missing or not collected, then
visit 1 data will be considered.
6.3. Retests, Unscheduled Visits and Early Termination D ta
In generai, fo  by-visit summaries, data recorded at thè nominai visit will be presented.
Unscheduled measurements will not be included in by-visit summaries. Listings will include
scheduled, unscheduled, retest and early discontinuation data.
6.4. Win owing Conventions
No visit window conventions are applicable for this study.
6.5.Statistical Tests
The default significant levei will be (5%); confidence inte vals will be 95% and all tests will be
two-sided, unless othewise specified in thè description of thè analyses.
6.6.Common Calculatìons
For quantitative measurements, change from baseline will be calciilated as;
• Test Value at Visit X - Baseline Vai e
And for change between Visit 3 and Visit 4 will be calculated as:
• Test Value at Visit 4 - Visit 3 Value
6.7.Software Version
All analyses will be conducted using SAS Enterprise Guide version 8.2.
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Hyp001_Final_V1.0
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Tempiale No.: CS_TP_BS016 Revision 7 Reference; CS_WI_BS005
Effective Date: 01No 2021
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7. Statistical Considerations
Summaries will include descriptive statistics for continuous variables (sample size [n], mean,
standard deviation [SD], median, minim m and maximum) and for categorica! va iables
(fi-cquency [n] and percentage), uniess otherwise stated in thè relevant section. Pe centages will be
based on thè number of patients within thè relevant an lysis population and treatment arm, or thè
number of patients with data available  here relevant.
If thè o iginai data has N decimai places, then thè summary statistics will have thè following
decimai places;
Minimu  and maximum: N
Mean, median, QI, Q3, confidence intervals, ratios: N + 1
Percentages will be reported to one decimai place. P-values should be reported to three decimai
places, except values <1.000 but >0.999 will be   esented as  >0.999  (e.g., 0.9998 is presented as
>0.999); and values <0.001 will be p esented as  <0.001   (e.g., 0.0009 is presented  s <0.001 )
T.l.Adjustments for Covariates and Factors to be Included in Analyses
The following cova iates/factors are used in thè analyses.
• 3'rcatment
• Age
• Gender
• Body Mass Index
• Baseline DBP
7.2. Multicenter Studìes
This study will be conducted by multiple investigators at multiple centers internationally. Center
pooling will not be carried out fo  use in analyses for this study.
7.3. Missin  Dat 
All analyses will be perfor ed on obse ved dat . Missing data will not be imputed for this study.
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
SD:N + 2
Hyp001_Final_V1.0
Aulhor: Aswin Nair
Version Number;
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Version Date:
11NOV2022
Tempiale No.: CS_TP_BS016 Re ision 7
Effective Date: 01Nov2021
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7.4. MuItipIe Comparisons/ Multìplìcìty
Not Applicable
7.5. E amination of Siibgroups
Subgroup anaiyses will be conducted as stated in thè exploratory analysis sections. It should be
noted that thè study was not designed to detect treatment differences with high statistica! power
within subgroups.
The following subgroups will be assessed and described within thè exploratory analysis sections
on ENR and mITT populations respectively.
• Hypertension grade at screening
• Presence of diabetes (patients with or without diabetes) at screening
• Presence of hypercholesterolemia (patients with or without hypercholesterolemia) at screening
Hypertension grade at screening is derived as follows;
- 140<=SBP< 160or90<=DBP<I00
- 160<=SBP< 180or 100< DBP<I10
Patients with presence of diabetes and hypercholesterolemia at screening will be identified from
thè medicai history data using thè preferred terms. Presence of diabetes can be identified using thè
preferred terms  Diabetes mellitus" Or “Type 2 diabetes mellitus" and hype cholesterolemia using
Dyslipidaemia  o   Hypercholesterolaemia  or “Hype Upid emi   or “Type Ila
hyperlipidaemia  or “Type V hyperlipidaemia .
Patients with hypercholesterolemia at screening can be identified based on thè clinica! significance
of thè total cholesterol vai e collected in thè blood chemistry laboratory data. If thè total
choiesterol at screening has clinical significance as per thè investigator s input, then thè patient
will be considered for hypercholesterolemia and thè details will be entered in thè medicai history
Appendix 1 shows conventions for presentation of data in outputs.
The templates provided with this SAP describe thè presentations for this study and therefore thè
format and content of thè summary tables, figures, and listings to be provided by IQVIA
Biostatistics.
Document: \ ieedc- nasc01\Biosdata\Menarini\Ne Aml\ZZA67778\Biostatistics\Docurrìentation\SAP\SAP_Menarini_MEIN21AmNe-
data.
8. Output Pr sentations
Hyp001_Final_V1,0
Author; Aswin Nair
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9. DISPOSITION AND WiTHDRAWA S
All patients who provide informed consent will be accoiinted for in this study.
9.1. Disposition
Patient disposition and withdrawals will be presented for All Patients.
Number of patients in each popiilation, including reasons for e cliision, will be presented fo  ENR
popiilation.
A listing of inclusion and exclusion criteria will be presented for thè Screen Failures.
9.2. ProtocoI Deviations
All protocol deviations (PD) will be discussed and reviewed on a case-by-case basis before thè
DBL at thè data review meeting. All PDs reviewed by Sponsor will be documented.
Individuai PDs will be p esented in a data listing. The number and percentage of patients with
Critical/Majo  PDs will be summarized by devi tion on ENR population. PD summary will be
ciassified into  Monothe apy  and  Combination The apy  based on thè incidence date of PD.
Addition l Criticai, Major and Minor PDs may be identified during data review and will be agreed
upon with thè Sponsor and reflected in thè Table and Listing as appropriate.
All PDs will be recorded and ciassified in Clinìcal Trial Management System (CTMS) before thè
Data review Meeting.
The impact of COVID-19 on study related procedures are collected on  COVID-19 Impact Log 
in eCRF. Impact Information which includes Assessment/Procedure Imp cted, Type of Impact,
and Reason for Impact will be  resented in a summary table and a data listing for ENR population.
10. Demographic and other Baseline Characteristics
Demogl'aphic data and other baseline characteristics will be presented for thè ENR population.
No statistica  testing will be car ied out for demographic or other baseline characteristics.
Document: \\ieedc- nasc01 Biosdata\Menarini NebAml\ZZA67778\Biostatistics\Documentation\SAP SAP Menarini MEIN21AmNe-
9.3.COVID-19 IMPACT
Hyp001_Final_V1,0
Author: Aswin Nair
Version Number:
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Tempiale No.: CS_TP_BS016 Revision 7
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The following demographic and other baseline characteristics will be reported for this study:
• Age (years)
• Age Category (<40 Years, >40 Years)
• Sex
• Childbearing potential
• Race
• Hypertensive Medication status at Screening (Visit 1)
- NEB 5mg or AML 5 mg
Other BBs or CCBs
• Weight (kg)
• Height (cm)
• BMI (kg m )
• Presence of Type 2 diabetes mellitus at Screening (Yes/No)
• Hypertension grade at Screening
• Presence of Hypercholesterolemia at Screening (with Hyperchoiesterolemia/ without
Hypercholesterolemia)
• Mean sitting DBF at Screening (mmHg)
• Mean sitting SBP at Screening (m Hg)
10.1. Derivations
• BM) (kg/ m ) =  eight (kg)/ height (m) 
Medicai History information will be presented by Monotherapy for thè ENR Popiilation.
• Medicai History data captured on eCRF form  Medicai Histoiy/Concurrent Diseases  will be
coded using Medicai Dictionary for Regulatory Activities ( edDRA, Version 24.1 or latest)
dictionaiy
o Medic i History conditions are defmed as those conditions whìch stopped prior to or
at Screening.
o Presented by SOC and PT.
A sepa ate listing for Medicai Procedu es information collected on eCRF form “Medicai
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11. Medical History and Procedures
Hyp001„Final_V1.0
Author: Aswin Nair
Version Number;
Final V1.0
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Effective Date: 01Nov2021
Version Date:
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11NOV2022
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rocedures  will be presented by Monotherapy forthe ENR Population.
12. CONCURRENT DiSEASE
Concurrent Disease will be presented for thè SAP population.
• Concurrent Diseases  ill be coded using Medicai Diction ry for Regulatory Activities
(MedDRA, Ve sion 24.1 ) dictionary
o Concurrent Diseases a e conditions started prior to or at Screening and are ongoing at
thè date of Screening,
o Presented by SOC and PT.
o Concurrent Diseases conditions are defined as those conditions recorded in thè eCRF
forni  Medicai History/Concurrent Diseases .
13. PRIOR AND CONCOMITANT MEDICATIONS
Medications, recorded in thè eCRF forni  Prior and Concomitant Medications , will be presented
for thè SAP population a d coded using WHO Drug dictionary Version 01SEP2020 or latest.
Frequency tabulations will be presented for prior and concomitant medications by primary
therapeutic subgroup (3rd level ATC code) and p eferred name for Monotherapy and Combination
Therapy.
See Appendix 2 for handling of partial dates for medications, in thè case where it is not possible
to define a medication as prior, concomitant, or post treatment, thè medication will be classified
by thè worst case, i.e., concomit nt.
•  Prior  medications are medications which started and stopped p io  to thè first dose of
monotherapy.
•  Concomitant  medications are medications which:
o started prior to, on or after thè first dose of study medication,
o AND ended on or after thè date of first dose of study medication or were ongoing at
thè end of thè study.
o Concomitant medications that a e started prior to thè first dose of Combination Therapy
will be summarized unde  “Monothe apy”.
o Concomitant medications that are started after thè first dose of Combination The apy
will be summarized under “Combination Therapy”.
Document: \ ieedc-vnasc01 Biosdata\Menarini NebAml\ZZA677 8\Biostatistics\Documentalion\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
Author: Aswin Nair Version Number: Final V1.0
Version Date:
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14. Study Medication Exposure
Exposiire to study medication for both Monotlierapy and Combination therapy in days wili be
presented for thè SAP populatio .
The date of first study medication adniinistration will be taken from thè eCRF  Exposure  forni.
The date of l st study medication will be taken from thè eCRF  End of Study Treatment  form.
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.
14.1. Derivations
Duration of exposure (days) = date of last study medication adniinistration   date of fìrst study
medication administration + 1.
15. Study Medication Compliance
Compliance to study medication (i.e., monotherapy and/or combination therapy) will be presented
for thè mITT and SAF populations.
A table consisting of summary statistics for percent compliance along with thè number an  percent
of patìents with complia ce in each of thè following groups:
Low: percentage of compliance <80%
- Normal: percentage of compliance =>80% - <=120%
High: percentage of compliance > 120%
on SAF population for Monotherapy, and mITT as well as SAF populations for Combination
Therapy. By visit (Visit2 and Visit 3) and overall compliance will be produced for Combination
Therapy.
A listing of drug accountability  ill be presented on  lTT and SAF populations by phase to
account for all drug distributed to each patient, including thè box number, total number tablets
dispensed, retu ned, consumed, lost (if any), percentage compliance and compliant (yes/no).
15.1. Derivations
Monotherapy and Combin tion Therapy compliance with study drug based on thè drug
accountability data will be calculated as thè number of tablets taken x 100 / expected number of
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tablets which shouid bave been taken expressed as a percentage.
Por Monotherapy, thè expected number of tablets to be taken = (Treatment End Date - Treatment
Start Date) + 1.
Por Combination Therapy, thè expected number of tablets to be taken = 2 * ((Treatment End Date
- Treatment Start Date) + 1).
Por patients who permanently stop thè study medication (i.e., monotherapy and/or combination
therapy), thè e pected numbe  of tablets will be calculated up-to thè date of study withdrawal.
16. Efficacy Outcomes
16.1. Primary Efficac 
16.1.1. Primaiy Efficacy V riable & Derivation
The p ima y efficacy variable is Change in mean sitting DBP between Visit 2 (Week 0) and Visit
4 (Week 8).
16.1.2. Iiifercurrent Evenf Handiin  and Data Imputatìon for Primaiy Efficacy Variable
Not Applicable.
16.1.3. Primaiy Analysis of Primaiy Efficacy Vari ble
The primary objective of this study is to test thè hypothesis that
HO: The e is no change in thè sitting DBP prior or post combination therapy.
HI : There is a difference in thè sitting DBP prior o  post combination therapy.
The primary efficacy analysis will be performed for thè mITT population. The above hypothesis
will be tested as following:
• Change f o  baseline in sitting DBP from prior and post combination therapy will be tested
using paired t-test. The p-value obtained from thè paired t-test will be presented.
• Assumption of Normality will be investigated using Wilk-Shapiro test. If thè data is found
to be non-Normal, thè paired t-test will be replaced by Wilcoxon signed rank test.
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Version Number:
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• The primary endpoint will be summarized descriptively using n, mean, median, SD, Ql,
Q3, minimum, and maximum.
• Only those patients for whom we bave DBP assessment resiiits available at both Week 4
and Week 8 wiii be considered.
16.1.4. Su plementaiy A alysis of Primaiy Effìcacy Variable
A repeated measure generai linear model (GLM) will be performed on thè priinary effìcacy
endpoint to test thè covariate effects and thè effects of interactions between thè covariates for thè
mITT popul tion. The GLM model will include change i  mean sitti g DBP as thè dependent
variable. repeated through visits Visit 3 (Week 4) and Visit 4 (Week 8). Age (Years), gender, body
mass index (BMI), and baseline DBP are considered as thè cova iates.
The GLM model is
Change from Baseline = Visit + Age + Gender + BMI + baseline DBP + Age*Gender + Age*BMl
+ Age*baseline DBP + Gender*BMl + Gende *baseline DBP + BMI*baseline DBP +
Age*Gender*BMI + Age*Gender*baseline DBP + Age*BMI*baseline DBP +
Gender*BMI*baseline DBP + Age*Gender*BMI*baseline DBP
A PROC MIXED proced re, with an unstructured covariance matri , is used for thè analysis and
thè corresponding p-values for each of thè covariates will be presented in a table.
16.1.5. Sensit vit  Analysis of Primaiy Effìcacy Va iable(s)
The sensitivity analyses will be conducted similar to thè primary effìcacy analysis including thè
repeated measure GLM using thè PP population.
16.2. Secondary Effìcacy
Secondary effìcacy variables will be analyzed using both thè inTTT as well as thè PP population.
16.2.1. Secondaiy Effìcacy Variables & Derivation 
• Change in mean sitting SBP
Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8).
• Change in mean sitting DBP and SBP
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Change in mean sitting DBP and SBP between Visit 3 (Week 4) and Visit 4 (Week 8) in patients
under e teinpo aneous combination of NEB/AML 5/5 mg versus patients uptitrated to thè
extemporaneous combination of NEB/AM  5 10 mg.
• Niimber and proportion of patients achieving thè BP goal
Niimber and proportion of patients achieving thè BP goal (sitting SBP/DBP < 130/80 mmHg) at
Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8).
16.2.2. A  lysis of Secondaiy Efficacy Variabics
16.2.2. i. Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8)
Change from baseline in sitting SBP from prior and post combination therapy will be compared
using paired t-test. The p-vahie will be p esented using a pai ed t-test comparing mean at baseline
and mean at Week 8. The secondaiy endpoint will be presented in a descriptive manner using n,
mean, median, SD, Ql, Q3, and minimum and maximum. Assumption of normality will be
investigated using Wilk-Shapiro test. If violation is observed, then paired t-test will be replaced by
Wilcoxon signed rank test.
Additionally, thè secondary end point of change in SBP between Visit 2 and Visit 4 will be
analyzed using a repeated measures GLM as described in Section 16.1.4 with Age (Years), Gender,
body mass index, and baseline SBP a  covariates to identify thè effect of covariates and interaction
between thè covariates.
16.2.2.2. Change in mean sitting DBP and SBP between Visit 3 (Week 4) and Visit 4
(Week 8)
Change in sitting SBP and DBP between patients under extemporaneous combination of
NEB/AML 5/5 m  versus patients uptitrated to thè extemporaneous combination of NEB/AML
5/10 mg will be compare  using independent samples t-test. The secondary endpoint will be
presented in a descriptive manner using n, mean, median, SD, Ql, Q3, and minimum and
maximum. Assumption of normality will be investigated using Wilk-Shapiro test. If thè data is
found to be non-Normal, thè independent samples t-test will be replaced by Wilcoxon r nk-sum
test.
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16.2.2.3. Number and proportion of patients achieving thè BP goal
The number of patients achieving thè BP goal (sitting BP < 130/80 mmHg) will be summarized
for Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8) along wìth percentage and 95% CI
(Clopper Pearson). A p-value usi g exact McNemar s test will be  resented to compare tiie
proportion of patients achieving thè BP goal (sitting BP < 130/80 mmHg) between Visit 2 and
Visit 3 as well as Visit 2 and Visit 4. A p-valiie using McNemar s test will be presented to
comp re thè proportion of patients achieving thè BP goal (sitting BP < 130/80 mmHg) between
Visit 3 and Visit 4.
16.3. Exploratory Efficacy
16.3.1. Exploratoiy Efficacy Variables & Derivations
• Change in mean sitting DBP and SBP between Visit 1 (Week -4) and Visit 2 (Week 0),
Visit 3 (Week 4) and Visit 4 (Week 8):
o In thè group of patients who were on NEB 5 mg and AML 5  g at Visit 1 (Week -
4) and continued to be on thè same therapies.
o In thè group of patients who switched to NEB 5 mg or AML 5 mg from any other
BBs o  CCBs at Visit 1 (Week -4).
• To assess change in mean sitting DBP and SBP, for uncontrolled patients at Visit 3 (Week
4), between Visit 2 (Week 0) and Visit 3 (Week 4).
• Numbe  and proportio  of patients achieving thè BP goal (sitting BP < 130/80 mmHg) at
Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8):
o In thè group of patients who were on NEB 5 mg and AML 5 mg at Visit I (Week -
4) and continued to be on thè same therapies.
o In thè g oup of patients who switched to NEB 5 mg or AML 5 mg from any othe 
BBs o  CCBs at Visit I (Week -4).
• Number and proportion of patients divided into subgroups according to thè hypertension
giade, thè presence of diabetes and/or of hypercholesterolemia achieving thè BP goal
(sitting BP < 130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8).
o In thè group of patients  ho were on NEB 5 mg and AML 5 mg at Visit 1 (Week -
4) and continued to be on thè same therapies.
o In thè group of patients, who switched to NEB 5 mg or AML 5 mg from any othe 
BBs or CCBs at Visit 1.
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16.3.2. Analysis of Explor toiy Efficacy Variables
Exploratory efficacy variables will be siimmarized in a descriptive manner using ENR and mITT
populations for Visits 1, 2, 3 and 4.
• Change in sitting DBP and SBP from Visit I (Week -4) wili be using paired t-test. The p-
value obtained from thè paired t-test will be presented for thè visits - Visit 2 (Week 0),
Visit 3 (Week 4) and Visit 4 (Week 8). Assumption ofNormality will be investigated using
Wilk-Shapiro test. If thè data is found to be non-Normal, then paired t-test will be replaced
by Wilcoxon signed rank test. A descriptive summa y using n, mean, median, SD, Ql, Q3,
minimum, and maximum is also presented.
• Change in mean sitting DBP and SBP for uncontrolled patients between Visit 2 (Week 0)
and Visit 3 (Week 4) will be using paired t-test. The p-value obtained from thè paired t-test
along with n, mean, median, SD, Ql, Q3, minimum, and ma imum will be presented.
Assumption of No mality will be investigated using Wilk-Shapiro test. If thè data is found
to be non- ormal, then paired t-test will be replaced by Wilcoxon signed rank test.
• The number of patients achieving BP goal (sitting BP < 130/80 mmHg) will be summa ized
for Visits 2,3, and 4, along with percentage and 95% CI for thè proportion. A p-value using
exact McNem   s test will be p esented to compare thè proportion of patients achieving
thè BP goal (sitting BP < 130/80 mmHg) between Visit 2 and Visit 3 as well as Visit 2 and
Visit 4. A p-value using McNemar s test will be presented to compare thè proportion of
patients achieving thè BP goal (sitting BP < 130/80 mmHg) between Visit 3 an  Visit 4.
• The number of patients achieving B  goal (sitting BP < 130/80  mHg) will be summa ized
for Visits 2,3 and 4, along with percentage for each of thè subgrou  specified under section
7.5 ofthe SAP.
17. Quality of Life An lysis
Not Applicable.
18. SAFETY OUTCOMES
All outputs for safety outcomes will be based on thè SAP population.
There will be no statistica  comparisons between thè treatment groups fo  safety data, unless
otherwise specified with thè relevant section. 
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18.1. Adverse Events
Adverse Events (AEs) will be coded iising Medicai Dictionary for Regulatoiy Activities
(MedDRA) centrai coding dictionary, Version 25.0 or latest.
Treatment eme gent adverse events (TEAEs) are defined as new AEs that occur on or after thè
date/time of thè first admi istration of study medication (i.e., monotherapy and/or combination
the apy) o  worsen if an AE started p ior to thè start of first administration of study medication.
TEAEs that occii red or worsened on or after thè date/time of thè first administration of
Monother py biit before thè date/time of thè first administration of Combination Therapy wil! be
summarized under  Monothe apy .
TEAEs that occurred or worsened on or after thè date/time of thè first administration of
Combination Therapy will be s mma ized under  Combination Therapy .
See Appendix 2 for handiing of partial dates for AEs. In thè case  here it is not possible to define
an AE as treatment emergent or not, thè AE  ill be classified by thè worst case, i.e., treatment
emergent.
An overall summary of number of subjects within each of thè categories described in thè sub-
section below, will be provided as specified in thè templates.
Listings will include TEAEs and Non-TEAEs.
18.1.1. All TEAEs
Incidence of TEAEs will be presented by Syste  Organ Class (SOC) and Preferred Term (PT) and
broken down further by ma imum severity and relationship to study medication (i.e., monotherapy
and/or combination therapy).
18.1.1.1. Severity
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after thè first
dose of study medication (i.e., monotherapy and/or combination therapy) with a missing severity
will be classified as severe. If a subject  eports a TEAE more than once within that SOC/ PT, thè
AE with thè worst-c se severity will be used in thè corresponding severity summaries.
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18.1.1.2. Relationship to Stiidy Medication
Relationship, as indicated by thè Investigator, is classed as  Not Related ,  Related  (increasing
severity of relationship). A  related  TEAE is defìned as a TEAE witli a relationship  o study
medication (i.e., monotherapy and/or combination therapy) as  Ce tain Related ,  P obable
Related ,  Possible Related” or  Unassessable” to study medication. TEAEs with a missing
relationship to study medication will be regarded as  P obable Related” to study medication. If a
patient reports thè same AE more than once within that SOC/ PT, thè AE with thè worst-case
relationship to study medication will be used in thè corresponding relationship su maries.
18.1.2. TEAE  Le  iii  to  iscoiitiiiuation of St  y Medica ion
TEAEs leading to permanent discontinuation of study medication (i.e., monotherapy and/or
combination therapy) are those events for which “Action Taken with Study Treat ent” is recorded
as  D ug withdrawal  on thè Adverse Event page of thè eCRF.
For TEAEs leading to discontinuation of study medication, summaries of incidence rates
(frequencies and percentages) by SOC and PT will be prepared.
18.1.3. Serious Adverse Events
Serìous adverse events (SAEs) a e those events recorded as  Serious” on thè Adverse Events page
of thè (e)CRF. A summa y of serious TEAEs by SOC and PT will be prepa ed.
18.1.4. Advei' SC Events Leading to Death
TEAEs leading to Death are those events which a e recorded as “Fatai” for thè Outeome field on
thè Adverse Events page of thè (e)CRF. A summary of TEAEs leading to death by SOC and PT
will be prepared.
18.2. De ths
If any patients die during thè study, thè information will be presented in a summary table and a
data listing using SAF population. If a patient died during Monotherapy, then thè data will be
siimmarized  nder Monotherapy, else thè summary will be p ovided under Combination Therapy.
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18.3. Laboratory Evaluatìons
Res lts from thè centrai laboratory  ill be included in thè reporting of this study for Hematology,
Se um Chemistry, Urine Pregnancy Test, and Coagul tion. A list of labo atory assessments to be
included in thè outpiits is included in protocol Section 8.2.3.
Presentations will use SI Units.
The following summaries will be provided for laboratory data:
• Actual and change from baseline by visit (for quantitative measurements) for Combination
Therapy using SAP population.
• A by-patient listing of all laboratory data and pregnancy test data will be presented for both
Monotherapy and Combination therapy using thè SAP population.
18.4. ECG Evaluatìons
The following ECG pa ameters will be reported for this study:
• PR Interval (msec)
• QRS Interval (msec)
• RR Interval (msec)
• QT Inte val (msec)
• QTcF Inte val (msec) [derived]
. HR (bpm)
• Ove all assessment ofECG (Investigator s judgment):
o Norm l
o Abnormal, Not Clinically Significant (ANCS)
o Abnormal, Clinically Significant (ACS)
The following summ ries will be provided for ECG data:
• Actual and change from baseline by visit (for quantitative measurements).
• Shift from b seline ofECG Inte pretation Results.
• ECG parameters recorded in eCRF fonti  12 Lead ECG , will be summarized using thè SAP
population for thè Combination therapy. All ECG data will be listed for both Monotherapy and
Combination Thera y using thè SAP population.
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18.5. Vital Si ns
The following Vital Signs measurements will be reported for this study:
• Sitting Systolic Blood Pressure (mmHg)
• Sitting Diastolic Blood Pressure (mmHg)
• Pulse Rate (bpm)
• Res iratoiy Rate (breaths/min)
• Body Temperature (®C)
The following summaries will be p ovided for vital signs data;
• Actual and change from baseline by visit for Monotherapy and Combination therapy using thè
SAP population.
• A by-p tient listing of all vital signs data will be presented for both Monotherapy and
Combination therapy using thè SAP population.
18.6. Physical Examination
The following summaries will be provided for physical examination data for combination therapy
by visit on SAP population:
• Shift from baseline according to thè physical examination fìndings.
• Physical Exa ination pa ameters will be summarized using thè SAP population fo  thè
Combination therapy. All Physical E amination data  ill be listed for both Monotherapy and
Combination Therapy using thè SAP population.
18.7. Other Safety Assessments
No other safety assessment will be collected for this study.
The other variables and/or domains not summarized o  presented are:
• Comments
• Contacts
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These domains and/or variables will not be summarized orpresented, but will be available in thè
clinical study database, SDTM and/or ADaM datasets.
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20. References
Dobson, A. J. (2002).  In inirodiicfion lo generaìized linear models, 2nd ed. Chapnian & Hall/CRC.
http: /ww\v.ema.europa.eu docs/en_GB docuinenl_librafy/ScientÌf c_guideline 2010 09/WC500096793.pdf
Little, R., & Yaii, L. (1996). Intent-to-Treat Analysi.s for Lon itudinal Studies with Drop-Outs, Bioineirìcs , voi 52,
1324-1333.
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11NO 2022
Template No.: CS_TP_BS016 Revision 7
Effecti e Date: 01Nov2021
Reference: CS Wl BS005
Copyright © 2009,2010,2012, 2016,2018, 2019, 2021 IQVIA. All rights resen ed. The contents of this document are confidential
and proprietary to IQVIA Holdings Ine. and its subsidiaries. Unaulhorized use, disclosure or reproduction Is striclly prohibited.


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PROTOCOL MEIN 21/AmNe-Hyp/001
Page 33 of 39
APPENDIX 1. Programming Conventions for Outputs
IQVIA Outp t Conventions
Outputs will be presented accordin  to thè following:
Global Bios > Processes > GBIOS Processes - Implementation Giiidelines and Templates >
General Guidelines and Templates > Output Conventions.
Dates & Times
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Depending on data available, dates and times will take thè form yyyy-nim-ddThh:mm:ss.
Spellin  Format
English US
Presentation of Treatment Groups
For outputs, treatment groups will be re resented as follows and in thè given order:
Therapy
Treatment
Group
For Tables, L stin s
and Figures
Monotherapy
NEB 5mg
NEB 5mg
Monotherapy
AML 5mg
AML 5mg
Combination
Therapy
NEB+AML (5mg) NEB+AML (5mg)
Combination
Therapy
NEB+AML
(lOm )
NEB+AML (lOmg)
Presentation of Visits
Visit 1 (Week -4)
Vìsit 2 (Week 0)
Visit 3 (Week 4)
Document: \\ eedc-vnasc01\Biosdata\Menarini NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Final_V1.0
Author: Aswin Nair Version Number: Final V1.0
Version Date; 11Nov2022
Tempiale No.; CS_TP_BS016 Revision 7 Reference: CS_WI_BS005
Effecti e Date: 01Nov2021
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contente of this document are confidential
and proprietary to IQVIA Holdings Ine. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictiy prohibited.


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PROTOCOL MEIN 21/AmNe-H p/001
Page 34 of 39
Visit4 (Week 8)
Early Temiination
Por outpiìts, visits will be represented as follows and in that order:
ong Namc (default)
Short Name
Screening (Visit 1)
Scr (VI)
Baseline (Week 0) or Visit 2 (Week 0)
BL(WO) or V2 (WO)
Visit 3 (Week 4)
V3 (W4)
Visit 4 (Week 8)
V4 (W8)
Early Termination
ET
Listìn s
All listings will be ordered by thè following (unless otherwise indicated in thè template):
• Treatment groiip (Monotherapy and Combination Therapy),
• Center-subject ID,
• Date (where applicable).
Document: \ ieedc-vnasc01\Biosdata\Menarini\N8bAml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_MEIN21AmNe-
Hyp001_Fina V1.0
Author: Aswìn Nair Version Number: Final VI.0
Version Date: 11Nov2022
Template No.: CS_TP_BS016 Revision 7 Reference: CS_WI_BS005
Effecti e Date: 01Nov2021
Copyright © 2009, 2010, 2012,2016, 2018, 2019, 2021 IQVIA. All rig ts reserved. The contente of this document are confidential
and proprietary to IQVIA Holdings Ine. and its subsldiarles. Unaut orized use,  isclosure or reproducllon is strictiy pro ibited.


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PROTOCOL MEIN/21 AmNe-Hyp/001
Statistica! Analysis Pian
Page 35 of 39
Reference Code
• Paired t-test
ods trace on;
proc ttest data=input_data h0=0;
paired VISITX VISITY;
ods outp t TTests=test;
run;
ods trace off;
• Normality assumption check
ods trace on;
proc univ rì te data=indata norma) plot;
var change from baseline;
histogram  normal kerneI(color=red);
ods output TestsForNormalÌty=nonn(where=(test="Shapiro-Wilk"));
un;
ods trace off;
• Wilcoxon Signed Rank Test
ods trace on;
proc univ  iate data indata imi0=0 loccount;
var change from baseline;
ODS Output TestsForLocation=test LocationCounts=LOCC_one;
run;
• Exact McNemars Test
ods trace on;
ods output McNema sTest=McNemarsTest;
proc freq data=indata orde =data;
tables VISITX*VISÌTY/agree alpha 0.05 ;
exact mcnem;
weight ZZZ/zeros;
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostatistics\Documentation\SAP\SAP Menarini MEiN21AmNe-
un;
Hyp001_Final_V1.0
Author: Aswin Nair
Version Number:
Final V1.0
Version Date:
11NOV2022
Tempia e No.: CS_TP_BS016 Re ision 7
Effective Date: 01Nov2021
Reference: CS Wl BS005
Copyright ©2009, 2010,2012, 2016,2018, 2019, 2021 IQVIA. All rights reser ed. T e contents of this document are confìdenlial
and proprietary to IQVIA Holdings Ine. and its substdiaries. Unauthorized use, disclosure or reproduclion is strictly prohibited.


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PROTOCOL MEIN/21/AmNe-Hyp/001
Statistica! Analysis Pian
Page 36 of 39
• Independent sample t-test
ods trace on;
proc ttest d ta=ìndata h0=0;
class xxx;
var change froi  baseline;
ruii;
ods t ace off;
• Wicoxon Rank Sum Test
ods trace on;
proc npar vay d ta=indata wilcoxon;
by by_variables;
class xxx;
var change from baseline;
ods output WilcoxonTest=wt;
run;
• Repeated measures GLM
p oc mixed data=indata;
class visit sex;
model change f o  baseline = Visit Age Gender BMl baseline DBP Age*Gender
Age*BMl_Age*baselÌne_DBP Gende *BMI Gender*baseline_DBP BM]*basel ne_DBP
Age*Gender*BMl_Age*Gender*baseline_DBP Age*BMI*baseline_DBP Gender*BMl*baseline_DBP
Age*Gender*BMI*baseline_DBP;
repeated visit;
u ;
Document: \\ieedc-vnasc01\Biosdata\Menanni\Ne Aml\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini MEIN21AmNe-
Hyp001_Final_V1.0
Author; Aswin Nair
Version Number:
Final V1.0
Version Date;
11NOV2022
Tempiale No.: CS_TP_BS016 Revision 7
Effeclive Date; 01Nov2021
Reference: CS Wl BS005
Copyright ©2009, 2010, 2012, 2016, 2018, 2019, 2021 IQ IA. All rights reserved. T e confents of Ihis document are confìdential
and proprietary to IQVIA Holdings Ine. and its subsidiaries. Unauthorized use, disclosure or reproduclion is strictiy prohibited.


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PROTOCOL MEIN/21/AmNe-Hyp/001
Statistica! Analysis Pian
Page 37 of 39
APPENDIX 2. Partial Date Conventions
Impiìted dates will NOT be presented in thè listings.
Algorithm for Treatment Emer ence of Adverse Events:
START DATE
STOP DATE
ACTION
Known
Known/Partial/
Missing
If start date < study  ed start date, then not TEAE
If start date >= study med start date, then TEAE
Partial, but known
components show that it
cannot be on or after
study med start date
Known/Partial/
Missing
Not TEAE
Partial, coiild be on or
after st dy med start date
OR Missing
Known
If stop date < study med start date, then not TEAE
If stop date >= study med sta t date, then TEAE
Partial
Impute stop date as latest possìble date (i.e. last
day of month if day unknown or 3 Ist Decomber if
day and month are unknown), then:
If stop date < study med start date, then not TEAE
If stop date >= study med start date, then TEAE
Missing
Ass med TEAE
Document: \\ieedc-vnasc01\Biosdata\Menarìni\NebAml\ZZA67778\Biosta istics\Documentation\SAP\SAP_Menarini_ME!N21AmNe-
Hyp001_Final_V1.0
Aulhor: Aswin Nair Version Number: Final V1.0
Version Date; 11Nov2022
Tempiale No.: CS_TP_BS016 Re ision 7 Reference: CS_WI_BS005
Effective Date; 01No 2021
Copyright © 2009,2010,2012, 2016,2018, 2019, 2021 iQVIA. All r ghts reserved. The contente of this document are confi ential
and proprietary to IQVIA Holdin s Ine. and its subsidiaries. Unaulhorized use, disclosure or reproduction is striclly prohibited.


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PROTOCOL MEIN/21/AmNe-Hyp/001
Page 38 of 39
Al orithm for Prior / Concomitant Medications:
START
DATE
STOP
DATE
ACTION
Known
Known
If stop date < study med start date, assign as prior
If stop date >= study med start date and start date <= study med
end date, assign as concomitant
If stop date >= study med start date and start date > study med
end date, assign as post study
Partial
Impute stop date as latest possible date (i.e. last day of  onth if
day unknown or 31 st Decomber if day and month are unknown),
then:
If stop date < study med start date, assign as prior
If stop date >= study med start date and start d te <= study med
end date, assign as concomitant
If stop date >= study med start date and start date > study med
end date, assign as post treatment
Missing
If stop date is missing could never be assumed a prior medication
If start date <= study med end date, assign as concomitant
If start date > study med end date, assign as post treatment
Partial
Known
Impute start date as earliest possible date (i.e. fi st day of month
if day unknown or Ist J nuary if day and month are unknown),
then:
If stop date < study med start date, assign as prior
If stop date >= study med start date and start date <= study med
end date, assign as concomitant
If stop date >= study med start date and start date > study med
end date, assign as post t eatment
Document: \\ieedc-vnasc01\Biosdata\Menarini\NebAmi\ZZA67778\Biostatistics\Documentation\SAP\SAP_Menarini_ME!N21AmNe-
Hyp001_Final_V1.0
Aulhor: Aswin Nair Version Number; Final V1.0
Version Date: 11 Nov2022
Tempiale No.: CS_TP_BS016 Re ision 7 Reference: CS_WI_BS005
Effective Date; 01Nov2021
Copyrig t © 2009, 2010.2012,2016,2018, 2019,2021 IQ IA. All rights reserved. Theconlenls of fhis document are confidential
and proprietary to IQVIA Holdings Ine. and it$ subsidiaries. Unauthorized use, disclosure or reprodudion is sirìctiy prohibited.


Menarìnì
PROTOCOL MEIN/21/AmNe-Hyp/001
Page 39 of 39
START
DATE
STOP
DATE
ACTION
Partial
Impute start date as earliest possible date (i.e. first day of inonth
if day Linknown or 1 st January if day  nd month are unknown)
and impute stop date as latest possible date (i.e. last day of month
if day unknown or 31st Decomber if day and month are
unknown), then:
If stop date < study med start date, assign as prior
If stop date >= st dy med start date and start date <= study med
end date, assign as concomitant
If stop date >= study med start date and start date > study med
end date, assign as post treatment
Missing
Impute start date as ea liest possible date (i.e. first day of month
if day unknown or Ist January if day and month are unknown),
then:
If stop date is missing could never be assumed a prior medication
If start date <= study med end date, assign as concomitant
If start date > study med end date, assign as post treatment
Missing
Known
If stop date < study  ed start date, assign as prior
If stop date >= study med start date, assign as concomitant
Cannot be assigned as  post treatment 
Partial
Imputo stop date as latest possible date (i.e. last day of month if
day unknown or 31 st Decomber if day and month are unknown),
then:
If stop date < study med start date, assign as prior
If stop date >= study med start date, assign as concomitant
Cannot be assigned as ‘post treatment’
Missing
Assign as concomitant
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Document: \\ieedc- nasc01\Biosdata\Menarini\NebAml\ZZA67778\Biostatistics\Documentalion\SAP\SAP_Menarini__MEIN21AmNe-
Hyp001_Final_V1.0
Author: Aswin Nair Version Number: Final V1.0
Version Date: 11 Nov2022
Tempiale No.: CS_TP_BS016 Re ision 7 Reference: CS_WI_BS005
Effecti e Date; 01Nov2021
Copyright © 2009, 2010,2012,2016,2018,2019, 2021 IQVIA. All rights reserved. The contents of Ihis document are confidenlial
and proprìelary to IQVIA Holdings Ine. and its subsidìaries. UnauthorIzed use, disclosure or reproduction is strictiy pro ibited.


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E!ectronic Si nature Manifestation
This page is a manifestation of thè electronic signature(s) used in compliance with thè organization's
electronic signature policies and procedures
Si ner Fu!!
Name
Meanin  of Signature
Date and Time
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education,  rainin  and experience to perform this
task)
23 Nov 20  
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Miiller
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education, training and experience to perform this
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