Interventional Clinical Trial to Assess Efficacy and Safety of the Extemporaneous Combination of Zofenopril Calcium and Amlodipine in Grade 1-2 Hypertensive Patients Versus Each Monotherapy - (MASOLINO Study)
Phase: PHASE4
Conditions: Hypertension
Sponsor: Menarini International Operations Luxembourg SA

 
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Enclosure to:   □ Guideline              □ Policy              x Procedure            □ Working Instruction 
 
Sponsor: Menarini International Operations Luxembourg SA 
Study Code: : MEIN/20/ZoAm-Hyp/001 
Protocol Version 1 .0   of 1     23/04/2021 
  
 
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PROTOCOL TITLE 
CLINICAL STUDY PROTOCOL 
 
 
Interventional clinical trial to assess efficacy and safety of the extemporaneous combination of 
zofenopril calcium and amlodipine in grade 1-2 hypertensive patients versus each monotherapy – 
(MASOLINO Study) 
 
 
Protocol Code  
 
MEIN/20/ZoAm-Hyp/001 
 
EudraCT (or National Clinical 
Trial Identified Number) 
2021-000745-40 
Protocol Phase (if applicable) 
IV 
Study type and design 
Interventional, multi-centre, open-label study 
Protocol Version Number 
1.0 
Protocol Version Date 
23 April 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 
 
Ph. (+352) 2649761 - Fax (+352) 26497649 
Coordinating Investigator 
Professor Massimo Volpe 
Via Di Grottarossa, 1035 Roma 
 
CRO 
BIORASI 

 
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Study Code: : MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0   of 1     23/04/2021 
  
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Study Code: : MEIN/20/ZoAm-Hyp/001 
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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES FROM PREVIOUS VERSION .................................................. 2 
TABLE OF CONTENTS ........................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 6 
1 
RESPONSIBILITIES .......................................................................................................... 8 
2 
PROTOCOL SYNOPSIS .................................................................................................... 9 
Inclusion Criteria ............................................................................................................ 12 
Exclusion Criteria ........................................................................................................... 13 
2.1 
Study Scheme ............................................................................................................. 17 
2.2 
Study Flow Chart ....................................................................................................... 19 
3 
STUDY RATIONALE AND BACKGROUND INFORMATION .................................. 22 
3.1 
Assessment of Potential Risks and Benefits .............................................................. 23 
4 
TRIAL OBJECTIVES AND ENDPOINTS...................................................................... 24 
5 
STUDY DESIGN .............................................................................................................. 28 
5.1 
Procedures and Study Visits ...................................................................................... 29 
6 
SELECTION OF SUBJECTS ........................................................................................... 33 
6.1 
Informed Consent Process ......................................................................................... 33 
6.2 
Inclusion and Exclusion Criteria ................................................................................ 33 
 Inclusion Criteria ................................................................................................ 33 
 Exclusion Criteria ............................................................................................... 34 
 Screening Failures ............................................................................................... 36 
7 
STUDY TREATMENT .................................................................................................... 36 
7.1 
Study Treatment Formulation, Appearance, Packaging, and Labeling ..................... 36 
7.2 
Study Treatment Distribution and Return / Destruction ............................................ 40 
7.3 
Product Storage and Stability ..................................................................................... 40 
7.4 
Study Product Compliance ......................................................................................... 41 
7.5 
Concomitant Therapy(ies) .......................................................................................... 41 
7.6 
Not permitted medications ......................................................................................... 42 
7.7 
Rescue Medicine ........................................................................................................ 42 
8 
STUDY ASSESSMENT AND PROCEDURES .............................................................. 42 
8.1 
Assessment of Efficacy .............................................................................................. 46 
8.2 
Assessment of Safety ................................................................................................. 46 
9 
SAFETY DATA MANAGEMENT .................................................................................. 52 
9.1 
Adverse Event (AE) ................................................................................................... 52 
9.2 
Drug Relationship ...................................................................................................... 52 
9.3 
Adverse Drug Reaction (ADR) .................................................................................. 53 
9.4 
Seriousness ................................................................................................................. 54 
9.5 
Adverse Event / Adverse Drug Reaction Intensity .................................................... 54 

 
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9.6 
Adverse Event / Adverse Drug Reaction Expectedness ............................................ 55 
9.7 
Serious Unexpected Adverse Drug Reaction (SUSAR) ............................................ 55 
9.8 
Individual Case Safety Report (ICSR) ....................................................................... 55 
9.9 
Collection, Recording and Reporting of AEs ............................................................ 55 
9.10 Management of Serious AEs (SAEs) including laboratory abnormalities ................ 56 
9.10.1 Reporting Duties of the Investigator ................................................................... 56 
9.10.2 Reporting Duties of the Sponsor ......................................................................... 56 
9.11 Management of Non-serious AEs (NSAEs) including laboratory abnormalities ...... 57 
9.11.1 Reporting Duties of the Investigator ................................................................... 57 
9.12 Management of any laboratory abnormality .............................................................. 57 
9.13 Management of pregnancy exposure cases ................................................................ 58 
10 WITHDRAWAL CRITERIA ........................................................................................... 59 
11 LOST TO FOLLOW UP ................................................................................................... 61 
12 STATISTIC ....................................................................................................................... 61 
12.1 Statistical Methods (Blinding and Randomization) ................................................... 61 
12.2 Determination of Sample Size ................................................................................... 62 
12.3 Analysis Populations .................................................................................................. 62 
12.4 Analysis Variables ..................................................................................................... 63 
12.5 Statistical Analysis ..................................................................................................... 63 
 Descriptive statistics ........................................................................................... 63 
 Primary (efficacy) analysis ................................................................................. 63 
 Sensitivity analysis .............................................................................................. 64 
 Secondary (efficacy) analysis ............................................................................. 64 
 Exploratory (efficacy) analysis ........................................................................... 65 
 Subgroup analysis ............................................................................................... 65 
 Safety analysis .................................................................................................... 65 
 Interim analysis and stopping rules ..................................................................... 65 
 Data imputations ................................................................................................. 65 
12.6 Protocol Deviations and Protocol Amendments ........................................................ 66 
12.7 End of Study Visit ...................................................................................................... 66 
12.8 Statistical Analysis Plan ............................................................................................. 66 
13 STUDY DISCONTINUATION AND CLOSURE ........................................................... 67 
14 DIRECT ACCESS TO SOURCE DATA / DOCUMENTS ............................................. 68 
15 QUALITY CONTROL AND QUALITY ASSURANCE ................................................ 68 
15.1 Study Monitoring / Data Quality Control .................................................................. 68 
15.2 Case Report Forms ..................................................................................................... 69 
15.3 Quality Assurance ...................................................................................................... 70 
16 ETHICS ASPECTS ........................................................................................................... 70 
16.1 Ethics Committees ..................................................................................................... 71 

 
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16.2 Subject’s Insurance .................................................................................................... 71 
17 PERSONAL DATA PROTECTION SECTION .............................................................. 71 
17.1 General Principles on Personal Data Compliance ..................................................... 71 
17.2 Acknowledgment ....................................................................................................... 72 
17.3 Data Controllers and Data Processors ........................................................................ 72 
17.4 Duties of the Parties involved in the performance of the study ................................. 73 
17.5 Archiving of the clinical trial master file and code pairing list ................................. 75 
17.6 Information notice on personal data protection and pseudo-anonymisation ............. 78 
17.7 Genetic Data ............................................................................................................... 79 
17.8 Transfer of subjects’ data outside the European union .............................................. 79 
17.9 Exercise of subjects’ data privacy rights .................................................................... 79 
17.10 Future research ........................................................................................................... 80 
18 PUBLICATION POLICY AND RESULTS ..................................................................... 80 
19 REFERENCES .................................................................................................................. 81 
20 PROTOCOL APPROVAL PAGE .................................................................................... 83 
21 INVESTIGATOR’S APPROVAL PAGE ........................................................................ 84 
22 APPENDICES................................................................................................................... 85 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION DEFINITION 
ACE 
Angiotensin Converting Enzyme 
ACE-i 
Angiotensin Converting Enzyme inhibitors 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AML  
Amlodipine  
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CCBs 
Calcium Beta Blocker  
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CV 
Cardiovascular Event 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
FDC 
Fixed Dose Combination 
FPI 
First Patient In  
IMP 
Investigational Medicinal Product 
ISCR 
Individual Case Safety Report 
IUD  
Intrauterine Device  
IUS 
Intrauterine hormone-releasing system 
IWRS 
Interactive Web Response System 
MACE 
Major Adverse Cardiovascular Events 
NSAE 
Non-Serious Adverse Events 
PP 
Protocol Population 
PDE 
Phosphodiesterase inhibitors 
RCT 
Randomized controlled trial 
SAE 
Serious Adverse Events 
SBP 
Systolic Blood Pressure 
SD  
Standard deviation  
SS 
Sample Size 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 

 
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TEAE 
Treatment Emergent Adverse Event 
UNL 
Upper Normal Limit  
UPT 
Urine Pregnancy Test 
ZOF  
Zofenopril  
 
 
 

 
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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: Sabrina Vignolo 
Address: Via Sette Santi 1-3, 50131, Firenze 
Phone:  +39 055 56809145                 
  
  e-mail: svignolo@menarini.it 
Study Medical Expert (SME):               
Name:  Marco Salvatore 
 
Address: Via dei sette santi 1-3, 50131, Firenze 
Phone:  +39 055 56809581                 
  
  e-mail: msalvatore@menarini.it 
Study Drug Safety Manager (SDSM):  
Name:  Jaleh Khabirinejad 
 
Address: 5D, Rue Eugene Ruppert L-2453 
Luxembourg 
Phone:  +352 26497696                
  
  e-mail: jkhabirinejad@menarini.lu 
Coordinating Investigator  
Name:  Professor Massimo Volpe 
 
Address: Via Di Grottarossa, 1035 Roma 
Phone: 06 33775654                   
  
  e-mail: massimo.volpe@uniroma1.it 
CRO  
Name:  Biorasi  
 
Address: 18851 NE 29th Ave #800, Aventura, FL 
33180 USA 
Phone:                 +1 (786) 388-0700 
  
  e-mail:  masolino@biorasi.com  
Statistician  
Name 
John Reber 
 
Address: Statistician and SAS Programmer, 
Consultant. Foxhound Analytics LLC 
Phone: (218) 770-8145                  
  
  e-mail: jreber@foxhound-analytics.com  
 
 

 
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Protocol Version 1.0   of 1     23/04/2021 
  
 
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2 
PROTOCOL SYNOPSIS 
 
Title 
 
 
Acronym  
Sponsor Study 
Code  
Interventional clinical trial to assess efficacy and safety of the 
extemporaneous combination of zofenopril calcium and amlodipine 
in grade 1-2 hypertensive patients versus each monotherapy  
 
MASOLINO Study 
MEIN/20/ZoAm-Hyp/001 
 
Study product, 
Dosage and 
Regimen:  
-Investigational 
Product 
-Reference 
Therapy 
(comparator) 
 
Extemporaneous combination of Zofenopril (ZOF) 30 mg (ATC 
code: C09AA15) with Amlodipine (AML) 5 mg (ATC code: 
C08CA01) or Amlodipine (AML) 10 mg (ATC code: C08CA01) will 
be administered orally once daily. 
Study Type and 
Design 
This study is a phase IV, open-label, multicentre, multinational study 
with two study periods, treating patients with grade 1-2 hypertension, 
blood pressure (BP) ranging from ≥140/90 mmHg to ≤179/109 
mmHg while on treatment with any angiotensin converting enzyme-
inhibitors (ACE-i) or Calcium Channel Blockers (CCBs) including 
ZOF  30 mg or AML 5 mg respectively.  
The study is designed with a run-in period of 4 weeks and an 
assessment period of 8 weeks.  
  
Phase 
Phase IV 
Objectives* 
 
 
Primary Objective: To assess the anti-hypertensive efficacy of the 
extemporaneous combination of ZOF 30 mg with AML 5 mg or 
AML 10 mg in lowering the sitting diastolic BP between Visit 2 
(Week 0) and Visit 4 (Week 8) in patients with uncontrolled BP 

 
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Protocol Version 1.0   of 1     23/04/2021 
  
 
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previously treated with ZOF (30 mg) or AML (5 mg) monotherapies 
for at least 4 weeks.  
 
Secondary objectives:  
●To assess the antihypertensive efficacy of the extemporaneous 
combination of ZOF 30 mg in combination with AML 5 mg or AML 
10 mg in lowering sitting systolic BP between Visit 2 (Week 0) and 
Visit 4 (Week 8) in patients with uncontrolled BP previously treated 
with ZOF 30 mg or AML 5 mg  monotherapies for at least 4 weeks. 
●To assess the antihypertensive efficacy of the extemporaneous 
combination of ZOF/AML 30/10 mg vs. ZOF/AML 30/5 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 
ZOF or AML 5 mg monotherapies for at least 4 weeks.  
●To evaluate the total number and percentage of patients who 
achieved the 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 (ZOF 
30 mg and AML 5 mg) and of the extemporaneous combinations 
(ZOF 30 mg and AML 5 mg or AML 10 mg) after 8 weeks of 
treatment. 
 
Endpoints* 
 
 
 
Primary Efficacy Endpoint: 
●Change in mean sitting DBP between Visit 2 (Week 0) and Visit 4 
(Week 8). 
 
Secondary Efficacy Endpoint: 
●Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 
(Week 8). 

 
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●Change in mean sitting DBP and SBP between Visit 3 (week4) and 
4 (Week 8) in patients on combination of ZOF/AML 30/5 with 
uncontrolled BP at Visit 3 and up titrated to the extemporaneous 
combination of ZOF/AML 30/10 mg 
●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). 
●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 (ZOF 30 mg and AML 
5 mg) and of the extemporaneous combination (ZOF 30 mg and 
AML 5 mg or AML 10 mg) after eight weeks of treatment.  
 
Exploratory Efficacy Endpoint:  
●Change in mean sitting SBP and DBP 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 ZOF and AML 5 mg at 
Visit 1 and started ZOF 30 mg or continued the same therapy 
AML 5 mg at Visit 1  
o in the group of patients who switched to ZOF 30 mg or AML 
5 mg from any other ACE-i or CCBs at Visit 1 
●Change in mean sitting SBP and DBP 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) and Visit 3 (Week 4):  
o in the group of patients who were on and AML 5 mg at Visit 
1(Week -4) and started ZOF 30 mg or continued the same 
therapy AML 5 mg 
o in the group of patients who switched to ZOF 30 mg or AML 
5 mg from any other ACE-i or CCBs at Visit 1 (Week- 4)   
●Number and proportion of patients divided in subgroup by the 
hypertension grade, the presence of diabetes and/or of 

 
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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 ZOF and AML 5 mg at 
Visit 1 (Week -4) and continued AML 5 mg and started ZOF 
30 mg 
o in the group of patients, who switched to ZOF 30 mg or AML 
5 mg from any other ACE-i or CCBs at Visit 1 (Week 4) 
 
Study Population: 
Subjects 
characteristics 
Number of 
Subjects 
●Male or female, Grade 1-2 uncontrolled hypertensive patients ≥18 
and ≤65 years of age 
●Considering a screening failure and a drop-out rate of 25%, the 
overall number of patients to be screened is 290. 
●216 patients are needed to complete the run- in period and start the 
assessment period to guarantee powered results  
 
Inclusion Criteria 
 
A patient will be considered eligible for inclusion in the study only if 
all the following criteria are met:   
1. Male or female Grade 1-2hypertensive patients:  with mean 
sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean sitting 
DBP ≥ 90 mmHg and ≤109 mmHg at Screening, with ≥18 
and ≤65 years of age, in monotherapy either with ZOF 30 mg 
or AML 5 mg, or any other ACE-I or CCBs (Felodipine, 
isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, 
and nisoldipine) for at least 1 months  before Visit 1 
(Screening). 
2. Patients who are able to understand and give written informed 
consent at Screening 
3. Patients who are available for the entire trial period and willing 
to adhere to the protocol requirements  
4. Ability to take oral medication and willing to adhere to the drug 
regimen 

 
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5. Female patients are eligible to participate if not pregnant, or not 
breastfeeding and must refrain from donating or storing eggs. 
For females of reproductive potential: use of highly effective 
contraception (e.g., 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 less than 1% per year) 
such as: 
• Combined (estrogen- and progestogen-containing) 
hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated 
with 
inhibition 
of 
ovulation 
(oral, 
injectable, 
implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner (performed at least 2 months 
before screening) (if 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. Known contraindications, presence of not recommended / 
contraindicated concomitant therapy allergies, or significant 
history of hypersensitivity to zofenopril, amlodipine, other ACE-

 
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Protocol Version 1.0   of 1     23/04/2021 
  
 
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inhibitors or dihydropyridines calcium channel blockers, or any 
related products (including excipients of the formulations as 
outlined in the Investigator’s Brochure [IB]) or), summary of 
product characteristics (SmPCs) or local package inserts for AML 
and ZOF 
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, haematological, or oncological, neurological, and 
psychiatric diseases. The same applies for immunocompromised 
and/or neutropenic patients 
3. Patients having a history of the following within the last 6 months: 
myocardial infarction, unstable angina pectoris, percutaneous 
coronary intervention, bypass surgery, valve replacement 
(transcatheter 
aortic 
valve 
implantation, 
MitraClip), 
cerebrovascular accident (stroke, heart failure, hypertensive 
encephalopathy, cerebrovascular accident (stroke), or transient 
ischemic attack. Patients with who have undergone other surgery 
that in the in the opinion of the Investigator may limit the ability to 
evaluate the efficacy or safety of the tested medications. 
4. Patients with secondary hypertension of any aetiology such as 
renal 
diseases, 
pheochromocytoma, 
Cushing’s 
syndrome 
hyperaldosteronism, renovascular disease, thyroid disorders  
5. Patients with severe heart failure (New York Heart Association 
classification III-IV), a narrowing of the aortic or bicuspid valve, 
an obstruction of cardiac outflow (obstructive, hypertrophic 
cardiomyopathy) or symptomatic coronary disease 
6. Patients with clinical evidence of renal disease as per the 
Investigator’s judgement (including renovascular occlusive 
disease, nephrectomy and/or renal transplant, bilateral renal artery 
stenosis or unilateral renal artery stenosis in a solitary kidney, or 
severe renal impairment) 

 
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Study Code: : MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0   of 1     23/04/2021 
  
 
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7. Patients with history of angioneurotic oedema 
8. Patients with clinically relevant hepatic impairment  
9. Patients with sick sinus syndrome, including sino-atrial block 
10. Patients with second- or third-degree heart block (without a 
pacemaker) 
11. Participation in any other interventional drug trial or exposure to 
other investigational agents within 30 days before Screening (Visit 
1)  
12. Inability to cooperate or any condition that, in the opinion of the 
Investigator, could increase the patient’s risk of participating in the 
study or confound the outcome of the study 
13. Patients with conditions that, in the opinion of the Investigator, 
would prevent a careful adherence to the protocol 
14. Patients with severe hypotension  
15. Patients who suffer from shock (including cardiogenic shock) 
16. Patients treated with Amlodipine 10 mg and Zofenopril (other 
than 30 mg) 
 
Clinical Sites 
Number of Centres  
● 
Approximately 28 clinical sites 
List of Countries 
Russia, Hungary, Italy 
Study Duration 
(specify different 
study phases): 
 
• Screening Visit 1, (Week -4) 
• Run-in period from Visit 1(Week -4) to Visit 2 (Week 0) 
• Assessment period from Visit 2 (Week 0) to Visit 4 (Week 8): 
 
Subject Study 
Phases Duration 
 
The overall duration of the study will be 12 weeks. 
Screening Visit 1, (Week -4): Grade 1-2 hypertensive patients with 
blood pressure [BP] ranging from ≥140/90 mmHg to ≤179/109 
mmHg)  in treatment with any ACE-i or CCBs*, including ZOF 30 
mg or AML 5 mg (only dosage allowed) 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): eligible 
patients will enter a 4 weeks run-in period on the same day of the 

 
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screening visit. Patients previously receiving ZOF 30 mg or AML 5 
mg will continue the same treatment, patients receiving other ACE-i 
will be switched to ZOF 30 mg, while patients receiving CCBs will 
receive AML 5 mg. Patients entering this phase in therapy with ZOF 
30 mg or AML 5 mg should be in a 1:1 ratio. 
Assessment period from Visit 2 (Week 0) to Visit 4 (Week 8): 
patients having uncontrolled BP at Visit 2, will be assigned to the 
extemporaneous combination of ZOF 30 mg and AML 5 mg. After 4 
Weeks ± 2 days the BP will be assessed again (Visit 3): controlled 
patients (SBP/DBP ≤  130/80 mmHg)  will continue the same 
extemporaneous combination, while uncontrolled (SBP/DBP 
>130/80 mmHg)   patients will be up-titrated from extemporaneous 
combination ZOF/AML 30/5 mg to extemporaneous combination of 
ZOF/AML 30/10 mg for further 4 weeks ± 2 days (Visit 4, Week 8). 
 
At Visit 2 and Visit 3 patients with SBP/DBP value classified as 
Grade 3 (SBP ≥ 180 or DBP ≥ 110 mmHg) hypertension will be 
withdrawn from the study.  
 
*To be enrolled in the study, patients could be in monotherapy with 
one of the listed CCBs: felodipine, isradipine, lacidipine, lercanidipine, 
nicardipine, nifedipine, and nisoldipine.  
 
Statistical 
Assumptions 
 
 
 
 
 
 
The primary endpoint will be assessed before and after assessment 
period at Week 8, by a paired t-test using the Intention-to-treat (ITT) 
population and the Per-Protocol (PP) population. 
All the other continuous secondary/exploratory endpoints will be 
assessed before (Week 0) and after treatment (at Week 8) by a paired 
t-test. 
All secondary/exploratory endpoints related to proportion of patients 
achieving the BP goal at Week 4 and Week 8 will be analysed 
descriptively producing also the relative 95% CI to assess if there is a 
significant difference from Week 0 where all patients were 
uncontrolled. 

 
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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 (SD) for this difference of 10 mmHg. The mean change in 
DBP for the null hypothesis is set equal to 2 mmHg. 
 
2.1 
Study Scheme 
 
 
 
# There is not a randomization procedure 
 
§Allowed CCBs at screening: Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and 
nisoldipine.  
Subjects treated with Amlodipine 10 mg or Zofenopril other than 30 mg will not undergo screening procedures. 
Grade 1-2 hypertensive patients mean: Blood pressure [BP] ranging from ≥140/90 mmHg to ≤179/109 
mmHg) 

 
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Uncontrolled patients with Grade 1-2 hypertension mean: Sitting SBP/DBP >130/80 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 mean: SBP/DBP ≤130/80 mmHg 
 
 

 
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2.2 
Study Flow Chart 
The assessment schedule lists all the assessments and when they are performed. All data 
obtained from these assessments mut be supported in the subject’s source documentation. 
Subjects who prematurely discontinued the study for any reason should be scheduled for a visit 
as soon as possible.  All the assessments listed for the final visit (Visit 4) will be performed. At 
this final visit, all dispensed investigational treatment should be reconciled, and the adverse 
events and concomitant medications recorded in the eCRF. 
 
Informed consent must be signed prior to any study-related procedure.  

 
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VISIT 1 / WEEK -4 
VISIT 2 / 
WEEK 0± 2 
days 
VISIT 3 / 
WEEK 4± 2 
days 
VISIT 4 / WEEK 
8± 2 days 
Informed consent submitted  
 
 
 
 
IWRSf registration 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
Medical history 
 
 
 
 
Prior medications 
 
 
 
 
Demographic information 
(for more details see section 8) 
 
 
 
 
 
Concurrent diseases and medical 
conditions 
 
 
 
 
Monotherapy of ZOF 30 mg or AML 5 
mg dispensinga 
 
 
 
 
Extemporaneous combination of 
ZOF/AML 30/5 mg dispensing 
 
 
b 
 
Extemporaneous combination of 
ZOF/AML 30/10 mg dispensing 
 
 
c 
 
Study drug return/accounting 
(Compliance assessment) 
 
 
 
 
Concomitant medications 
 
 
 
 
Urine Pregnancy test 
 
 
 
 
Physical examination 
(for more details see section 8) 
 
 
 
 
Vital signs 
(for more details see section 8) 
 
 
 
 
Laboratory testsd 
 
 
 
 
Blood pressure assessment 
 
 
 
 
ECG 
 
 
 
 
AE/SAE assessmente 
 
 
 
 

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a. Patients on ZOF 30 mg or AML 5 mg will continue the same therapy for 4 weeks. Patients on any other 
ACE-i will be assigned to monotherapy with ZOF 30 mg and the patients on other CCBs (the allowed CCBs 
are: felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine) will be assigned 
to monotherapy with AML 5 mg
b. Only patients controlled at Visit 3 will receive ZOF/AML 30/5 mg
c. Only patients uncontrolled at Visit 3 will receive ZOF/AML 30/10 mg. 
d. To ensure patient safety, the patients will be contacted over phone within 24 hours, in case of any 
abnormality and clinically relevant laboratory test according to the Investigator’s judgement at any visit
e. The Investigator is expected to also record any AE which was ongoing at the last treatment dose and a
follow-up phone call should be made after 2 weeks from the last study visit.
In case AE was ongoing, the Investigator is expected to follow-up until the outcome of the AE has been
determined.
f. IWRS- Interactive Web Response System
g. The following procedure is applied only in case of COVID-19 restrictions.
h. Patients will be provided with an automatic blood pressure device to be used in case they are not able to go
to the study centre due to Covid-19 pandemic situation.
i. The patient will return the device at the last visit at the site
BP device provided to patientsh 
 
Patient diary provided to patientsg 
 
 
 
Patient diary to be returned by patient if 
used g 
 
 
BP device returned to sitei 


 
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3 
STUDY RATIONALE AND BACKGROUND INFORMATION 
 
The global prevalence of hypertension was estimated to be 1.13 billion in 2015, with a 
prevalence of over 150 million in central and eastern Europe. The overall prevalence of 
hypertension in adults is around 30 - 45%1. Elevated blood pressure (BP) was the leading 
global contributor to premature death in 2015, accounting for almost 10 million deaths and over 
200 million disability-adjusted life years2. 
There are two well-established strategies to lower BP: lifestyle interventions and drug 
treatment3. 
The drug treatment of hypertension is founded on very solid evidence, supported by the largest 
number of outcomes based RCTs in clinical medicine. Meta-analyses of RCTs including 
several hundred thousand patients have shown that a 10 mmHg reduction in SBP or a 5 mmHg 
reduction in DBP is associated with significant reductions in all major CV events (MACE) by 
20%, all-cause mortality by 10 - 15%, stroke by 35%, coronary events by 20%, and heart 
failure by 40%4,5. 
Guidelines have generated a variety of different strategies to initiate and escalate BP-lowering 
medication to improve BP control rates. In previous 2013 Guidelines, the emphasis was on 
initial use of different monotherapies, increasing their dose, or substituting for another 
monotherapy3.  
However, increasing the dose of monotherapy produces little improvement in lowering the BP 
and may increase the risk of adverse effects, whilst switching from one monotherapy to another 
is frustrating, time consuming, and often ineffective. Due to these reasons, 2018 ESC/ESH 
Guidelines have increasingly focused on the stepped care approach, initiating treatment with 
different monotherapies and then sequentially adding other drugs until BP control is achieved3. 
Despite this, BP control rates have remained poor worldwide, only 40% of patients with 
hypertension being treated and of these, only 35% being controlled to a BP of <140/90 mmHg1. 
This has become an even more pressing matter because, based on new evidence, current 
guidelines are recommending more stringent BP targets (on-treatment values of <130/80 
mmHg in the general population and <140/90 mmHg in older hypertensive people), which will 
make the achievement of BP control even more challenging3. 
Patients with hypertension are generally treated with multiple pharmaceutical products, Fixed 
Dose Combinations (FDC) have generated increasing interest and have been recommended in 
treatment guidelines due to advantages in dosing and compliance, leading to improved 
treatment outcomes 10,11. 

 
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One of the main reasons why the current treatment strategy has failed to achieve better BP 
control rates is the insufficient use of the combination treatment10,11. 
Blood Pressure is 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 inadequate 
therapy in most patients. Indeed, almost all patients in RCTs have required combinations of 
drugs to control their BP6. 
Zofenopril has been widely investigated for the treatment of patients with hypertension and its 
BP lowering effect has been compared with either placebo or with all the classes of 
antihypertensive drugs currently recommended for the treatment of hypertension. Although 
there are data in literature showing an added antihypertensive effect of Amlodipine or 
Zofenopril to other antihypertensive treatment,9 there is scarce evidence at the moment on the 
antihypertensive effect of the extemporaneous combination of ZOF and AML versus each 
monotherapy. The trial will be conducted in compliance with the protocol, GCP and the 
applicable regulatory requirements. 
Amlodipine (a CCB) and Zofenopril (an ACE inhibitor) are antihypertensive drugs widely 
prescribed as monotherapies in the real world, according to treatment guidelines. Both drugs 
have specific benefit-risk profiles with different mechanism of action9.  
Amlodipine belongs to the dihydropyridine class of calcium channel blockers7. Amlodipine, 
like other calcium channel blockers, 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 blood 
pressure monitoring7.  
 
3.1 
Assessment of Potential Risks and Benefits 
Extemporaneous combination of ACE-i and CCBs are often prescribed to control BP without 
major reported risks. Several clinical studies have demonstrated how this combination is 
effective in lowering BP12,13. Furthermore, the combination does not significantly increase the 
incidence of adverse events compared with either agent alone12,13. 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 monotherapy15. Hypertension to goal blood 

 
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pressure (BP) is an important objective. Approximately, 70% of patients with hypertension 
require 2 or more agents to achieve their target BP16. 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 stroke17.  
 
 
4 
TRIAL OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
• 
To 
assess 
the 
anti-
hypertensive efficacy of the 
extemporaneous 
combination of ZOF 30 mg 
in combination with AML 5 
mg or AML 10 mg in 
lowering 
the 
sitting 
diastolic BP between Visit 2 
(Week 0) and Visit 4 (Week 
8) 
in 
patients 
with 
uncontrolled BP previously 
treated with Zofenopril or 
Amlodipine 
(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 literature15,  
Secondary 
 
• 
To 
assess 
the 
antihypertensive efficacy of 
the 
extemporaneous 
combination of ZOF 30 mg 
in combination with AML 5 
mg or AML 10 mg in 
lowering sitting systolic BP 
(SBP) between Visit 2 
(Week 0) and Visit 4 (Week 
 
• 
Change in mean sitting SBP 
between Visit 2 (Week 0) 
and Visit 4 (Week 8). 
 
 
 
 
 
 
 
• 
Change in SBP after 8 
weeks 
of 
treatment 
is 
intended to show the added 
efficacy 
of 
the 
extemporaneous 
combination also on SBP 
considering its link to the 
cardiovascular 
disease 
(CVD) 

 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
8) 
in 
patients 
with 
uncontrolled BP previously 
treated with ZOF or AML 5 
mg  monotherapies for at 
least 4 weeks. 
 
• 
To 
assess 
the 
antihypertensive efficacy of 
the 
extemporaneous 
combination of ZOF/AML 
30/10 mg vs. ZOF/AML 
30/5 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 ZOF or AML 5 
mg monotherapies for at 
least 4 weeks 
 
• 
To 
evaluate 
the 
total 
number and percentage of 
patients who achieved the 
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 (ZOF 30 mg 
and AML 5 mg) after 4 
 
 
 
 
 
 
• 
Change in mean sitting DBP 
and SBP between Visit 3 
(Week 4) and 4 (Week 8) in 
patients on combination of 
ZOF/AML 
30/5 
with 
uncontrolled BP at Visit 3 
and up titrated to the 
extemporaneous 
combination of ZOF/AML 
30/10 mg 
 
 
 
 
• 
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). 
 
 
• 
Adherence to the treatments 
(percentage (%) 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 (ZOF 30 
mg and AML 5 mg) after 4 
weeks of therapy and of the 
 
 
 
 
 
 
 
• 
The number and proportion 
of 
patients 
with 
uncontrolled BP following 
the shift from ZOF/AML 
30/5 mg to ZOF/AML 
30/10 mg is very important 
to assess the contribution by 
AML 10 mg in reaching the 
BP target 
 
 
 
 
 
• 
The proportion of patients at 
target is a very important 
clinical 
indicator 
of 
therapeutic success  
 
 
 
 
• 
Monitoring compliance is 
extremely 
important 
to 
better 
understand 
the 
efficacy and tolerability of 
the 
extemporaneous 
combination 
 
• 
Incidence of ADRs, AEs, 
SAEs, vital signs, physical 
examination, 
ECG, 
and 

 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
weeks of therapy and of the 
extemporaneous 
combinations (ZOF 30 mg 
and AML 5 mg or AML 10 
mg) after 8 weeks of 
treatment. These objectives 
should be the same as the 
objectives contained in the 
body of the protocol. 
extemporaneous 
combination (ZOF 30 mg 
and AML 5 mg or AML 10 
mg) after eight weeks of 
treatment.    
 
concomitant 
medications 
needs to be studied to 
address 
safety 
and 
tolerability 
of 
the 
extemporaneous 
combination for a safe and 
optimal use of the treatment 
 
 
 
Exploratory objective 
• 
To assess change in mean 
sitting SBP and DBP 
between Visit 1 (week -4) 
and Visit 2 (Week 0), Visit 
3 (Week 4) and Visit 4 
(Week 8): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Change in mean sitting 
SBP and DBP between 
Visit 1 (week -4) and Visit 
2 (Week 0), Visit 3 (Week 
4) and Visit 4 (Week 8): 
 
In the group of patients who 
were on ZOF 30 mg and 
AML 5 mg at Visit 1 and 
continued 
the 
same 
therapies at Visit 1  
o In the group of patients 
who switched to ZOF 30 mg 
or AML 5 mg from any 
other ACE-i or CCBs at 
Visit 1 
o Change in mean sitting 
SBP 
and 
DBP, 
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) 
and Visit 3 (Week 4):  
• 
Evaluation of the 
antihypertensive efficacy of 
monotherapies and 
combination therapy in 
patients with different 
associated CV risk factors 
(Hypertension grade, 
presence of diabetes, and/or 
hypercholesterolemia) 
• 
 

 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
 
 
 
 
 
 
 
 
 
 
• 
To assess the 
antihypertensive efficacy at 
different time points in 
patients who (1) received 
ZOF or AMLO 
monotherapies before the 
run-in period, (2) received 
any other ACE-i or CCB 
monotherapies before the 
run-in period 
 
o In the group of patients 
who were on ZOF 30 mg 
and AML 5 mg at Visit 1 
(week -4) and continued 
with the same therapies  
o In the group of patients 
who switched to ZOF 30 
mg or AML 5 mg from any 
other ACE-i or CCBs at 
Visit 1 (week -4)   
 
 
• 
Number and proportion of 
patients divided in 
subgroup by 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 ZOF 30 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 ZOF 30 
mg or AML 5 mg from any 
other ACE-i or CCBs at 
Visit 1 (Week 4) 
 
 
 
 
 
 

 
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5 
STUDY DESIGN 
 
This is a phase IV, open-label, multicentre, multinational study with 2 study periods: a 4-week 
run-in period and an 8-week assessment period.  
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.  
Patients with Grade 1-2 hypertensive patients (blood pressure [BP] ranging from ≥140/90 
mmHg to ≤179/109 mmHg) on treatment with any angiotensin converting enzyme inhibitors 
(ACE-i) including Zofenopril 30 mg or with calcium channel blockers (CCBs) including 
Amlodipine 5 mg will be screened for eligibility (Visit 1).  
Allowed CCBs: Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, and 
nisoldipine. Patients treated with other dosages of Zofenopril (other than 30 mg) are not 
allowed to be screened. 
After screening, on the same day, eligible patients, will enter into a 4-week run-in period, 
during which patients on other ACE-i  will be assigned to monotherapy with ZOF 30 mg while 
patients on CCBs§ will be assigned to monotherapy with AML 5 mg for 4 weeks. Patients with 
on-going treatment zofenopril 30 mg and amlodipine 5mg will continue on the same treatment 
for 4 weeks. 
 
After the run-in period (4 weeks ± 2 days), BP will be further assessed (Visit 2), if BP levels 
are over the defined controlled target goal  (sitting SBP/DBP >130/80 mmHg), treatment is 
well tolerated and adherence to the treatments ranges from 80% to 120%, patients will enter the 
assessment period, where they will be assigned to the extemporaneous combination of ZOF 30 
mg and AML 5 mg. At Visit 2 patients with SBP/DBP values classified as Grade 3 (SBP ≥ 180 
or DBP ≥ 110 mmHg) hypertension will be withdrawn from the study.  
 
If patients, at Visit 2, after the run-in period, have a controlled BP (sitting SBP/DBP≤130/80 
mmHg) or do not tolerate the treatment or have an adherence range below 80% or superior to 
120%, they will be withdrawn from the study. 
 
The patients will be assessed for further 8 weeks (assessment period). 
After 4 weeks ± 2 days from Visit 2,during  the assessment period patients receiving the 
extemporaneous combination of ZOF 30 mg and AML 5 mg, will be further evaluated (Visit 
3):  controlled patients (sitting SBP/DBP ≤130/80 mmHg) will continue the same 

 
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extemporaneous combination for additional 4 weeks ± 2 days, while uncontrolled patients 
(sitting SBP/DBP >130/80 mmHg) will be up-titrated from ZOF/AML 30/5 mg to ZOF/AML 
30/10 mg for further 4 weeks ± 2 days.   
At Visit 3 patients with SBP/DBP values classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 
mmHg) hypertension will be withdrawn from the study. 
If patients at Visit 3, do not tolerate the extemporaneous combination treatment or they have an 
adherence range below 80% or superior to 120%, they will be withdrawn from the study. 
At the end of the assessment period (8 weeks ± 4 days) at Visit 4, the anti-hypertensive effect 
of the extemporaneous combination (ZOF/AML 30/5 mg and ZOF/AML 30/10 mg) will be 
evaluated. 
Efforts will be made to achieve 1:1 ratio in the enrolment of patients receiving any ACE-i or 
allowed CCBs (refer to section Subject Study Phases Duration for allowed CCBs). At Visit 2, a 
minimum of 45% of uncontrolled patients receiving treatment with ZOF 30 mg or AML 5 mg 
are required to enter the assessment period, in order to maintain a balance between the 2 
treatments during the assessment period. 
 
5.1 
Procedures and Study Visits 
 
Patients will attend a total of four visits during the study for a duration of 12 weeks. A total 
number of 290 patients will be screened considering 25% of drop-out rate, to obtain at least 216 
patients complete the run-in period and start with the assessment period. The description of the 
activities, procedures, and tests to be performed at each visit is detailed below:   
Screening Visit 1 (Week -4) 
The following procedures/assessments will be performed during the Screening Visit 1: 
• Informed consent 
• Interactive Web Response System (IWRS) registration to register the treatment 
allocation  
• Verification of inclusion and exclusion criteria 
• Collection and review of Medical history 
• Collection and review of Prior and concomitant medications 
• Collection of Demographic data 
• Recording of concurrent diseases and medical conditions 

 
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• Physical Examination 
• Vital sign measurements 
• BP Measurement 
• ECG 
• Perform Urine Pregnancy Test (UPT) to female of child-bearing potential 
• Perform Local Laboratory Tests 
• Adverse Event (AE) and Serious Adverse Event (SAE) Assessment 
• Paper instruction to use automatic blood pressure device, including patient’s diary 
provided to the patient 
• Automatic blood pressure device provided to patients: to be used in case of Covid-19 
pandemic situation emergency procedures (Section 2.3) 
 
Patients meeting all inclusion criteria and none of the exclusion criteria will enter the run-in 
period on the same day and will receive monotherapy of ZOF 30 mg or AML 5 mg. 
 
• Patients who are already on therapy with ZOF 30 mg or AML 5 mg will be 
provided with the same medication 
• Patients taking any other CCBs (refer to section Subject Study Phases 
Duration for allowed CCBs) will be provided with AML 5 mg, and patients 
taking any other ACE-i will be provided with ZOF 30 mg. Patients entering 
this phase in therapy with ZOF 30 mg or AML 5 mg should be as close as 
possible to a 1:1 ratio. 
Visit 2 (Week 0 ± 2 days):  
The following procedures/assessments will be performed at Visit 2: 
• Recording of concurrent diseases and medical conditions  
• Concomitant medications 
• Vital sign measurements 
• Physical Examination 
• BP Measurement 
• Urine pregnancy test (UPT) 

 
Corporate Medical Department 
 
Identification Number 
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Effective date 
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2.0, CURRENT 
Effective 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 31 a 91 
 
• Study Drug Compliance assessment by return of monotherapy ZOF and AML tablets 
(also empty blister) and IP accountability 
• AEs and serious adverse events (SAEs) assessment 
• IWRS update 
• Patient’s instruction to use the automatic blood pressure device, including patient’s diary 
to be returned at site by the patient 
 
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 assessment period 
and at this visit will be dispensed with extemporaneous combination of ZOF 30 mg and AML 
5 mg.  
To correctly evaluate the additional effect of the combination therapy, the number of patients 
with uncontrolled BP on AML or ZOF 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 arm (i.e., AML 
and ZOF) will be included at Visit 2 in order to maintain a balanced number of uncontrolled 
patients entering the assessment period for each drug (please refer to section 8 IWRS 
registration). 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 
enrol a greater number of patients being treated with the least represented drug in the 
assessment period. 
Visit 3 (Week 4 ± 2 days) 
The following procedures/assessments will be performed at Visit 3: 
• Recording of concurrent diseases and medical conditions  
• Concomitant medications 
• Vital sign measurements 
• Physical Examinations 
• BP Measurement 
• Urine pregnancy test (UPT) 
• Study 
Drug 
Compliance 
assessment 
(Study 
Drug 
Compliance 
assessment 
extemporaneous combination of ZOF 30 mg and AML 5 mg) return (also empty blisters) 
and IP accountability 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 32 a 91 
 
• AEs and serious adverse events (SAEs) assessment 
• IWRS updates 
• Patient’s instruction to use the automatic blood pressure device, including patient’s diary 
to be returned at site by the patient 
At Visit 3, BP will be assessed, and controlled patients will continue the same extemporaneous 
combination from ZOF/AML 30/5 mg, while uncontrolled patients (SBP/DBP >130/80 mmHg) 
will be up titrated to ZOF/AML 30/10 mg for a further 4 weeks 
Visit 4 (Week 8 ± 2 days) 
 The following procedures/assessments will be performed at Visit 4: 
• Recording of concurrent diseases and medical conditions 
• Concomitant medications 
• Vital sign measurements 
• Physical Examinations 
• BP Measurement 
• ECG 
• Perform Urine Pregnancy Test (UPT) 
• Perform Local Laboratory Tests 
• Patient’s instruction to use the automatic blood pressure device, including patient’s 
diary to be returned at site by the patient 
• Patients return of the automatic BP device to the site 
• Study Drug Compliance assessment [extemporaneous combination of ZOF 30 mg 
and AML 5 mg/10 mg) return (also empty blisters) and IP accountability] 
• AEs and serious adverse events (SAEs) 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  
 
The Investigator is expected to record any AE which was ongoing at the last treatment dose and 
a follow-up phone call should be made after 2 weeks from the last study visit. 
In case of an ongoing AE, the Investigator is expected to follow-up until the outcome of the AE 
has been determined. 
 

 
Corporate Medical Department 
 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 33 a 91 
 
The details of the study visits are described in the Study Flow Chart Section 2.3. 
 
6 
SELECTION OF SUBJECTS 
The following subject will be screened: 
 
• Male or female, (Grade 1-2), uncontrolled hypertensive patients ≥18 and ≤65 years of 
age 
• Considering a screening failure and a drop-out rate of 25%, the overall number of 
patients to be screened is 290. 
• 216 patients needed to complete the run-in period and enter the assessment period to 
guarantee powered results  
 
6.1 
Informed Consent Process 
Prior to the subject’s enrolment into the study and before performing any study-related 
procedures, the Investigator - or its authorized delegate - shall obtain the subject’s written, 
dated and signed informed consent to participate into the study and process personal data  for 
processing and transferring necessary documentation of the subject’s health and personal data 
to the CRO, Sponsor and its Affiliates, the competent Health Authorities 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 ICF refer to Section 17 PERSONAL DATA 
PROTECTION  ). 
Institution and Investigator undertake to duly inform subjects 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 subject 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 originally signed ICF in the Investigator’s File, and 
the subject 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 EC for approval. 
The Investigator will ensure that this new consent form is signed by all subjects subsequently 
entered in the study and those currently in the study, if affected by the amendment. 
 
6.2 
Inclusion and Exclusion Criteria 
 
 Inclusion Criteria 
 

 
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Pag. 34 a 91 
 
A patient will be considered eligible for inclusion in the study only if all the following criteria 
are met:   
1. Male or female Grade 1-2 hypertensive patients:  with mean sitting SBP ≥140 mmHg 
and ≤179 mmHg and/or mean sitting DBP ≥ 90 mmHg and ≤109 mmHg at Screening, 
with ≥18 and ≤65 years of age, on monotherapy either with ZOF 30 mg or AML 5mg or 
any other ACE-I or CCBs (Felodipine, isradipine, lacidipine, lercanidipine, nicardipine, 
nifedipine, and nisoldipine) for at least 1 month before Visit 1 (Screening). 
2. Patients who are able to understand and give written informed consent at Screening 
3. Patients who are available for the entire trial period and willing to adhere to the protocol 
requirements  
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 must 
refrain from donating or storing eggs. For females of reproductive potential: use of highly 
effective contraception (e.g., 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 less 
than 1% per year) such as: 
• Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner (performed at least 2 months before screening) (if the 
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: 
 

 
Corporate Medical Department 
 
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Pag. 35 a 91 
 
1. Known contraindications, presence of not recommended/contraindicated concomitant 
therapy allergies, or significant history of hypersensitivity to zofenopril, amlodipine, other 
ACE-inhibitors or dihydropyridines, or any related products (including excipients of the 
formulations as outlined in the Investigator’s Brochure [IB]), or summary of product 
characteristics (SmPCs) or local package inserts for AML and ZOF  
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, 
haematological, or oncological, neurological, and psychiatric diseases. The same applies for 
immunocompromised and/or neutropenic patients 
3. Patients having a history of the following within the last 6 months: myocardial infarction, 
unstable angina pectoris, percutaneous coronary intervention, bypass surgery, valve 
replacement (transcatheter aortic valve implantation, mitraclip),cerebrovascular accident 
(stroke, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or 
transient ischemic attack. Patients with who have undergone other surgery that in the in the 
opinion of the Investigator may limit the ability to evaluate the efficacy or safety of the tested 
medications. 
4. Patients with secondary hypertension of any aetiology such as renal diseases, 
pheochromocytoma, Cushing’s syndrome hyperaldosteronism, renovascular disease, thyroid 
disorders  
5. Patients with severe heart failure (New York Heart Association classification III-IV), a 
narrowing of the aortic or bicuspid valve, an obstruction of cardiac outflow (obstructive, 
hypertrophic cardiomyopathy) or symptomatic coronary disease 
6. Patients with clinical evidence of renal disease as per the Investigator’s judgement (including 
renovascular occlusive disease, nephrectomy and/or renal transplant, bilateral renal artery 
stenosis or unilateral renal artery stenosis in a solitary kidney, or severe renal impairment) 
7. Patients with history of angioneurotic oedema 
8. Patients with clinically relevant hepatic impairment  
9. Patients with sick sinus syndrome, including sino-atrial block 
10. Patients with second- or third-degree heart block (without a pacemaker) 
11. Participation in any other interventional drug trial or exposure to other investigational agents 
within 30 days before Screening (Visit 1)  
12. Inability to cooperate or any condition that, in the opinion of the Investigator, could increase 
the patient’s risk of participating in the study or confound the outcome of the study 

 
Corporate Medical Department 
 
Identification Number 
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Effective date 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 36 a 91 
 
13. Patients with conditions that, in the opinion of the Investigator, would prevent a careful 
adherence to the protocol 
14. Patients with severe hypotension  
15. Patients who suffer from shock (including cardiogenic shock) 
16. Patients treated with Amlodipine 10 mg and Zofenopril (other than 30 mg) 
 
 Screening Failures 
 
All patients who have signed an informed consent form but do not enter into the Run-in period 
(failure to meet at least one of the inclusion criteria and/or met at least 1 of the exclusion 
criteria) will be classified as a screening failure. Screening failures need to have the screening 
completion eCRF for run-in period, demographics, inclusion / exclusion criteria and any SAE 
collected. There will be no re-screening allowed for screening failure patients.  
 
7 
STUDY TREATMENT 
 
 
7.1 
Study Treatment Formulation, Appearance, Packaging, and Labeling 
 
Zofenopril calcium will be provided as 30 mg film coated tablets 
 
Amlodipine (as besylate) will be provided as 5 mg and 10 mg tablets 
 
The treatments administered during the run-in period of the study are AML 5 mg tablets or 
ZOF 30 mg film-coated tablets. The patients who are eligible (uncontrolled hypertension with 
sitting BP of SBP/DBP >130/80 mmHg, who tolerated the treatment and whose adherence to 
the therapies ranges from 80% to 120%) for the assessment period will be given a combination 
of AML 5 mg and ZOF 30 mg or AML 10 mg and ZOF 30 mg. Details on the study design is 
provided in Section 5. 
 

 
Corporate Medical Department 
 
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Effective date 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 37 a 91 
 
Study Treatment Name: 
Amlodipine 
Marketing Authorisation Holder:  
EG S.p.A. 
Via Pavia, 6 
20136 Milano 
Italy 
Zofenopril calcium 
Marketing Authorisation Holder: 
Laboratori Guidotti S.p.A. - Via 
Livornese 897, PISA – La Vettola 
Concessionario per la vendita: A. 
Menarini Industrie Farmaceutiche 
Riunite s.r.l., Via Sette Santi, 3 – 
Firenze, Italy 
Dosage Formulation: 
Tablets 
Film-coated tablets 
Unit Dose Strength(s)/Dosage 
Level(s): 
5 mg once daily 
10 mg once daily 
30 mg once daily 
Route of Administration:  
Oral 
Oral 
Dosing Instructions*: 
1 tablet of study medication to be 
administered with water, once daily 
and according to instructions provided 
by Principal Investigator 
1 tablet of study medication to be 
administered with water, once daily and 
according to instructions provided by 
Principal Investigator 
Packaging and Labelling: 
Study medication will be provided in 
its original marketed PVC//Aluminium 
blisters 
Study medication will be provided in its 
original marketed a 
PVDC/PVC//Aluminium blisters 
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 
storage conditions 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 storage conditions are 
needed. 
 
Study treatment dosage form, strength, formulation: 
Amlodipine 5 mg: AML 5 mg is white, round, tablet  
Amlodipine 10 mg: AML 10 mg is white, round, tablet with one break on one side  

 
Corporate Medical Department 
 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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Zofenopril calcium 30 mg: ZOF 30 mg is white, oblong film-coated tablet with break marks on 
both sides. 
 
Study treatment manufacturing 
The AML 5/10 tablets and ZOF 30 mg film-coated tablets will be sourced as authorized EU 
marketed products from a commercial supplier in the European market. 
Marketing Authorization Holders (MAH) are reported in relative SmPC7,8. 
 
Study treatment packaging and labelling 
The study treatment packaging and labelling operations are performed by 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 ZOF 30 mg and AML 5/10 mg will be provided in dedicated treatment Patient Kits to be 
dispensed at Visit 1 (Run In) and at Visit 2 and Visit 3 (Assessment). 
 
Visit 1 (Screening- start Run In) 
• ZOF 30 mg: each trial participant is provided with one labelled Patient Kit (blue label) 
containing 42 film-coated tablets (3 blisters of 14 tablets each) of zofenopril calcium 30 
mg. 
• AML 5 mg: each trial participant is provided with one labelled Patient Kit (yellow 
label) containing 42 tablets (3 blisters of 14 tablets each) of amlodipine 5 mg. 
 
Trial participant must be instructed by Investigator to take one tablet of ZOF 30 mg or AML  5 
mg, according to Study Protocol. 
 

 
Corporate Medical Department 
 
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State 
Effective date 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 39 a 91 
 
Visit 2 (start of Assessment) 
Participants with uncontrolled BP (>130/80 mmHg) will be provided with ZOF 30 mg and 
AML 5 mg while participants with controlled BP (≤130/80 mmHg) will be withdrawn from the 
study  
Each trial participant is provided with one treatment Patient Kit made up by 
• ZOF 30 mg: one labelled box (white label) containing 42 film-coated tablets (3 blisters 
with 14 film coated tablets each) of zofenopril calcium 30 mg 
• AML 5 mg: one labelled box (white label) containing 42 tablets (3 blisters with 14 
tablets each) of amlodipine 5 mg. 
 
The two white labelled boxes are then sealed together into a transparent plastic film to realize 
the treatment Patient Kit. 
Trial participant must be carefully instructed by Investigator to take simultaneously (at the 
same time): ZOF 30 mg (zofenopril calcium 30 mg) as one oblong film-coated tablet and AML 
5 mg (amlodipine 5 mg) as one round tablet, according to Study Protocol. 
 
Visit 3 (Assessment) 
Participants with controlled BP (≤130/80 mmHg) are provided with one treatment kit made 
up by: 
• ZOF 30 mg: one labelled box (white label) containing 42 film-coated tablets (3 blisters 
with 14 film coated tablets each) of zofenopril calcium 30 mg 
• AML 5 mg: one labelled box (white label) containing 42 tablets (3 blisters with 14 
tablets each) of amlodipine 5 mg. 
The two white labelled boxes are then sealed together into a transparent plastic film to realize 
the treatment kit. 
Trial participant must be carefully instructed by Investigator to take simultaneously (at the 
same time): ZOF 30 mg (zofenopril calcium 30 mg) as one oblong film-coated tablet and AML 
5 mg (amlodipine 5 mg) as one round tablet, according to Study Protocol. 
 
Participants with SBP/DBP values classified as Grade 3 hypertension will be withdrawn from 
the study 
Participants with uncontrolled BP (>130/80 mmHg) are provided with one treatment Patient 
Kit made up by: 

 
Corporate Medical Department 
 
Identification Number 
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Effective date 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 40 a 91 
 
o 
ZOF 30 mg: one labelled box (green label) containing 42 film-coated tablets (3 blisters 
with 14 film coated tablets each) of zofenopril calcium 30 mg 
o 
AML 10 mg: one labelled box (green label) containing 42 tablets (3 blisters with 14 
tablets each) of amlodipine 10 mg. 
The two green labelled boxes are then sealed together into a transparent plastic film to identify 
the treatment Patient Kit. 
Trial participant must be carefully instructed by Investigator to take simultaneously (at the 
same time): ZOF 30 mg (zofenopril calcium 30 mg) as one oblong film-coated tablet and AML  
10 mg (amlodipine 10 mg) as one round tablet (with one break on one side), according to Study 
Protocol 
 
7.2 
Study Treatment Distribution and Return / Destruction 
 
All the study drugs must be retained at the investigational site for accountability, destruction 
and return of study supplies.  
The investigator or designee will acknowledge receipt of the investigational product, 
documenting shipment content and condition.  
Accurate records of all investigational product dispensed, used, returned, and/or destroyed must 
be maintained.  
The investigator is responsible for ensuring the retrieval of all study supplies from patients. 
 
At the conclusion of the study, any unused investigational product will either be destroyed at 
the investigator site or be returned to the Sponsor or its designee for destruction and destruction 
will be documented appropriately.  
If no supplies remain, this fact will be documented appropriately 
Destruction of returned investigational products must carried out after written authorization of 
the Sponsor 
 
7.3 
Product Storage and Stability 
 
No special storage conditions are required. However, the verification of the storage conditions 
along with the relevant records will be monitored at the trial site. 
 

 
Corporate Medical Department 
 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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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. 
 
7.4 
Study Product Compliance 
 
The investigator must promote compliance by instructing the patient to the study treatment 
exactly as prescribed and by stating the compliance is necessary for the patient’s safety and the 
validity of the study. The investigator has to instruct patients to return the study treatment (if 
any or empty boxes for accountability) at each visit.  
 
Investigator should instruct the patient to take the study drug at the same time every day, in the 
morning. On the days of the patient’s visits, the investigator should instruct the patient to not 
take the study drug at home.  
 
In case a patient forgets to take a dose, he/she can by take the study drug the same day. Patients 
should not take the study drug after 16.00 (4 pm) on the visit days. The investigator should 
instruct the patient to not take the dose at home. 
 
The compliance to the treatment (percentage of actual doses taken versus doses to be taken) 
will be assessed by the investigator and/or study personnel at Visit 2 (Week 0), at Visit 3 
(Week 4) and at Visit 4 (Week 8).  This information should be captured in the source document 
and in the eCRFs at each visit.  
 
Adherence to treatment will be measured through treatment compliance which is 100 × (actual 
doses taken/planned dose). 
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) 
 
The investigator must instruct the patient to notify the study site about any new medication 
he/she takes after being enrolled into the study. All medication, procedures and significant non-
drug therapies administered after the patient was enrolled at the study must be recorded in the 

 
Corporate Medical Department 
 
Identification Number 
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Effective date 
FORM-000050125 
2.0, CURRENT 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 42 a 91 
 
appropriate eCRF. Each concomitant drug must be individually assessed against all exclusion 
criteria/prohibited medication. If the patient is already enrolled, please contact BIORASI to 
determine if the patient should continue participation in the study. 
 
7.6 
Not permitted medications 
 
Blood pressure modifying drugs,  even though used for other indications like alpha receptor 
blockers and agonists, beta receptor blockers and agonists, calcium antagonists, angiotensin 
converting enzyme (ACE) inhibitors, diuretics, centrally acting antihypertensives (e.g. 
clonidine, methyldopa, guanfacine), reserpine, moxonidine, chronic nitrate treatment (e.g. 
isosorbide dinitrate or isosorbide mononitrate), potassium sparing diuretics, potassium 
supplements, potassium-containing salt substitutes or other agents that increase serum 
potassium, PDE - inhibitors and angiotensin II antagonists will be prohibited during the study.  
 
The Investigator has to instruct patients to refer to the study doctor before they administer any 
medicinal substances or products listed in section 4.5 of the Zofenopril and Amlodipine 
SmPC7,8.    
 
7.7 
Rescue Medicine 
 
Not Applicable. 
 
8 
STUDY ASSESSMENT AND PROCEDURES 
 
The following study assessment and procedures will proceed according to the Study Flow 
Chart in Section 2.3.  
 
Informed Consent 
 
A signed and dated, study-specific, Independent Ethics Committee (IEC) approved consent 
form must be obtained from each patient at the Screening Visit and prior to performing any 
study related procedures. No study related procedures or activities may be performed until each 
patient is fully informed and the consent form is duly read, understood, signed and dated. All 
patients will be given a copy of the signed and dated consent form. The Investigator must store 

 
Corporate Medical Department 
 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 43 a 91 
 
the originally signed ICF in the Investigator’s File, and the patient will be provided with a copy 
of it. For more details, please refer to Section 6.   
 
 Inclusion/Exclusion Criteria 
 
All patients who sign the ICF will be evaluated for inclusion and exclusion criteria to determine 
patient eligibility as described in Section 6.1. If the patient is determined to be ineligible prior 
to enrolment, the reason(s) for ineligibility must be documented by the Investigator. 
Verification of all inclusion and exclusion criteria, including all baseline assessments, will take 
place at the Screening Visit.  
 
Medical History 
A complete medical history for each patient will be recorded at the Screening Visit. A complete 
review of all current diseases, history of hypertension, and their respective durations and 
treatments will be conducted, and the relevant documentations will be filed in the Source 
Documentation.  
 
Prior medication 
 
 
At the Screening Visit, all medications taken within the 30 days prior to the start of the study 
will be recorded as Prior Medication with the corresponding indication, start and stop dates. 
Prior medications may include prescription, over-the counter (OTC) and all dietary 
supplements. A particular focus will be on prior medication to treat hypertension including 
zofenopril or amlodipine status and dosage.  
 
Demography 
 
After the informed consent has been signed and the patient’s eligibility to participate in the 
study has been determined at the Screening Visit, basic demographic information, including 
age, gender, race, height, and weight. The BMI (kg/m2) will be calculated will be recorded. 
Smoking status will be documented in the source documents and Ecrf. For female patients, the 
menopausal status would also be documented. 
 
IWRS registration: 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 44 a 91 
 
 
At Visit 1 all screened patients will be registered via Interactive (IWRS) to one of the allocated 
treatments: zofenopril 30 mg and amlodipine 5 mg. The investigator or his/her delegate will 
contact the IWRS after confirming that the patient fulfils all the inclusion /exclusion criteria. 
The percentage of enrolled patients coming from each monotherapy treatment, Zofenopril 30 
mg / Amlodipine 5 mg will be capped at 50% at Visit 2. 
IWRS must be updated at each visit, registering the status of the patient (failure, ongoing and 
which therapy the patient’s is administering) 
 
Concurrent diseases and medical conditions 
 
At each of the study visits (1, 2, 3, and 4) current diseases and medical conditions will be 
recorded including their date/time of diagnosis, duration, and treatment. Adverse event will be 
conditions arising after the start of the study, which should be recorded as adverse events as 
described in Section 9.1.  
 
Monotherapy of zofenopril 30 mg or amlodipine 5 mg dispensing 
 
• At the Screening Visit (Visit 1): 
o Patients who are currently being treated with zofenopril (ZOF) 30 mg or 
amlodipine (AML) 5 mg will continue the same therapy for 4 weeks.  
o Patients on any other ACE-i will be assigned to monotherapy with ZOF 30 mg 
for 4 weeks.  
o Patients on other CCBs (the allowed CCBs are: felodipine, isradipine, 
lacidipine, lercanidipine, nicardipine, nifedipine, and nisoldipine) will be 
assigned to monotherapy with AML 5 mg for 4 weeks. 
 
The study drugs will be dispensed such that patients have sufficient supply to last until the next 
visit (Visit 2). All patients will be counselled to keep the packaging and any remaining drug to 
be surrendered during Visit 2.  
Extemporaneous combination of ZOF/AML 30/5 mg dispensing 
 
At Visit 2 (after the run-in period (4 weeks ± 2 days) of monotherapy) if BP remains 
uncontrolled (sitting SBP/DBP >130/80 mmHg), treatment is well tolerated and adherence to 

 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 45 a 91 
 
the treatments ranges from 80% to 120%,  patients will enter the assessment period, where they 
will be assigned to the extemporaneous combination of ZOF 30 mg and AML 5 mg.  The study 
drugs will be dispensed such that patients have sufficient supply to last until the next visit (Visit 
3). All patients will be counselled to keep the packaging and remaining drug to be collected 
during Visit 3.  
At Visit 2 patients with SBP/DBP values classified as Grade 3 hypertension (SBP ≥ 180 or 
DBP ≥ 110 mmHg) will be withdrawn from the study. 
 
At Visit 3, if BP is controlled (≤130/80 mmHg), patients will continue the same 
extemporaneous combination ZOF/AML 30/5 mg for additional 4 weeks ± 2 days (Visit 4).   
 
Extemporaneous combination of ZOF/AML 30/10 mg dispensing 
 
At Visit 3, if BP is controlled, patients will continue the same extemporaneous combination for 
additional 4 weeks ± 2 days (Visit 4).  Uncontrolled patients (sitting SBP/DBP >130/80 
mmHg), will be up titrated from AML 5 mg to AML 10 mg for further 4 weeks ± 2 days (Visit 
4).  
At Visit 3 patients with SBP/DBP values classified as Grade 3 (SBP ≥ 180 or DBP ≥ 110 
mmHg) hypertension will be withdrawn from the study 
 
Study drug return/accounting (Compliance assessment) 
 
The study drugs will be dispensed on site such that patients have sufficient supply to last until 
the next visit. All patients will be counselled to keep the packaging and remaining drug to be 
returned to the site staff at the subsequent visit.  Site staff will collect the unused drug and 
packaging and provide an assessment of compliance at Visits 2, 3, and 4.  
 
Concomitant medications 
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. The concomitant medications will be recorded at the Screening 
Visit and each subsequent visit during the study.  
 

 
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8.1 
Assessment of Efficacy 
 
The primary objective of this study is to assess the anti-hypertensive efficacy of the 
extemporaneous combination of ZOF 30 mg in combination with AML 5 mg or AML 10 mg in 
lowering the sitting diastolic BP between Visit 2 (Week 0) and Visit 4 (Week 8) in patients 
with uncontrolled BP previously treated with Zofenopril or Amlodipine (5 mg) monotherapies 
for at least 4 weeks. The primary efficacy endpoint is change in mean sitting DBP between 
Visit 2 (Week 0) and Visit 4 (Week 8). To achieve this objective, the efficacy parameter BP 
will be measured at all visits as described below.  
 
Blood Pressure (BP) 
 
BP will be measured in both arms at the screening visit (Visit 1) to detect possible between-arm 
differences. The arm with the higher value of mean DBP will be identified as the reference arm 
and will be used at all subsequent visits for BP monitoring. Blood pressure measurements 
should be performed as nearly as possible at the same time of the day (7:00 – 12:00 a.m.), on 
the same arm, and using the same calibrated equipment at each visit.  
All BP measurements will be performed after at least 10 minutes rest in sitting position in 
triplicate (spaced by at least 1 minute) and once standing using an automatic device provided 
by MENARINI. The mean of the three recordings in sitting position will be used as the BP 
value for that visit and recorded in the source document and in the eCRF. All BP measurements 
during the treatment phase will be performed as through readings (i.e. 24 + 2 h after the last 
drug intake). Thus, the study drug should be taken at morning time Post-BP measurement.   
For this purpose, patients will be instructed to take study treatment at the same time each day 
except on the days of study visits when study treatment will be taken after all visit evaluations 
have been performed. 
 
8.2 
Assessment of Safety 
 
Safety will be assessed through collection of treatment-emergent AEs, serious AEs (SAE), , 
that started after the first dose of study treatments (incidence, severity, seriousness, treatment 
causality), and physical examination (, vital signs, BP, and heart rate). Safety assessments will 
be performed at time points as described in Section  9. 
 

 
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Pag. 47 a 91 
 
Urine Pregnancy test 
 
Study medication should not be given to pregnant female. Therefore, Urine Pregnancy tests 
will be performed in all females of childbearing potential at Screening and each subsequent 
visit during the study.  
 
Physical examination 
 
The Investigator (or site staff) must perform a complete physical examination at Screening and 
each subsequent visit during the study.  At the Screening visit height, weight (in indoor 
clothing but without shoes) and body mass index [BMI] calculation will be recorded. At all 
visits, the physical examination will include general appearance, skin, head, neck, ear-nose-
throat (ENT), heart, lungs, abdomen, extremities, neurological, musculoskeletal and lymph 
nodes. Information pertaining to physical examinations must be included in the source 
documentation at the study site. Any new finding, or worsening of a previous finding, should 
be reported as a new AE. 
 
Vital Signs 
 
Body temperature (°C) and heart rate will be measured under the same conditions at Screening 
and all subsequent visits (Visit 2, Visit 3, and Visit 4). If possible, vital sign assessment should 
be performed by the same study site staff member using the same validated device throughout 
the study. Blood pressure will also be measured at all visits as described above.  
Vital signs should be performed prior to taking the blood samples. 
 
Electrocardiograms 
 
In this study, Local ECG will be used and will be performed by a qualified clinical site 
physician. All 12-lead electrocardiogram (ECG) will be standardized recordings. Single 12-lead 
ECGs will be performed at Screening (Visit 1) and at Visit 4. Additional 12-lead ECG will be 
performed at other times if judged to be clinically appropriate or if the on-going review of the 
data suggests a more detailed assessment of ECG is required. ECGs will be performed in 
triplicate at Visit 1 and Visit 4.  
 

 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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The patient must rest in a supine position for 5 minutes before the ECG is obtained. ECG 
tracings (paper or electronic) should be reviewed and interpreted by the Investigator or a 
qualified clinician. ECG parameters including ventricular rate, RR-Interval [ms], PR-Interval 
[ms], Rhythm (sinusal - other), PR, QRS, QT, QTcF, and QTcB intervals will be recorded. 
 
If QTcF > 450 ms, it should be evaluated and used for clinical decision: another triplicate ECG 
is indicated and if required should be discussed with the Sponsor and/or medical monitor.  
 
The original ECGs must be appropriately signed, collected and archived at the study site.  
Printouts and related copies for each ECG will include date, time, initials of the 
technician/nurse, and initials of the Investigator who reviewed the printout and should be 
properly archived at site. 
Clinically relevant abnormalities should be recorded first on the source documents by the PI 
and then on the relevant section of the eCRFs. 
 
Laboratory tests 
 
A local laboratory will be used for laboratory evaluation. Clinical laboratory tests (chemistry 
and haematology) will be conducted at Screening (Visit 1) and Visit 4. Blood and urine 
samples for pregnancy test will be collected, processed, and analysed locally and in accordance 
to the research site’s SOPs. 
 
The maximum volume of blood to be taken is approximately 40 mL, which will be the total 
blood collected during the study.  
 
The results should be evaluated for criteria defining AE and reported as such if the criteria are 
met. In all cases, the investigator must document in the source documents, the clinical 
considerations (i.e. results were or was not was clinically significant and/or medically relevant) 
in allowing or disallowing the patient to continue in the study. 
 
To ensure patient safety, the patients will be contacted over phone within 24 hours, in case of 
any abnormality and clinically relevant laboratory test according to the Investigator’s 
judgement at any visit. The results of laboratory tests will be returned to the Investigator, who 
is responsible for 

 
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Pag. 49 a 91 
 
reviewing and filing these results. Note: Patients who will be reported 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 bilirubin level >1.5 × ULN) will be withdrawn from treatment and study. 
 
The following parameters Haematology and Serum Chemistry parameters will be assessed: 
 
Haematology 
Serum Chemistry 
Red blood cell 
White blood cell 
Haemoglobin 
Haematocrit 
Platelets 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils absolute 
Lymphocytes absolute 
Monocytes absolute 
Eosinophils absolute  
Basophils absolute 
 
 
ALT 
Albumin 
Alkaline phosphatase 
AST  
Direct bilirubin 
Total bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Triglycerides 
Cholesterol 
High- and low-density lipoprotein 
Chloride     
eGFR 
Blood glucose 
Potassium 
Uric acid  
 
 
AE/SAE Assessments 
 
The assessment of adverse events (AEs) by seriousness and relationship will be performed at 
all visits. AEs that occur after a patient has signed the ICF and prior to exposure to study drug 
will be recorded on the case report form and will not be considered treatment emergent adverse 
events (TEAEs).  
 
 

 
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Pag. 50 a 91 
 
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 “SARS-CoV-2” and the disease it causes has been named 
“Coronavirus Disease 2019” (COVID-19). On 08 March 2020, the World Health Organization 
(WHO) 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 health authorities 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 participants, 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 protocol, will be resumed as soon as possible 
thereafter. 
This section describes the COVID-19 mitigation plans for MASOLINO 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 participants were affected by such changes. Communications with Sponsor 
regarding the implementation of the herein described mitigation measures should be 
documented in the source documents. 
 
Informed consent 
 
 

 
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This paragraph is applicable only in case a patient needs to re-consent in study participation. 
Initial informed consent signature must be provided at site during Visit 1 (Screening) 
Each participant must be provided with new information that might impact their willingness to 
participate in the study in a timely manner. Should the participant need to re-consent if 
permitted by investigative site procedures and local regulations, the informed consent form can 
be mailed to the participant. 
The participant can sign the consent form at home and mail it to the study site. Alternatively, 
the PI or designee can visit the participant at home to present the changes to the study and 
obtain the informed consent form signature at the participant’s home. If the participant 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 
participant. 
 
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 participant may not be able to reach the study site. In 
such cases, the study treatment will not be dispensed to the participants at the site. Instead, the 
study treatment may be distributed to the participants’ 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. Participants 
will be informed and trained on the new dispensing procedures. Participants 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 participant to return to site via courier. 
 
Study assessment and procedures 
 
The Screening visit is a mandatory in clinic/hospital visit and therefore should be performed at 
the site. The Principal Investigator continues to be responsible for reviewing all study -related 
assessments. 
The participant 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 

 
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Pag. 52 a 91 
 
In such cases, these assessments will be performed by the health care professionals (study staff 
or qualified designee) at participant’s home, if allowed per country regulations. 
 
At Visit 1 patients will be provided with an automatic BP device, instructions, on how to 
measure BP, and a diary to record the relevant BP values. In the case of COVID-19 restrictions, 
all patients will be able to measure BP themselves. All patients will be fully trained by the 
investigator or delegated site staff and training will be recorded in the relevant source 
documentation. Patients will note the BP measurements in the diary and communicate it to the 
appropriate site staff. The diary will be returned at the first on-site visit if possible or it will be 
delivered via mail/e-mail.  
 
9 
SAFETY DATA MANAGEMENT 
 
9.1 
Adverse Event (AE) 
 
Any untoward medical occurrence in a subject or clinical trial subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related to the medicinal product. 
 
9.2 
Drug Relationship 
 
The relationship between an AE and study drugs 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 

 
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Pag. 53 a 91 
 
information (AE reappearance after drug reintroduction) is not required to fulfil this 
definition. 
− 
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 (ADR) 
 
An ADR is any untoward and unintended response to an investigational medicinal product 
related to any dose administered. 
The definition implies a reasonable possibility of a causal relationship between the event and 
the Investigational Medicinal Product (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: 
1. 
Certain 
2. 
Probable 
3. 
Possible 
4. 
Un-assessable 
 
An AE is not considered as ADR when the relationship is judged as: 
1. 
Unlikely 
2. 
Not related 
 

 
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9.4 
Seriousness 
 
An AE/ADR is considered Serious when: 
1. 
Results in death; 
2. 
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 hospitalisation or prolongation of existing hospitalisation; 
− 
results in persistent or significant disability / incapacity; 
− 
is a congenital anomaly/birth defect; 
− 
is another medically important condition that may jeopardise 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 fulfil the conditions for the definition 
of Serious AE / 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. 
− 
Severe: makes it impossible to perform routine activities; in case of laboratory tests, 
when there is a significant abnormality. 
 

 
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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 
(summary of product characteristics for Zofenopril and Amlodipine)7,8. 
 
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. 
SUSARs 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 subject at a particular point of time. 
 
9.9 
Collection, Recording and Reporting of AEs 
 
At each visit the Investigator will collect and assess any occurred subjective or objective AE 
occurred to each subject after his / her signature of the informed consent. 
The Investigator should manage as AE any laboratory test abnormality (newly occurring after 
the IMP administration or worsening of previously known abnormalities) considered as 
clinically relevant: i.e. values significantly above or under normal range or which require an 
intervention or diagnostic tests, or may result in the IMP discontinuation. 
Any AE communicated by the subject or by the subject’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 
recognised AE identifying an ICSR, both serious and non-serious, whether or not thought to be 
drug-related, observed in or reported by the subject (or relatives / delegates), specifying the 
judgement 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. 

 
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The Investigator is expected to also record any AE which was ongoing at the last treatment 
dose and a follow-up phone call should be made after 2 weeks from the last study visit. 
The Investigator is expected to follow up any AE occurred during the study, including the 
follow-up period, until the outcome of the AE has been determined. 
The Investigator must report all the collected information on any ICSR with Serious and 
Non Serious AE (whether or not thought to be related to the investigational drug), providing 
the concerned eCRF-AE pages/ by alert email), after the first knowledge of the occurrence 
of the case, to: 
 
When relevant, also the eCRF pages concerning medical history, concomitant medication, and 
laboratory tests will be placed at Sponsor disposal by email. 
 
9.10 Management of Serious AEs (SAEs) including laboratory abnormalities 
 
9.10.1 Reporting Duties of the Investigator 
The Investigator must report all the collected information on any eCRF with SAE (whether 
or not thought to be related to the investigational drug), as above specified, 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 
provided no later than 24 hours after the knowledge, by the Investigator to the CRO by 
email (MEIN/20/ZoAm-Hyp/001-safety@biorasi.com) 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/Ethics Committee. 
 
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 Ethics Committees as required, with these deadlines 
CRO Pharmacovigilance Officer: 
 
Email:  MEIN/20/ZoAm-Hyp/001-safety@biorasi.com 
 
Fax: +1 (786) 221-3531 
 
Tel: +1 (786) 388-0700 
 
Mobile: N/A 

 
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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 
drug. 
 
When appropriate and applicable the Sponsor will arrange the adequate information also to the 
Investigators. 
 
9.11 Management of Non-serious AEs (NSAEs) including laboratory abnormalities 
 
9.11.1 Reporting Duties of the Investigator 
The Investigator must report all the collected information on any eCRF with NSAE (whether 
or not thought to be related to the investigational drug), as above specified, 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 
knowledge, by the Investigator to the CRO by email, to be forwarded to the Sponsor. 
 
9.12 Management of any laboratory abnormality 
 

 
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Any laboratory test abnormality which is considered by the Investigator as 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 every 2 
months by the CRO and the Sponsor. 
 
 
9.13 Management of pregnancy exposure cases 
 
The Investigator is expected to record in the provided form ( Pregnancy Exposure Form)any 
case of pregnancy exposure occurring in a female subject or in a male subject’s partner during 
the treatment and follow-up periods, sending it within 5 days after being made aware of the 
pregnancy, to the CRO by email, 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.  
 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile as described below. 
 
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 centre 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) 

 
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State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
08, Jan 2021 
 
Sponsor: Menarini International Operations Luxembourg SA 
Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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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 
 
Patients are free to discontinue the trial at any time without giving their reasons without losing 
the right to future medical care. Patients who withdraw from the trial will also be withdrawn 
from the investigational medicinal product.  
 Patients who voluntarily withdraw their consent can do so for any of the following reasons: 
 
• 
Does not want to participate in the study anymore 
• 
Does not permit further collection of personal data 
 
The investigator should make a reasonable effort to understand the primary reason for the 
patient’s decision to withdraw his/her consent and record this information. 
 
Study participants may, at any moment, be withdrawn by the Investigator, if considered 
appropriate. Patients can be withdrawn for any of, but not limited to, the following reasons: 
 
• 
If the patient meets an exclusion criterion (newly developed or not previously 
recognized) that precludes further study participation 
• 
Adverse events: when during the conduct of the study, adverse events occur 
that, in the Investigator’s judgement, are of such a nature or severity to 
recommend treatment withdrawal 
• 
Failure to comply with requirements of the protocol including, but not limited 
to evidence of non-compliance with inclusion/exclusion criteria during the 
study or patient non-compliance with key study procedures 

 
Corporate Medical Department 
 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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• 
By request of the patient including explicit withdrawal of patient’s consent to 
participate  
• 
Patient’s failure to report to study visits 
• 
Patient’s loss to follow-up (for guidance see Section 11) 
• 
Withdrawal by Investigator’s judgement: Investigator may choose to withdraw 
a patient from the study if the Investigator deems it in the best interest of the 
patient to discontinue. 
 
Patients who satisfy the following criteria will also be withdrawn from the study:  
 
• 
If at Visit 2 patients have a controlled BP (sitting SBP/DBP ≤130/80 mmHg) 
or do not tolerate the treatment or have an adherence range below 80% or 
superior to 120%.  
• 
If at Visit 3 the patients do not tolerate the extemporaneous combination 
treatment or have an adherence range below 80% or superior to 120%.  
• 
Patients with 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). 
 
If a patient has been withdrawn due to an AE, the Investigator must immediately contact the 
relevant pharmacovigilance contact (see Safety Data Management section). The reason for 
patient withdrawal must be well-documented in the Electronic Case Report Form (eCRF). 
The eCRF should capture the date and specific underlying reason for discontinuation of 
study product or patient discontinuation/withdrawal. Study treatment must be discontinued, 
and no further assessment conducted, and the data that would have been collected at 
subsequent visit will be considered missing.  Further attempts to contact the patient are not 
allowed unless safety findings require communication or follow-up. All effort should be 
made to complete the assessment prior to study withdrawal. A final evaluation at the time of 
the patient’s study withdrawal should be made as detailed in Early termination visit 
scheduled assessment.  
Patients who discontinue from the study early will complete an early termination visit.  
 

 
Corporate Medical Department 
 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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Subjects who prematurely withdrawn from study medication or from the study will not be 
replaced. These subjects will not be considered lost to follow-up. 
 
11 LOST TO FOLLOW UP 
 
A patient will be considered lost to follow-up if he or she fails to return for 2 or more scheduled 
visits and is unable to be contacted by the study site staff.  
 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit.  
The site staff will attempt to contact the patient and reschedule the missed visit within 2 business 
days. Site staff will 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 
(e.g. letters, telephone calls) to regain contact with the patient.  Each contact attempt should be 
documented in the patient’s medical record or study file.  
 
12 STATISTIC 
 
This section outlines the major features of statistical analyses. More detailed methodology for 
summary and statistical analysis of data collected in this study will be documented in the 
statistical analysis plan (SAP), which will be maintained by the sponsor and completed prior to 
locking the database. The SAP may modify the plans outlined in the protocol; however, any 
major modifications of the primary endpoint definition and/or its analysis will also be reflected 
in a protocol amendment.  
 
Any additional or supplemental data analyses performed independently by the investigator 
should be submitted to the Sponsor. 
 
12.1 Statistical Methods (Blinding and Randomization) 
 
This is a non-randomized, unblinded study. Unless specified otherwise, all statistical testing 
will be two-sided and will be performed using a significance (alpha) level of 0.05. 

 
Corporate Medical Department 
 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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12.2 Determination of 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 (SD) for this difference of 10 mmHg. The mean change in DBP for 
the null hypothesis is set equal to 2 mmHg. To achieve this, a total of 290 patients will be 
enrolled, allowing for a 25% withdrawal rate. 
 
12.3 Analysis Populations 
 
A total of three populations will be used for all summaries and analyses. Study participants 
who have satisfied the population criteria will be classified in the designated population and 
will only be included in analyses for which they have available data. 
 
Data analysis will be performed using the following analysis sets. 
 
The Safety Population 
The Safety population is defined as all study participants who sign the informed consent, meet 
all screening criteria, are enrolled, and receive at least one dose of the assigned treatment 
during the run-in period. This population will be used for safety analyses. 
 
The Efficacy Population 
The Efficacy population is defined as all study participants in the Safety population who 
complete the 4-week run-in period and the Visit 2 blood pressure assessment.  This will be 
population for efficacy analysis. 
 
The Per-Protocol Population  
The Per-Protocol (PP) population is defined as all study participants in the Efficacy population 
who were dosed according to protocol, complete the required study visits, and do not 
experience any major protocol deviations that may impact the primary efficacy assessment 
through end of treatment.   

 
Corporate Medical Department 
 
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Effective date 
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2.0, CURRENT 
Effective 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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12.4 Analysis Variables 
The primary endpoint (i.e. change in sitting Diastolic Blood Pressure from Visit 2 to Visit 
4) and primary statistical analysis specifications will be detailed in 12.5.2. Secondary endpoints 
and their respective statistical analyses are summarized in 12.5.4 while safety analyses in 
12.5.7. Data handling and imputation methods are reported in 12.5.9. 
 
12.5 Statistical Analysis 
 Descriptive statistics 
Descriptive statistics for categorical variables (such as gender, race, and ethnicity) will include 
the number and percent of study participants with each characteristic. Percentages will be 
based on the number of study participants with non-missing values. Descriptive statistics for 
ordinal and continuous variables will include the number of study participants with non-
missing values, mean, median, standard deviation, minimum value, and maximum value. 
Intervals representing 95% confidence will be presented when appropriate. Graphical displays 
will be present when appropriate. 
 
All relevant data collected in the eCRF will be shown for each study participant in the 
individual study participant data listings. 
 
Disposition 
 
A tabulation of the disposition of study participants will be presented, including the number 
enrolled, the number treated, and the reasons for study discontinuation. Summaries of the 
number in each analysis set will be presented. Entry criteria violations and protocol deviations 
will be listed. 
 
Demographics and Baseline 
Demographic and baseline characteristic data summarization will be performed. Data to be 
tabulated will include study site, gender, age, race, and ethnicity, as well as baseline 
characteristics related to medical history. 
 
 Primary (efficacy) analysis 
For the primary efficacy analysis of the primary endpoint, the change in sitting Diastolic Blood 
Pressure (DBP) from Visit 2 to Visit 4 will be assessed using a paired t-test. A Type I error 

 
Corporate Medical Department 
 
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2.0, CURRENT 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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threshold of 0.05 will be used to test the null hypothesis that the mean reduction in DBP is 0 
mmHg against a two-sided alternative. The Efficacy population will be used to analyse the 
primary endpoint. 
 
 Sensitivity analysis 
A sensitivity analysis for the primary endpoint will be conducted by replicating the primary 
endpoint analysis under each of the following: 
1. Per-protocol population 
2. Imputation of missing data using last-observation-carried-forward (LOCF) 
3. Analysis stratified by study site 
4. Analysis stratified by gender 
5. Analysis stratified by age group 
Further details of these analyses will be presented in the SAP 
 
 Secondary (efficacy) analysis 
The secondary efficacy endpoints are derived from the primary objective and will be used to 
support the conclusion of the primary efficacy endpoint, provided that the primary efficacy 
endpoint is met. The secondary endpoints will be analysed as follows: 
 
1. Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8). 
Endpoint (1) will be analysed using a paired t-test with the null hypothesis that the 
mean change in SBP is 0 mmHg from Visit 2 to Visit 4.  
 
2. Change in mean sitting DBP and SBP between Visit 3 (week4) and Visit 4 (Week 8) in 
patients uncontrolled at Visit 3 and up titrated to the extemporaneous combination of 
ZOF/AML 30/10 mg. 
Endpoint (2) will be analysed using paired t-test for DBP and SBP with null hypotheses 
of 0 mmHg mean change from Visit 3 to Visit 4.  
 
3. 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). 
 Endpoint (3) will be analysed using a 95% binomial confidence interval for adherence 
for each visit. 
 

 
Corporate Medical Department 
 
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Effective date 
FORM-000050125 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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4. 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). 
 Endpoint (4) will be analysed using a 95% binomial confidence interval for adherence 
for each visit.  
 
In addition, all continuous efficacy variables will be summarized for all study visits using 
descriptive statistics for both actual values and change-from-baseline values. The Efficacy 
population will be used to analyse the secondary endpoints. 
 
 Exploratory (efficacy) analysis 
The exploratory efficacy endpoints assessing change-from-baseline BP will be analysed using 
mixed models for repeated measured (MMRM). The models will include treatment subgroup, 
analysis visit, treatment subgroup-by-visit interaction, the baseline BP value as a covariate, and 
patient as a random effect. An unstructured covariance structure was used to model the within-
patient errors. The exploratory efficacy endpoint for proportion of patients achieving controlled 
BP will be analysed using a logistic MMRM with similar terms. 
 
Additional details will be summarized in the Statistical Analysis Plan. 
 
 Subgroup analysis 
Further subgroups analyses besides those described in the exploratory endpoints will be defined 
in the Statistical Analysis Plan. 
 
 Safety analysis 
Safety and tolerability of the monotherapies (ZOF 30 mg and AML 5 mg) and of the 
extemporaneous combination (ZOF 30 mg and AML 5 mg or AML 10 mg) will be evaluated 
using the Safety population. The variables for this safety endpoint are laboratory tests, physical 
examination, vital signs, 12-lead ECG, and incidence of AEs and SAEs. 
 
 Interim analysis and stopping rules 
There will be no interim analyses for this study. 
 
 Data imputations 
Missing BP values that occur after baseline will be imputed for the sensitivity analysis using 
LOCF (see 12.5.3).  Any missing data for BP at baseline will not be imputed. No other standard 

 
Corporate Medical Department 
 
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Effective date 
FORM-000050125 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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imputations of missing efficacy data will be applied unless it is described later in the SAP in 
the respective data section. 
 
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, GCP and applicable Regulatory Requirements should 
be immediately reported to the Sponsor. 
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, i.e. are likely to have an impact on the safety of the subjects, 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 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 will be 
notified of this protocol amendment. 
Any substantial amendments of the protocol will be integrated in an updated study protocol. 
The Principal Investigator must ensure full compliance with the updated study protocol. 
 
12.7 End of Study Visit  
The final subject last visit that occurs on Week 8 ± 2 days will be considered to be end of 
study. 
 
12.8 Statistical Analysis Plan 
The statistical analysis plan (SAP) will be finalized before the study. 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 of the original primary endpoint or of the original 
primary analyses will occur during the study, these changes will be the subject of a substantial 
protocol amendment. 
All statistical analyses not pre-specified and run after additional/exploratory analyses. 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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13 STUDY DISCONTINUATION AND CLOSURE 
 
Menarini International Operations may discontinue this study prematurely for reasonable 
cause. Possible reasons for early termination or temporary suspension of the study include, 
but is not limited to: 
• 
Study closure based on PI decision and/or 
• 
Study closure based on Sponsor decision and/or 
• 
Study closure based on Regulatory or other oversight bodies initiation and/or 
• 
Review of serious, unexpected, and related AEs and/or 
• 
Non-compliance.  
 
In case this study was temporarily suspended or prematurely terminated, written notification 
documenting the reason for study suspension or termination will be provided by the 
suspending or terminating party at a reasonable time in advance of the intended termination.  
 
The Investigator may also discontinue this study at his/her site for reasonable cause after 
notifying the IEC and providing written notice to Menarini International Operations at a 
reasonable time in advance of the intended termination.  
 
Please note advanced notice is not required by either party if the study is stopped due to safety 
concerns.  
 
Menarini International Operations and the Investigator should take the following steps to 
follow up on patient safety and ensure data integrity: 
 
• 
Immediately notify the pharmacovigilance officer at Biorasi 
• 
Notify the IEC within 24 hours 
• 
Contact all patients by phone and distribute written communication that the study has 
been stopped  
• 
Advise all patients to report for an early termination visit 
• 
Make plans to follow all patients for AEs for two months after the study has been 
stopped or for as long as it takes for any AE/SAEs to resolve, whichever is longer 
• 
Instruct study staff to enter all data in the case report form and ensure their completion 
 

 
Corporate Medical Department 
 
Identification Number 
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Effective date 
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2.0, CURRENT 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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14 DIRECT ACCESS TO SOURCE DATA / DOCUMENTS 
 
The Investigator and/or Institution will permit trial related monitoring, audits, EC review, and 
regulatory inspections, providing direct access to source data/documents upon request. 
 
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 subjects 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 ICH 
GCP, and with applicable regulatory requirement(s). 
 
The monitoring of the conduct of the study and progress of the clinical investigation will 
proceed in accordance to the Monitoring Plan. The purpose of the Monitoring Plan is to 
establish guidelines for managing, monitoring, and working with Investigational Sites for this 
study. 
The Monitoring Plan provides information that will be used by Clinical Research Associates 
(CRAs) to ensure the quality of the data including the type, frequency, and extent of 
monitoring, who will be provided reports of monitoring and whether independent audits of the 
monitoring activities will be conducted. The Monitoring Plan also provides detailed 
information about the number of study sites, Site Initiation Visits (SIVs), Study Site Visits 
(SSVs), Interim monitoring visits (IMVs), and close-out visits. 
 
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. 
 
Quality checks that will be performed on trial documents and on the collected data include, but 
is not limited to, ICF review and source data verification.  Detailed information can be found in 
the Monitoring Plan.   
 

 
Corporate Medical Department 
 
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The Investigator agrees to allow access to all study materials 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. 
 
15.2 Case Report Forms 
 
Patient data will be entered into the IBM Clinical Development electronic data capture (EDC) 
system.  
 
Menarini International Operations, or its designee, will supply to the site personnel access to 
the electronic case report forms. These forms will be used to transmit information collected 
during the study to Menarini International Operations or its designee and regulatory authorities, 
as applicable. The Investigator may formally designate authority to complete eCRFs to 
qualified staff by completing the signature log and requesting access rights to the EDC system 
for the designee. Every user of the system will be made aware of the fact that username and 
password should never be shared, and their electronic signature constitutes the legally binding 
equivalent of a hand-written signature.  
Electronic CRFs (eCRFs) must be completed for each patient who signs the ICF for the study. 
Screening study data will be collected on the eCRF for all patients only. The system 
automatically records all changes in an electronic audit trail and requires a “reason for change” 
to be picked from a pre-defined list. If the reason for the correction is not obvious, a brief 
explanation (e.g. transcription error) should accompany the change. All information recorded 
on the eCRF forms must reflect the information in the patient source documents.  
For screen failed patients, the Investigator or designee will capture in source the patient’s 
demographic data, data collected from all completed screening procedures, and reason for 
screen failure. Only the patient’s demographic data, informed consent, reason for screen failure 
and SAEs will be entered in the EDC. 
 
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. 
 
The Investigator will review the eCRFs for completeness and accuracy and electronically sign 
each set of eCRFs. Menarini International Operations personnel (or their representatives) will 

 
Corporate Medical Department 
 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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periodically review the eCRFs for completeness and accuracy. Menarini International 
Operations personnel (or their representatives) will be allowed access to all source documents 
in order to verify eCRF entries.  
On the eCRF, patients will be identified by the patient number/code, assigned at the Screening 
Visit. The patient number/code will be assigned as stipulated in the Data Management Plan.   
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 data entry 
expectations are that the eCRFs will be entered within 5 business days of a patient’s visit. Any 
eCRF queries should be answered by the site within 5 business days.  SAE/Coding queries 
must be answered by the site within 3 business days.  
The Investigator will be responsible for entering study data into the eCRF in accordance to the 
eCRF user guidelines.  
 
15.3  Quality Assurance 
 
Quality Control will be performed according to applicable SOPs. The study may be audited by 
Quality Assurance representatives of Menarini International Operations (or their designee). All 
necessary related data and documents will be made available for inspection.    
 
All clinical activities conducted under this protocol is subject to GCP regulations. This includes 
audits / inspections by the Sponsor, and / or by national / international Health Authority 
representatives at any time. Principal Investigators must agree to the inspection of the study 
site, facilities, and of study related records by the Health Authority 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 conducted in compliance with this study protocol, the recommendations on 
biomedical research on human subjects of the Declaration of Helsinki, International Conference 
of Harmonisation – Good Clinical Practices (ICH-GCP) Guidelines, EU-Directives and 
Regulations and national requirements for the participating countries.  
 

 
Corporate Medical Department 
 
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Protocol Version 1.0 of 1     23/04/2021 
  
 
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16.1  Ethics Committees 
 
Before starting the study in a study site, Study Protocol and relevant documentation (Subject 
information leaflet, Informed Consent Form and the Investigator’s Brochure and other 
documents, according to National Regulations) must be submitted to and approved by the 
Ethics Committees (EC) and the Health Authorities (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 Subject’s Insurance 
 
For subjects 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 subjects in the ICF and / or provided as a separate document, in accordance with national 
requirements. 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, the EU Regulation on clinical trials on medicinal products for human use 536/2014, 

 
Corporate Medical Department 
 
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laws applicable in countries where the data subject is based –i.e.., Russian privacy laws, 
particularly Data Protection Act No. 152 FZ dated 27 July 2006 (“DPA”) and various 
regulatory acts adopted to implement the DPA”. This section defines the appropriate technical 
and organisational measures that shall be implemented to protect information and personal data 
processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or 
destruction or accidental loss as well as to assure the fulfilment of subjects’ privacy rights. 
 
17.2 Acknowledgment 
 
The Site, the Principal investigator, 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 (i.e. the EU General Data Protection Regulation 679/2016 and the EU 
Regulation on clinical trials on medicinal products for human use 536/2014) and laws 
applicable in countries where the data patient is based –i.e.., Russian privacy laws, particularly 
Data Protection Act No. 152 FZ dated 27 July 2006 (“DPA”) and various regulatory acts 
adopted to implement the DPA and local laws (i.e. the laws of all the countries 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 Luxemburg law, it has to 
mandatorily comply with Luxemburgish and EU laws  on data protection: therefore The Site, 
the Principal investigator, 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 Principal investigator, the Local Laboratory, the 
CRO 
 
17.3 Data Controllers and Data Processors 
 
The Sponsor, the Site, the Principal investigator and the CRO - acknowledge that according 
to the applicable privacy laws, Sponsor and Site - will act as independent data controllers 
while CRO and the Principal investigator 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 
Principal Investigator - as its data processor. However, if specific local laws or regulations 
mandate a different definition of the privacy roles, the Sponsor, the Site, the Principal 

 
Corporate Medical Department 
 
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investigator and the CRO - will implement the relevant legal instruments (e.g. if pursuant to 
the local laws the Site is a data processor of the Sponsor, a Data Processing Agreement will 
be finalised; if pursuant to the local laws Sponsor and Site are join controllers, a Joint 
Controllership Agreement will be finalised).  
 
For clinical trials where the Principal Investigators are the owners of the Site, this provision 
may not apply. In such cases, the Principal Investigator might be considered as a Data 
Controller 
 
17.4 Duties of the Parties involved in the performance of the study 
 
Collection and use of patient’s date 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 Principal investigator, 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- use the same 
protocol terminology/definitions], shall implement the following safety measures (physical, 
logical, organizational, technical, electronic, I.T. 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 Principal Investigator shall adopt all the necessary 
measures to prevent or minimise the risks of theft, fire, flooding, partial or total loss, 
accidental disclosure or illegal/unauthorised 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 
Principal Investigator  shall ensure that the actual measures they have implemented are fit-
for purpose and law-compliant, and in particular:  
- in order to minimise 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 

 
Corporate Medical Department 
 
Identification Number 
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State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
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Sponsor: Menarini International Operations Luxembourg SA 
Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 74 a 91 
 
least every three months and feature at least 8 characters, with upper-case and lower-case 
recognition, containing at least three "special" 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 (e.g. 
“johnbrown80”) or easily predictable strings of characters (e.g. “qwerty”, “12345”, “admin”, 
“user”, etc.); 
 - adequate cryptographic protection measures shall be put in place for data “at rest” and “in 
transit” (these include, for example, file system or database cryptography, or any other 
equivalent IT measure which renders data unintelligible to those who are not authorised 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 (i.e. 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 centralised database(s) used to process study’s 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 CENTRALISED DATA BASE. The centralised 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 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 (i.e. password 
change);  

 
Corporate Medical Department 
 
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Effective date 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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(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-anonymisation” process). The Principal investigator  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 Local Laboratory and /or the CRO, Site/Principal 
Investigator shall securely store a separate list (e.g.: identification log) with the 
identification code, together with all signed informed consents, in accordance with the 
security measures as defined above.  
The subject code pairing list (i.e. the list that where the Patient ID is linked to the patients’ 
identification data such as name and surname), shall be archived by the Principal 
Investigator.  
 
(v) 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 Centre and/or the to 
the competent authorities (including data protection authorities) and Ethics Committees 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, the Principal investigator, the CRO and the Local  
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 Centre and the Principal 
Investigator shall archive the content of the clinical trial master file, 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 (i.e. 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 Principal Investigator. 
 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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The content of the clinical trial master file shall be archived in a way that ensures that it is 
readily available and accessible, upon request, to the competent authorities. 
 
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. 
Any transfer of ownership of the content of the clinical trial master file shall be documented. 
The new owner shall undertake the responsibilities set out in this protocol. The Sponsor 
appoints Clinical Operations Director as responsible person/s for archives. Access to 
archives shall be restricted to those individuals.Once mandatory data retention time for the 
clinical trials master file has elapsed, the Centre/Principal Investigator shall seek the 
authorisation of the Sponsor to destroy the clinical trial master file.  
Data Breach 
 
Data Breach is an incident regarding personal data security and leading to the accidental or 
unlawful destruction, loss, alteration, unauthorised 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, Principal Investigator, Vendor etc data loss is when the data may still exist, 
but the Site, sponsor, CRO, Principal Investigator , Vendor 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, Vendor Site, sponsor, CRO, Principal Investigator. 
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 (e.g. an unauthorised 
access to a locked storage room containing paper files with personal data), and/or 
electronic/IT anomalies (e.g. 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 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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(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 
Menarini Clinical Operations Director  the sponsor’s Data Protection Officer 
(dpo@menarini.com),  the Site and the Biorasi’s Data Protection Officer (DPO@biorasi.co)  
for data breach incidents and shall provide the following information: 
(i) 
Anomalous Event / Data Breach Type (e.g. data loss, unauthorized access, loss of 
company device, etc.). 
(ii) 
Person or source that first reported the Anomalous Event/Data Breach;  
(iii) 
Date and Time when the person who first reported the Anomalous Event / Data Breach 
became aware of it;  
(iv) Anomalous Event / Data Breach Date and Time (actual or presumed);  
(iv) 
Place (specify if actual or alleged) where the Anomalous Event / Data Breach 
occurred;  
(v) 
Anomalous Event / Data Breach Description;  
(vi) 
Indicate the source of the Anomalous Event / Data Breach (e.g. I.P. source) - (if 
relevant);  
(viii) Indicate the affected infrastructure / system / application / cloud/ software / hardware / 
database and their location;  
(ix) List or describe the processing/storage systems affected by the Anomalous Event/Data 
Breach (if relevant);  
(x) Number of data patients involved (if known);  
(xi) Amount of allegedly breached data  
(xii) 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.  
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 European Union, 
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. Categorise the breach;  

 
Corporate Medical Department 
 
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State 
Effective date 
FORM-000050125 
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Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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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 minimise 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-anonymisation 
 
Prior to patients’ enrolment in the study, the Principal Investigator 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 Principal Investigator 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 patients about:  
(i) the applicable data protection legislation  
(ii) what kind of data shall be collected during the study listing them in detail or by category;  
(iii) the purpose of data processing e.g. performance of the study, pharmacovigilance, 
registration of new drugs and the legal basis;  
(iv) whether granting the consent(s) to process personal data is a necessary or an optional 
condition to take part in the study;  
(v) 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 (vi) the pseudonymisation procedure and scope;  
(vii) who can access patients’ data and under what circumstances Principal Investigator, Site, 
Sponsor during monitoring activities, audit, etc., regulatory authorities during inspection etc, 
Ethics Committee];  
(viii) the period of data retention/storage as defined in Paragraph 19;  
(ix) to which entities/countries outside the EU patients’ data will be transmitted [list here the 
non-EU countries] (if applicable), as per Paragraph 18.7. 
(x) patients’ data protection rights as defined by the [EU General Data Protection Regulation 
679/2016, and laws applicable in countries where the data patient is based –i.e.., Russian 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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privacy laws, particularly Data Protection Act No. 152 FZ dated 27 July 2006 (“DPA”) and 
various regulatory acts adopted to implement the DPA].  
(xi) Data Controllers / Data Processors and the relevant contact details  
(xii) Sponsor’s Data Protection Officer contacts (DPO) 
 
17.7 Genetic Data 
Not applicable 
 
17.8 Transfer of subjects’ 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 Principal investigator, 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, patients’ specific consent only where permitted under 
Chapter V of the GDPR, on one of the basis set out under art. 49 GDPR.  
 
LIST HERE THE NON-EU COUNTRIES/ENTITIES WHERE DATA CAN BE 
EXPORTED:  
USA,  
RUSSIA 
Nevertheless, if Sponsor registers and markets the: Amlodipine and Zofenopril calcium in non-
EU countries, data may have to be submitted to the Authorities in charge of monitoring the 
safety and reliability of medicines in those countries. The updated list of foreign countries is 
available upon request. 
17.9 Exercise of subjects’ data privacy rights 
 
Each study patient has the right to contact the Sponsor, the Site, the Principal investigator, the 
Local  Laboratory, the CRO to exercise the rights afforded to the patient by the law, including 
the  ones afforded  under articles 15 to 22 of Regulation (EU) 2016/679 or under Data 
Protection Act No. 152 FZ dated 27 July 2006 and implementing acts,, 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 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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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 anonymised or frozen; oppose to the processing of his/her data for 
legitimate reasons. Each patient- has the right to lodge a complaint with his/her local 
supervisory authority and/or to notify to the Data Protection Officer any use of his/her personal 
data the patient- regards as inappropriate. Each study patient is free to withdraw at any time 
from the study. In such case, each study patient may ask the Sponsor, the Site, the Principal 
investigator, the Local Laboratory, the CRO - to destroy/delete his/her personal data (including 
his/her biological samples), 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 he Site, 
the Principal investigator, the Local Laboratory, the CRO receive a request for data privacy 
rights exercise, the concerned recipient shall immediately inform the Sponsor DPO by email 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 Principal investigator, the Local 
Laboratory, the CRO - shall implement adequate organisational measures to reply to patients 
within the above-mentioned deadline 
 
17.10 Future research 
 
In the context of additional research activities, patients’ data will be processed, anonymised 
and transferred abroad, and may be shared with future research partners –this will take place 
in a format that prevents patients’ identification.  
18 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 the Sponsor. 
All information concerning the study, the drug as well as data and results of the study are 
confidential and property of the Sponsor. 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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The Sponsor will prepare the clinical trial 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. 
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. 
 
19 REFERENCES 
 
1. 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. 
2. 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. 
3. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 
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. 
4. 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;387:957–67. 
5. 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 
6. Mensah GA, Bakris G. Treatment and control of high blood pressure in adults. Cardiol Clin. 
2010;28:609–22 
7. Amlodipine SmPC 
8. Zofenpril SmPC 
9. Borghi C, Omboni S, Reggiardo G, et al. Efficacy of zofenopril in combination with 
amlodipine in patients with acute myocardial infarction: a pooled individual patient data 
analysis of four randomized, double-blind, controlled, prospective studies. Curr Med Res 
Opin. 2018;34(10):1869-1874. 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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10. Wright, J. M., Musini, V. M., & Gill, R. (2018). First-line drugs for hypertension. The 
Cochrane 
database 
of 
systematic 
reviews, 
4(4), 
CD001841. 
https://doi.org/10.1002/14651858.CD001841.pub3 
11. Kawalec P, Holko P, Gawin M, Pilc A. Effectiveness of fixed-dose combination therapy in 
hypertension: systematic review and meta-analysis. Arch Med Sci. 2018;14(5):1125-1136. 
doi:10.5114/aoms.2018.77561 
12. Jamerson KA, Nwose O, Jean‐Louis L, et al. Initial angiotensin‐converting enzyme 
inhibitor/calcium channel blocker combination therapy achieves superior blood pressure 
control compared with calcium channel blocker monotherapy in patients with stage 2 
hypertension. Am J Hypertens. 2004; 17: 495– 501. 
13. Bahl, V. K., Jadhav, U. M., & Thacker, H. P. (2009). Management of hypertension with the 
fixed combination of perindopril and amlodipine in daily clinical practice: results from the 
STRONG prospective, observational, multicenter study. American journal of cardiovascular 
drugs: 
drugs, 
devices, 
and 
other 
interventions, 
9(3), 
135–142. 
https://doi.org/10.1007/BF03256570 
14. Frank J. Managing hypertension using combination therapy. Am Fam Physician. 
2008;77(9):1279-1286. 
15. Li, Y., Wei, F. F., Wang, S., Cheng, Y. B., & Wang, J. G. (2014). Cardiovascular risks 
associated with diastolic blood pressure and isolated diastolic hypertension. Current 
hypertension reports, 16(11), 489. https://doi.org/10.1007/s11906-014-0489-x 
16. Volpe M, Rosei EA, Ambrosioni E, et al. 2012 consensus document of the Italian Society of 
Hypertension (SIIA): strategies to improve blood pressure control in Italy: from global 
cardiovascular risk stratification to combination therapy. High Blood Press Cardiovasc Prev. 
2013;20(1):45-52. doi:10.1007/s40292-013-0007-2 
17. Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. 
European Heart Journal. 2011 Oct;32(20):2499-2506. DOI: 10.1093/eurheartj/ehr177 
18. Amlodipine IB 
19. Zofenopril IB 
 
 
 
 
 
 

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20 PROTOCOL APPROVAL PAGE 
Stm\Y Tttte: Intervcntlonal clinical trial to asseas efficacy and safety of the extemporaneous 
compudion of zofenopril calcium and amlodipino in grade 1-2 hypertcrnaivo padcota versus 
eacbm1onotbenpy (MASOLINO Study) 
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FORM-000050125

27 April 2021

 
Corporate Medical Department 
 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
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Sponsor: Menarini International Operations Luxembourg SA 
Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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21 INVESTIGATOR’S APPROVAL PAGE 
 
I understand that all information concerning the product that Menarini supplied Zofenopril and 
Amlodipine in connection with this study protocol are confidential information. This 
information includes: Protocol, Investigator’s Brochure, Case Report Form etc. 
 
I understand that any change in this study protocol must be approved in writing by Menarini 
International Operations Luxembourg and the Co-ordinating Investigator, submitted to the 
Ethics Committee and Health 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 
International Operations Luxembourg 
 
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 Centre File is stolen or anyhow damaged, I will promptly inform 
the Sponsor and declare it to the Competent Authorities 
 
Principal Investigator: ____________________________________________________ 
 
Signature & Date: _________________________________________________________    
 
 
 
 

 
Corporate Medical Department 
 
Identification Number 
Version Number 
State 
Effective date 
FORM-000050125 
2.0, CURRENT 
Effective 
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Sponsor: Menarini International Operations Luxembourg SA 
Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 85 a 91 
 
 
22 APPENDICES 
 
Appendix 1: Declaration of Helsinki 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended 
by the: 
 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki 
as a statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient’s best interest when providing 
medical care.” 

 
Corporate Medical Department 
 
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FORM-000050125 
2.0, CURRENT 
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Sponsor: Menarini International Operations Luxembourg SA 
Study Code: MEIN/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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4.         It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The physician’s 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6.         The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for 
all human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research patients. 
9.         It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research patients. The responsibility for the protection of research patients 
must always rest with the physician or other health care professionals and never with the 
research patients, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable international 
norms and standards. No national or international ethical, legal or regulatory requirement 
should reduce or eliminate any of the protections for research patients set forth in this 
Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to 
the environment. 
12.       Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and appropriately 
qualified physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 87 a 91 
 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research patients. 
15.       Appropriate compensation and treatment for patients who are harmed as a result of 
participating in research must be ensured. 
 
 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or groups 
affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18.       Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be satisfactorily 
managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
 
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot be carried 
out in a non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
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Scientific Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should 
include information regarding funding, sponsors, institutional affiliations, potential conflicts 
of interest, incentives for subjects and information regarding provisions for treating and/or 
compensating patients who are harmed as a consequence of participation in the research 
study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions. 
 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, the 
sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research patients set forth in this 
Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by 
the committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions. 
 
Privacy and Confidentiality 
24.       Every precaution must be taken to protect the privacy of research patients and the 
confidentiality of their personal information. 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 89 a 91 
 
11 Informed Consent 
25.       Participation by individuals capable of giving informed consent as patients in 
medical research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent may be 
enrolled in a research study unless he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, 
each potential patient must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential patient must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential patients as well as to the methods used to deliver 
the information. 
After ensuring that the potential patient has understood the information, the physician or 
another appropriately qualified individual must then seek the potential patient’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the 
non-written consent must be formally documented and witnessed. 
All medical research patients should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential patient is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28.       For a potential research patient who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
patient, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research patient who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician must 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 90 a 91 
 
seek that assent in addition to the consent of the legally authorised representative. The 
potential patient’s dissent should be respected. 
30.       Research involving patients who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research group. In such circumstances the physician must seek informed consent from the 
legally authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving patients with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been approved 
by a research ethics committee. Consent to remain in the research must be obtained as soon 
as possible from the patient or a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such research. 
In such situations the research may be done only after consideration and approval of a 
research ethics committee. 
 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no intervention is 
necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be patient to additional risks of serious or irreversible 
harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
 

 
Corporate Medical Department 
 
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/20/ZoAm-Hyp/001 
Protocol Version 1.0 of 1     23/04/2021 
  
 
Pag. 91 a 91 
 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed to 
participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. Researchers have 
a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. All parties should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as positive 
results must be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the publication. Reports 
of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert advice, 
with informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician’s judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.