Conditions: Hypertension
Keywords: Hypertension Combination Therapy Zofenopril Nebivolol Fixed Dose Combination
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 283
Healthy volunteers: no

Brief summary:
Open-label, interventional clinical trial to assess effectiveness and safety of the extemporaneous combination of nebivolol and zofenopril calcium in grade 1 to 2 hypertensive patients versus each monotherapy

Detailed description:
This is a study with 2 periods (a run-in period of 4 weeks and an assessment period of 8 weeks). 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 (ACEi) or beta blockers (BBs) including ZOF 30 mg or NEB 5 mg respectively will be screened for eligibility (Visit 1).

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

* Patients on ZOF 30 mg or NEB 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 while patients on any other BB will be assigned to monotherapy with NEB 5 mg, respectively, for 4 weeks.

After the 4 weeks of monotherapy in the run-in period, if BP at Visit 2, remains uncontrolled (sitting Systolic Blood Pressure/Diastolic Blood Pressure \>130/80 mmHg) despite an adherence to the treatments ranging from 80% to 120%, the patients will start treatment (Week 0, Visit 2) with the extemporaneous combination of NEB 5 mg/ZOF 30 mg (NEB/ZOF) and will be assessed for further 8 weeks (assessment period).

If the patients, at Visit 2 after the Run-In period, have controlled BP (sitting Systolic Blood Pressure/Diastolic Blood Pressure ≤130/80 mmHg), and/or do not tolerate the treatment, and/or do not maintain the adherence to the therapy (range from 80% to 120%), these patients will not be continued further in the study.

At the end of the assessment period (Visit 3) the anti-hypertensive effect of the extemporaneous combination of NEB 5 mg and ZOF 30 mg will be evaluated.

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

Arms:
arm 1: MONOTHERAPY PERIOD (one month): patients will be treated with Zofenopril 30 mg. COMBINATION THERAPY PERIOD (two months) patients will be treated with the extemporaneous combination of Zofenopril 30 mg and Nebivolol 5mg arm 2: MONOTHERAPY PERIOD (one month): patients will be treated with Nebivolol 5 mg. COMBINATION THERAPY PERIOD (two months) patients will be treated with the extemporaneous combination of Zofenopril 30 mg and Nebivolol 5 mg

Interventions: intervention 1: Zofenopril 30 mg intervention 2: Nebivolol 5 mg intervention 3: Zofenopril 30 mg + Nebivolol 5 mg
Intervention descriptions: intervention 1: Film-Coated tablets administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake intervention 2: Tablet administered as one single dose to be taken in the morning (from 6 am to 10 am) with no restriction on food intake intervention 3: Both Film coated tablets of Zofenopril 30 mg and Nebivolol 5 mg Tablets will be taken in the morning (from 6 am to 10 am) with no restriction on food intake

Protocol document:
Prot_000.pdf: 
 
 
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CONFIDENTIAL                                                                                                                                                1 
 
CLINICAL STUDY PROTOCOL 
Open-label, Multicenter, multinational, interventional clinical trial to Assess effectiveness and 
SAfety of the extemporaneous Combination of nebivolol and zofenopril Calcium in grade 1 to 
2 hypertensive patIents versus each mOnotherapy – MASACCIO study 
Sponsor name 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 
Protocol Code 
MEIN/19/ZoNe-HYP/001 
EudraCT (or National Clinical Trial 
Identified Number) 
2020-002340-23 
Protocol Phase (if applicable) 
IV 
Study type and design: 
Multicenter, open-label, interventional study  
Protocol Version Number 
Version 1 
Protocol Version Date 
16 July 2020 
Coordinating Investigator  
Professor Massimo Volpe 
CRO 
IQVIA 
CONFIDENTIALITY STATEMENT 
The information in this document contains information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by law. In any event, persons to whom 
the information is disclosed must be informed that the information is privileged or confidential 
and may not be further disclosed by them. These restrictions on disclosure will apply equally to 
all future information supplied to you which is indicated as privileged or confidential. 
 
 
ClinicalTrials.gov: NCT05257148


 
 
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Summary of Changes from Previous Version 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
 
N/A 
First emission 
 
 
 
 
 
 
 


 
 
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CONFIDENTIAL                                                                                                                                                3 
 
 
TABLE OF CONTENTS 
 
1. 
RESPONSIBILITIES 
8 
2. 
PROTOCOL SYNOPSIS 
10 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
19 
4. 
STUDY SCHEME 
21 
4.1 
Study Flow Chart ........................................................................................................ 22 
5. 
STUDY RATIONALE AND BACKGROUND INFORMATION 
23 
5.1 Assessment of Potential Risks and Benefits .................................................................... 25 
6. 
TRIAL OBJECTIVES AND ENDPOINTS 
26 
7. 
STUDY DESIGN 
29 
7.1 
Procedures and Study Visits ....................................................................................... 31 
8. 
SELECTION OF PATIENTS 
33 
8.1 
Inclusion and Exclusion Criteria .................................................................................. 34 
8.1.1. 
Inclusion Criteria 
34 
8.1.2 
Exclusion Criteria 
35 
8.1.3 
Screening Failures 
36 
9. 
STUDY TREATMENT 
37 
9.1 
Study Treatment Formulation, Appearance, Packaging, and Labelling ....................... 39 
9.2 
Study Treatment Distribution and Return/Destruction ................................................. 40 
9.3 
Product Storage and Stability ..................................................................................... 40 


 
 
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9.4 
Study Product Compliance ......................................................................................... 41 
9.5 
Concomitant Therapies ............................................................................................... 41 
9.6 
Non-Permitted Medications......................................................................................... 41 
9.7 
Rescue Medication ..................................................................................................... 41 
10. STUDY ASSESSMENT AND PROCEDURES 
42 
10.1 
Assessment of Efficacy ............................................................................................... 42 
10.2 
Assessment of Safety ................................................................................................. 42 
10.2.1 
Physical Examination: 
43 
10.2.2 
Vital Signs 
43 
10.2.3 
Clinical Laboratory Tests 
43 
10.2.4 
Electrocardiograms 
44 
11. SAFETY DATA MANAGEMENT 
45 
11.1 
Adverse Event ............................................................................................................ 45 
11.2 
Drug Relationship ....................................................................................................... 45 
11.3 
Adverse Drug Reaction ............................................................................................... 46 
11.4 
Seriousness ................................................................................................................ 46 
11.5 
Adverse Event/Adverse Drug Reaction Intensity ......................................................... 47 
11.6 
Adverse Event/Adverse Drug Reaction Expectedness ................................................ 47 
11.7 
Serious Unexpected Adverse Drug Reaction .............................................................. 48 
11.8 
Individual Case Safety Report .................................................................................... 48 
11.9 
Collection, Recording, and Reporting of AEs .............................................................. 48 
11.10 Management of Serious AEs (SAEs) Including Laboratory Abnormalities ................... 49 
11.11 Management of Nonserious AEs Including Laboratory Abnormalities ......................... 50 


 
 
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11.12 Management of Any Laboratory Abnormality .............................................................. 51 
11.13 Management of Pregnancy Exposure Cases .............................................................. 51 
12. WITHDRAWAL CRITERIA 
52 
13. LOST TO FOLLOW-UP 
54 
14. STATISTICS 
54 
14.1 
Statistical Methods (Blinding and Randomization) ...................................................... 54 
14.2 
Determination of Sample Size .................................................................................... 54 
14.3 
Analysis Populations................................................................................................... 54 
14.4 
Analysis Variables ...................................................................................................... 55 
14.5 
STATISTICAL ANALYSIS........................................................................................... 56 
14.5.1 
Descriptive Statistics 
56 
14.5.2 
Primary (efficacy) Analysis 
56 
14.5.3 
 Sensitivity Analysis 
57 
14.5.4 
Secondary (efficacy) Analysis 
57 
14.5.5 
Exploratory (Efficacy) Analysis 
57 
14.5.6 
Subgroup Analysis 
58 
14.5.7 
Safety Analysis 
59 
14.5.8 
Interim Analysis and Stopping Rules 
59 
14.5.9 
Data Imputations 
60 
14.6 
Protocol Deviations and Protocol Amendments .......................................................... 60 
14.7 
Statistical Analysis Plan .............................................................................................. 61 
15. STUDY DISCONTINUATION AND CLOSURE 
61 
16. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
61 


 
 
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17. QUALITY CONTROL AND QUALITY ASSURANCE 
62 
17.1 
Study Monitoring/Data Quality Control ........................................................................ 62 
17.2 
Case Report Forms .................................................................................................... 62 
17.3 
Quality Assurance ...................................................................................................... 63 
18. ETHICAL ASPECTS 
63 
18.1 
Ethics Committees ...................................................................................................... 63 
18.2 
Patient’s Insurance ..................................................................................................... 63 
19. DATA PROTECTION LAWS COMPLIANCE 
64 
19.1 
Acknowledgement ...................................................................................................... 64 
19.2 
Data Controllers and Data Processors ........................................................................ 65 
19.3 
Duties of the Parties Involved in the Performance of the Study ................................... 65 
19.4 
Data Breach ............................................................................................................... 69 
19.5 
Information notice on personal data protection and pseudo-anonymization ................ 71 
19.6 
Genetic Data .............................................................................................................. 72 
19.7 
Transfer of patient’s data outside the European Union ............................................... 72 
19.8 
Exercise of patients’ data privacy rights ...................................................................... 72 
19.9 
Future research .......................................................................................................... 73 
20. DATA HANDLING AND RECORDS KEEPING 
73 
21. PUBLICATION POLICY AND RESULTS 
74 
22. REFERENCES 
75 
23. Protocol Approval Page 
77 
24. Investigator’s Approval Page 
78 
25. APPENDICES 
79 


 
 
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25.1 
Appendix 1: Declaration of Helsinki ............................................................................ 79 
 


 
 
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CONFIDENTIAL                                                                                                                                                8 
 
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: Eleonora Droghetti 
Address: Via Sette Santi 1-3, 50131, Firenze 
Phone: +39 055 56809665 
Fax: + 39 055 56809961 
e-mail:  edroghetti@@menarini.it  
Study Medical Expert (SME):  
Name: Marco Salvatore 
Address: via dei sette santi 1-3, Firenze 
Phone: (055) 56809581 
Fax: (055) 56809710 
e-mail: msalvatore@menarini.it  
Study Drug Safety Manager (SDSM):  
Name: Jaleh Khabirinejad 
Address: 5D, Rue Eugene Ruppert L-2453 Luxembourg 
Phone: +352 26497696 
Fax: +352 26497649 
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: IQVIA 
Address: 3 Forbury Place, 23 Forbury Road, Reading, RG1 
3JH, United Kingdom 
Statistician  
Name: Susmita Sanyal 
 
Address: IQVIA, 2nd Floor, iSprout, Purva Summit Building, 
Whitefield, Kondapur, Hyderabad, India 
e-mail: susmita.sanyal@quintiles.com  


 
 
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CONFIDENTIAL                                                                                                                                                9 
 
 
Sponsor Statistician 
Name: Andrea Nizzardo  
 
Address: Via Sette Santi 1-3, 50131, Firenze 
Phone: + 39 055 5860 7243 
e-mail: anizzardo@menarini-ricerche.it  
 


 
 
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CONFIDENTIAL                                                                                                                                                10 
 
 
2. PROTOCOL SYNOPSIS 
Title 
 
 
 
Sponsor Study Code  
Open-label, multicenter, multinational interventional clinical trial to 
assess effectiveness and safety of the extemporaneous combination of 
nebivolol and zofenopril calcium in grade 1 to 2 hypertensive patients 
versus each monotherapy  
MEIN/19/ZoNe-HYP/001 
Study product, Dosage 
and Regimen: 
-Investigational Product 
Extemporaneous combination of nebivolol (NEB) 5 mg tablets (Anatomical 
Therapeutic Chemical [ATC] code: C07AB12) with zofenopril calcium (ZOF) 
30 mg tablets (ATC code: C09AA15) 
Study Type and Design 
This is a phase IV, open-label, multicenter, multinational study with 2 study 
periods (a run-in period of 4 weeks and an assessment period of 8 weeks). 
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) or beta blockers (BBs) including ZOF 30 mg or 
NEB 5 mg respectively will be screened for eligibility (Visit 1). 
On the same day, the eligible patients will enter into a run-in period after 
Screening, during which: 
 
Patients on ZOF 30 mg or NEB 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 while patients on any other BB will be assigned to 
monotherapy with NEB 5 mg, respectively, for 4 weeks 
After the 4 weeks of monotherapy in the run-in period, if BP at Visit 2, 
remains uncontrolled (sitting SBP/DBP >130/80 mmHg) despite an 
adherence to the treatments ranging from 80% to 120%, the patients will 


 
 
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CONFIDENTIAL                                                                                                                                                11 
 
start treatment (Week 0, Visit 2) with the extemporaneous combination of 
NEB 5 mg/ZOF 30 mg (NEB/ZOF) and will be assessed for further 8 weeks 
(assessment period). 
If the patients, at Visit 2 after the Run-In period, have controlled BP (sitting 
SBP/DBP ≤130/80 mmHg), and/or do not tolerate the treatment, and/or do 
not maintain the adherence to the therapy (range from 80% to 120%), these 
patients will not be continued further in the study. 
At the end of the assessment period (Visit 3) the antihypertensive effect of 
the extemporaneous combination of NEB 5 mg and ZOF 30 mg will be 
evaluated. A total number of 290 patients will be screened considering 25% 
of drop-out rate, to obtain approximately 216 completed patients at the end 
of the study.  
Phase 
IV 
Objectives 
Primary objective: 
● To assess the antihypertensive effect of the extemporaneous 
combination of NEB 5 mg and ZOF 30 mg in lowering sitting DBP 
after 8 weeks of treatment, in patients with uncontrolled BP who were 
previously treated with NEB or ZOF monotherapies for at least 4 
weeks 
Secondary objectives: 
● To assess the antihypertensive effect of the extemporaneous 
combination of NEB 5 mg and ZOF 30 mg in lowering sitting SBP 
after 8 weeks of treatment in patients with uncontrolled BP, after at 
least 4 weeks of treatment with NEB or ZOF monotherapies 
● To evaluate the total number and percentage of patients who 
achieved the BP goal (sitting BP ≤130/80 mmHg) at Visit 2 and 
Visit 3 
● To assess compliance to the monotherapy and extemporaneous 


 
 
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combination (actual doses taken versus planned doses to be taken) 
● To evaluate the safety and tolerability of the ZOF and NEB 
monotherapies, and the extemporaneous combination of NEB 5 mg 
and ZOF 30 mg after 8 weeks of treatment  
Exploratory objective: 
● To assess the antihypertensive efficacy at different time points in 
patients who (1) received NEB or ZOF monotherapies before the 
run-in period,   
(2) received any other ACE-i or BB monotherapies before the run-in 
period  
● To assess the antihypertensive effect on patients, based on their 
hypertension grade, presence or absence of hypercholesterolemia, 
presence or absence of diabetes at Visit 2 and Visit 3 
Endpoints 
Primary endpoint: 
● Change in mean sitting DBP between Week 0 (Visit 2) and Week 8 
(Visit 3) 
Secondary endpoint: 
● Change in mean sitting SBP between Week 0 (Visit 2) and Week 8 
(Visit 3) 
● Total number and proportion of patients achieving the BP goal 
(sitting BP ≤130/80 mmHg) at Week 0 (Visit 2) and Week 8 (Visit 3) 
● Adherence to treatment will be measured through treatment 
compliance which is 100 × (actual doses taken versus planned 
doses to be taken) from Visit 1 to Visit 2 for the monotherapies and 
from Visit 2 to Visit 3 for the extemporaneous combination  
● Safety and tolerability of the NEB and ZOF monotherapies, as well 
as extemporaneous combination between NEB 5 mg and ZOF 
30 mg will be measured by adverse events (AEs), SAEs, AEs of 
special interest (AEOSI), vital signs, physical examination, 


 
 
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CONFIDENTIAL                                                                                                                                                13 
 
electrocardiogram (ECG), and concomitant medications at Week 0 
(Visit 2) and Week 8 (Visit 3) 
 
Exploratory endpoint: 
● Change in mean sitting SBP and DBP between Visit 1 and Visit 2 : 
(a) in the group of patients who were on ZOF 30 mg and NEB 5 mg 
at Visit 1 and continued on the same treatment until Visit 2 and (b) in 
the group of patients, who switched to ZOF 30 mg or NEB 5 mg from 
any other ACE-i or BB at Visit 1 until Visit 2. 
● Change in mean sitting SBP and DBP between Visit 1 and Visit 3: (a) 
in the group of patients who were on ZOF 30 mg and NEB 5 mg at 
Visit 1 and continued on the same treatment until Visit 2 and (b) in 
the group of patients who switched to ZOF 30 mg or NEB 5 mg from 
any other ACE-i or BB at Visit 1 until Visit 2. 
● Number and proportion of patients achieving the BP goal (sitting BP 
≤130/80 mmHg) at Visit 2 and Visit 3 evaluated in the patients: (a) 
who were on ZOF 30 mg and NEB 5 mg at Visit 1 or (b) who 
switched to ZOF 30mg or NEB 5 mg from any other ACE-i and BB at 
Visit 1 
● Number and proportion of patients, divided in subgroups based on 
the hypertension grade, the presence or absence of diabetes, the 
presence or absence of hypercholesterolemia achieving the BP goal 
(sitting BP ≤130/80 mmHg) at Visit 2 and Visit 3 
 
Study Population: 
Patients characteristics 
Number of Patients 
Approximately, 290 male or female Caucasian uncontrolled hypertensive 
patients between ≥18 and <65 years of age, who are on treatment with ZOF 
or NEB, or, on any other ACE-i or BBs, for at least 1 month, will be screened 
for eligibility. 
A total drop-out rate of 25% from Visit 1 to Visit 3, has been considered. A 


 
 
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CONFIDENTIAL                                                                                                                                                14 
 
patient will be considered eligible to be enrolled in the study only if he/she 
meets all of the inclusion criteria and none of the exclusion criteria. 
Inclusion criteria: 
1. Male or female Caucasian uncontrolled hypertensive patients (see 
definition in criterion 3) ≥18 and <65 years of age, in monotherapy 
either with ACE-i or BBs since at least 1 month, at Screening (Visit 1) 
2. Patients are able to understand and have freely given written 
informed consent at Screening 
3. Patients with mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or 
mean sitting DBP ≥ 90 mmHg and ≤109 mmHg at Screening (Visit 1) 
4. Patient who are able to comply with all study procedures and who 
are available for the duration of the study 
5. Ability to take oral medication and willing to adhere to the drug 
regimen 
6. A female patient of childbearing potential is eligible to participate if 
she is not pregnant, or not breastfeeding. A woman is considered 
fertile following menarche and until becoming postmenopausal 
unless permanently sterile. Women of childbearing potential must 
agree to use of highly effective contraception (eg, method of birth 
control throughout the study period and for 4 weeks after study 
completion defined as a method which results in a failure rate of less 
than 1% per year) and also must refrain from donating or storing 
eggs during this time. Highly effective contraception methods can be: 
 
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) 


 
 
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CONFIDENTIAL                                                                                                                                                15 
 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomized partner (provided that partner is the sole 
sexual partner of the trial participant and that the 
vasectomized partner has received medical assessment of 
the surgical success) 
7. A male patient with female partner 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: 
Patients who meet any of the following criteria will not qualify for entry into 
the study: 
1. Known contraindications, allergies, or hypersensitivities to any of the 
study medications or excipient as outlined in the investigators 
brochures (IBs), summary of product characteristics (SmPCs) or 
local package inserts for NEB 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, 
hematological, 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, heart failure, hypertensive 


 
 
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CONFIDENTIAL                                                                                                                                                16 
 
encephalopathy, cerebrovascular accident (stroke), or transient 
ischemic attack 
4. Patients with secondary hypertension of any etiology such as renal 
diseases, pheochromocytoma, or Cushing’s syndrome 
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. History of angioneurotic edema 
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. History of bronchospasm and bronchial asthma 
12. Patients with bradycardia (heart rate <60 bpm) 
13. Patient with metabolic acidosis 
14. Patients with severe peripheral circulatory disturbances 
15. Participation in another study within the last 4 weeks 
16. Patients with diseases that, in the opinion of the Investigator, prevent 
a careful adherence to the protocol 
17. Pregnant and breastfeeding women. NOTE: a pregnancy test will be 
performed on all women of childbearing potential at each study visit 
 
Clinical Sites 
15 investigational clinical sites 


 
 
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CONFIDENTIAL                                                                                                                                                17 
 
Number of Centers  
List of Countries 
European Union countries 
Study Duration (specify 
different study phases): 
 
This study will last 12 weeks. 
Screening Visit (Visit 1, week -4)  
Uncontrolled hypertensive patients receiving treatment with any ACE-i or 
BBs including ZOF 30 mg or NEB 5 mg will be screened for eligibility. 
Run-in period (4 weeks): from Visit 1 (Week-4) to Visit 2 (Week 0) 
Eligible patients from Screening will enter the run-in period on the same day. 
Patients previously receiving ZOF or any other ACE-i will enter into the 
run-in period with ZOF monotherapy while patients receiving NEB or any 
other BBs will enter into the Run–in period with NEB monotherapy in a 1:1 
ratio. 
Assessment period (8 weeks): from Visit 2 (Week 0) to Visit 3 (Week 8) 
Patients experiencing uncontrolled BP after 4 weeks of monotherapy, will be 
given the extemporaneous combination of NEB 5 mg and ZOF 30 mg at 
Week 0 (Visit 2) and will be assessed for 8 weeks (assessment period). 
Patients with controlled BP (sitting SBP/DBP ≤130/80 mmHg) and/or 
patients who do not tolerate the treatment at Week 0 (Visit 2) will be 
withdrawn from the study. 
Only uncontrolled BP patients, whose adherence to the treatment (actual 
doses taken compared to planned doses to be taken) ranges from 80% to 
120%, will enter the assessment period. 
Patient Study Phases 
Duration 
 
For patients completing the study, participation will last up to 12 weeks: 
● 4 weeks of run-in period (monotherapy) 
● 
8 weeks of assessment period (extemporaneous combination) 


 
 
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CONFIDENTIAL                                                                                                                                                18 
 
Statistical Assumptions 
The primary endpoint will be assessed before and after assessment period 
at Week 8, by a paired t-test using the ITT population and the Per protocol 
(PP) population. All other secondary endpoints will be assessed before 
(Week 0) and after treatment (at Week 8). 
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 to 
8 weeks 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. 


 
 
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CONFIDENTIAL                                                                                                                                                19 
 
3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION 
DEFINITION 
ACE-i 
angiotensin converting enzyme-inhibitors 
ADR 
adverse drug reaction 
AE 
adverse Event 
AEOSI 
adverse events of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
BB 
beta blocker 
BP 
blood pressure 
CRO 
contract research organization 
DBP 
diastolic BP 
EC 
ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDC 
Fixed-dose combination 
GCP 
good clinical practice 
HA 
health authority 
ICF 
informed consent form 
ICH 
International Council for Harmonisation  
ICSR 
individual case safety report 
ITT 
Intent-to-treat 
NEB 
Nebivolol 
NSAE 
Nonserious AE 
PI 
Principal Investigator 


 
 
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CONFIDENTIAL                                                                                                                                                20 
 
PP 
per protocol 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic BP 
SD 
standard deviation 
SmPC 
summary of product characteristics 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TMF 
trial master file 
ULN 
upper limit of normal 
ZOF 
zofenopril calcium 
 


 
 
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CONFIDENTIAL                                                                                                                                                21 
 
4. STUDY SCHEME  
 
 
BP: Blood pressure, NEB: Nebivolol, ZOF: Zofenopril calcium, ACE-i: Angiotensin converting enzyme-inhibitors, BB: 
Beta blockers 
 
 
Patients meeting the eligibility criteria at Screening (Visit 1), will enter the run-in period on the same day 
 
Patients who were on ZOF or NEB treatment at Screening, will continue to receive the same drugs; the 
patients on any other ACE-i will start ZOF and patients who were on any other BB will start NEB from the 
same day 
 
Only patients with uncontrolled BP (sitting SBP/DBP >130/80 mmHg) and whose adherence to the treatment 
ranges from 80% to 120%, will enter the assessment period to receive the extemporaneous combination of 
NEB and ZOF; while the patients with controlled sitting BP (SBP/DBP ≤130/80 mmHg) and/or the patients 
who do not tolerate the treatment and patients with uncontrolled BP whose adherence to the therapy do not 
range 
from 
80% 
to 
120%, 
will 
be 
withdrawn 
from 
the 
study.


 
 
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CONFIDENTIAL                                                                                                                                                22 
 
4.1 
Study Flow Chart 
 
 Study Procedures/ Assessments 
Visit 1 (Week -4) 
Visit 2 (Week 0)a 
Visit 3 (Week 8)a 
Screening + 
Start of Run-in 
Periodb 
Start of 
Assessment 
Period 
End of 
Assessment 
Period 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Medical history 
X 
 
 
Prior medication 
X 
 
 
Demography (age, sex, race) 
X 
 
 
Concurrent diseases and 
medical conditions 
X 
X 
X 
Antihypertensive treatment 
with NEB or ZOF 
monotherapyc 
X 
 
 
Study drug dispensingd 
 
X 
 
Study drug return and 
accountability (Compliance 
assessment)  
 
Xe 
Xf 
Concomitant medications 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
Physical examination 
X 
X 
X 
Vital signs 
X 
X 
X 
Laboratory testg 
X 
 
X 
Blood pressure 
X 
X 
X 
ECG 
X 
X 
X 
AE/SAE assessment 
X 
X 
Xh 


 
 
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CONFIDENTIAL                                                                                                                                                23 
 
ACE-i: Angiotensin converting enzyme-inhibitors; AE: Adverse event; BB: Beta blockers; ECG: 
electrocardiogram; EOT: End of treatment; NEB: nebivolol; SAE: serious adverse event; ZOF: zofenopril 
calcium 
a: For Visit 2, a window of ±2 days will be allowed at Week 0; and for Visit 3, a window of ±3 days will be 
allowed at Week 8  
b: Patients meeting the eligibility criteria at Screening, will enter the run-in period on the same day 
c: Patients on ZOF 30 mg or NEB 5 mg at Screening will continue the same therapy. Patients on any other 
ACE-i or BBs at Screening will be assigned to monotherapy with ZOF 30 mg or NEB 5 mg, respectively 
d: Patients will be provided with the extemporaneous combination of NEB 5 mg with ZOF 30 mg 
e: Adherence to monotherapies will be checked at the beginning of Visit 2 
f: Adherence to the extemporaneous combination of NEB 5 mg with ZOF 30 mg will be checked at the end 
of Visit 3 
g: 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 
h: Patients having any ongoing AE/SAE at the end of the treatment, will be followed for further 2 weeks via a 
phone call to check about the status of the AE/SAE 
5. 
STUDY RATIONALE AND BACKGROUND INFORMATION 
Based on office blood pressure (BP), 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% to 45%.1 Elevated BP was the 
leading global contributor to premature death in 2015, accounting for almost 10 million deaths 
and over 200 million disability-adjusted life years.2 
The 2 well-established strategies to lower BP are lifestyle interventions and drug treatment.3 
The drug treatment of hypertension is found on very solid evidence, supported by the largest 
number of outcome-based randomized clinical trials (RCTs) in clinical medicine. Meta-analyses 
of RCTs including several hundred thousand patients have shown that a 10 mmHg reduction in 
systolic blood pressure (SBP) or a 5 mmHg reduction in diastolic blood pressure (DBP) is 
associated with significant reductions in all major cardiovascular (CV) events by approximately 
20%, all-cause mortality by 10% to 15%, stroke by approximately 35%, coronary events by 
approximately 20%, and heart failure by approximately 40%.4,5 


 
 
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CONFIDENTIAL                                                                                                                                                24 
 
Guidelines have generated a variety of different strategies to initiate and escalate BP-lowering 
medication to improve BP control rates. In previous guidelines, the emphasis was on initial use 
of different monotherapies, increasing their dose, or substituting for another monotherapy. 
However, increasing the dose of monotherapy produces little additional BP-lowering and may 
increase the risk of adverse effects. For these reasons, more recent guidelines have 
increasingly focused on the stepped care approach, initiating treatment with different 
monotherapies and then sequentially adding other drugs until BP control is achieved.3 
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 mmHg.1 
This has become an even more pressing matter based on the new evidence. As the 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) provided that the 
treatment is well tolerated, it will make the achievement of BP control even more challenging.3 
Patients with hypertension are generally treated with multiple pharmaceutical products, 
fixed-dose combinations (FDCs) have generated increasing interest and have been 
recommended in treatment guidelines due to advantages in dosing and compliance, leading to 
improved treatment outcomes. 
One of the main reasons why the current treatment strategy has failed to achieve better BP 
control rates is the insufficient use of combination treatment. 
Blood pressure is a multiregulated 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 in 
most patients. Indeed, almost all patients in RCTs have required combinations of drugs to 
control their BP.6 
Nebivolol (NEB, a beta blocker [BB]) and zofenopril calcium ([ZOF], an angiotensin converting 
enzyme [ACE]-inhibitor [ACE-i]) are antihypertensive drugs widely prescribed as monotherapies 
in the real world. Both drugs have specific benefit-risk profiles with different mechanisms of 
action. Beyond its beta receptor-blocking effects, nebivolol has a vasodilatory action, 


 
 
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CONFIDENTIAL                                                                                                                                                25 
 
presumably mediated by its ability to increase availability of vascular endothelial nitric oxide. 
Nebivolol shows a distinct hemodynamic profile including reduced peripheral vascular 
resistance and a neutral impact on cardiac output, metabolic profile, and overall tolerability. 
Because this mechanism of action appears to be independent of its renin inhibitory effects, an 
additional BP-lowering effect could be anticipated when nebivolol is combined with a blocker of 
the renin-angiotensin system.7 
Zofenopril calcium 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 
anti-hypertensive drugs currently recommended for the treatment of hypertension. Overall, 
clinical studies in patients with mild to moderate essential hypertension found that treatment 
with zofenopril calcium 30 to 60 mg/day was at least as effective and well tolerated as usual 
therapeutic dose regimens of other most widely used anti-hypertensive drugs.8 
Despite data showing an added effect in providing NEB or ZOF to other anti-hypertensive 
treatment,9 there is scarce evidence at the moment on the anti-hypertensive effect of NEB/ZOF 
combination versus each monotherapy. 
This study aims to assess the efficacy of NEB/ZOF, provided as an extemporaneous 
combination, in reducing systolic and diastolic BP in Grade 1 to 2 hypertensive patients versus 
each monotherapy. 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and 
the applicable regulatory requirements. 
5.1 Assessment of Potential Risks and Benefits 
 
Extemporaneous combination of ACE-i and BBs are often prescribed to control BP without 
major reported risks. In many cases, combination therapy improves rates of BP control and 
requires less time to achieve target BP with equivalent or better tolerability than higher-dose 
monotherapy. Patients with comorbidities may benefit from the effects of different 
antihypertensive medications classes. Approximately, 70% of patients with hypertension require 
2 or more agents to achieve their target BP.7 In a meta-analysis published in 2010, FDCs of 


 
 
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CONFIDENTIAL                                                                                                                                                26 
 
antihypertensive agents not only improved compliance by 21%, but also allowed for a 50% 
increase in persistence with therapy.10 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 stroke.11 
Using combination therapy could also drive a potential economic advantage, including reduced 
need to switch medications and long-term improvement in control of BP.7 
6. 
TRIAL OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PRIMARY 
 
 
To assess the antihypertensive 
effect of the extemporaneous 
combination of NEB 5 mg and ZOF 
30 mg in lowering sitting DBP after 
8 weeks of treatment, in patients 
with uncontrolled BP who were 
previously treated with NEB or ZOF 
monotherapies for at least 4 weeks  
Change in mean sitting DBP between 
Week 0 (Visit 2) and Week 8 (Visit 3) 
The association between 
elevated DBP and increased 
mortality risk has been 
reported several times in 
literature.12 
SECONDARY 
 
 
● 
To assess the antihypertensive 
effect of the extemporaneous 
combination of NEB 5 mg and 
ZOF 30 mg in lowering sitting 
SBP after 8 weeks of treatment 
in patients with uncontrolled BP 
after at least 4 weeks of 
treatment with NEB or ZOF 
monotherapies 
● 
To evaluate the total number 
and percentage of patients who 
● 
Change in mean sitting SBP 
between Week 0 (Visit 2) and 
Week 8 (Visit 3) 
 
 
 
 
 
 
● 
Total number and proportion 
Change in SBP after 
8 weeks of treatment will 
show the added efficacy of 
the extemporaneous 
combination 
 
 
 
 
 
 
 
The proportion of patients 
at target is a very 


 
 
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CONFIDENTIAL                                                                                                                                                27 
 
achieved the BP goal (sitting BP 
≤130/80 mmHg) at Visit 2 and 
Visit 3 
 
● 
To assess compliance to the 
monotherapy and 
extemporaneous combination 
(actual doses taken versus 
doses to be taken) 
 
 
 
 
 
● 
To evaluate the safety and 
tolerability of the ZOF and NEB 
monotherapies, and the 
extemporaneous combination of 
NEB 5 mg and ZOF 30 mg after 
8 weeks of treatment 
of patients achieving the BP 
goal (sitting BP 
≤130/80 mmHg) at Week 0 
(Visit 2) and Week 8 (Visit 3) 
 
● 
Adherence to treatment will 
be measured through 
treatment compliance which is 
100 × (actual doses taken 
versus planned doses to be 
taken) from Visit 1 to Visit 2 
for the monotherapies, and 
from Visit 2 to Visit 3 for the 
extemporaneous combination 
 
● Safety and tolerability of the 
NEB and ZOF 
monotherapies, as well as 
extemporaneous combination 
between NEB 5 mg and ZOF 
30 mg will be measured by 
AEs, SAEs, AEOSI, vital 
signs, physical examination, 
ECG, and concomitant 
medications at Week 0 (Visit 
2) and Week 8 (Visit 3) 
important clinical indicator 
of therapeutic success 
 
 
 
 
Monitoring compliance is 
extremely important to 
better understand the 
efficacy of the 
extemporaneous 
combination 
 
 
 
 
 
 
 
Incidence of ADRs, AEs, 
SAEs, vital signs, physical 
examination, ECG, and 
concomitant medications 
needs to be studied to 
address safety and 
tolerability of the 
extemporaneous 
combination 
 
EXPLORATORY 
 
 
 
To assess the antihypertensive 
efficacy at different time points 
in patients who (1) received 
NEB or ZOF monotherapies 
before the run-in period,   
 
Change in mean sitting SBP and 
DBP between Visit 1 and Visit 2: 
(a) in the group of patients who 
were ZOF 30 mg and NEB 5 mg 
at Visit 1 and continued on the 
Evaluation of the 
antihypertensive efficacy of 
monotherapies and 
combination therapy in 
patients with different CV risk 


 
 
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CONFIDENTIAL                                                                                                                                                28 
 
(2) received any other ACE-i or 
BB monotherapies before the 
run-in period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To assess the antihypertensive 
effect on patients, based on 
their hypertension grade, 
presence or absence of 
hypercholesterolemia, presence 
or absence of diabetes at Visit 2 
and Visit 3 
same treatment until Visit 2  and 
(b) in the group of patients who 
switched to ZOF 30 mg or NEB 5 
mg from any other ACE-i or BB at 
Visit 1 until Visit 2 
 
Change in mean sitting SBP and 
DBP between Visit 1 and Visit 3: 
(a) in the group of patients who 
were on ZOF 30 mg and NEB 5 
mg at Visit 1 and continued the 
same and (b) in the group of 
patients who switched to 
ZOF 30 mg or NEB 5 mg from any 
other ACE-i or BB at Visit 1 until 
Visit 2 
 
Number and proportion of patients 
achieving the BP goal (sitting BP 
≤130/80 mmHg) at Visit 2 and 
Visit 3 evaluated in patients: (a) 
who were on ZOF 30 mg and 
NEB 5 mg at Visit 1 or (b) who 
switched to ZOF 30 mg or NEB 
5 mg from any other ACE-i and 
BB at Visit 1 
 
Number and proportion of 
patients, divided in subgroups 
based on the hypertension grade, 
the presence or absence of 
diabetes, the presence or 
absence of hypercholesterolemia 
achieving the BP goal (sitting BP 
≤130/80 mmHg) at Visit 2 and 
factors 


 
 
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CONFIDENTIAL                                                                                                                                                29 
 
Visit 3 
ACE-i: Angiotensin converting enzyme-inhibitor; ADR: adverse drug reaction; AE: Adverse event; AEOSI: Adverse event 
of special interest; BB: beta blocker; BP: blood pressure; CV: Cardiovascular; DBP: diastolic blood pressure; ECG: 
Electrocardiogram; NEB: Nebivolol; SAE: serious adverse event; SBP: systolic blood pressure; ZOF: Zofenopril calcium 
7. 
STUDY DESIGN 
This is a phase IV, open-label, multicenter, multinational, interventional study to assess the 
effectiveness and safety of the extemporaneous combination of NEB and ZOF in grade 1 to 2 
hypertensive patients versus each monotherapy (NEB or ZOF). 
The study will be conducted in approximately 15 sites in the European Union countries. The 
total study duration is 12 weeks including a run-in period of 4 weeks and an assessment period 
of 8 weeks. 
At Visit 1, after providing informed consent, the eligible grade 1-2 hypertensive patients (with 
blood pressure [BP] ranging from ≥140/90 mmHg to ≤179/109 mmHg), who were on treatment 
since at least 1 month, with any ACE-i or BB including ZOF 30 mg and NEB 5 mg will be 
screened for the eligibility criteria including BP. On the same day, the eligible patients will enter 
the run-in period of 4 weeks (Week -4 to Week 0). Efforts will be made to achieve 1:1 ratio in the 
enrolment of patients receiving any ACE-i or BB. The eligibility for grade 1-2 hypertension will 
be based upon the European Society of Cardiology/European Society of Hypertension 
(ESC/ESH) guidelines 2018, and the BP criteria is defined as mean sitting SBP ≥140 mmHg 
and ≤179 mmHg and/or mean sitting DBP ≥90 mmHg and ≤109 mmHg. 
During the run-in period of 4 weeks (Week -4 to Week 0): 
● 
Patients on ZOF 30 mg or NEB 5 mg will continue the same therapy. Patients on any 
other ACE-i will be assigned to monotherapy with ZOF 30 mg and the patients on any 
other BB will be assigned to monotherapy with NEB 5 mg, respectively. 
Patients with controlled BP (sitting SBP/DBP ≤130/80 mmHg), at Week 0 (Visit 2), patients with 
uncontrolled BP (sitting SBP/DBP >130/80 mmHg) whose adherence to the treatment is not 
included from 80% to 120% or patients who cannot tolerate one of the monotherapies will not 
proceed further into the study. 


 
 
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CONFIDENTIAL                                                                                                                                                30 
 
After the run-in period, the patients will be treated with the extemporaneous combination of NEB 
5 mg and ZOF 30 mg for 8 weeks (assessment period), ie, from Week 0 (Visit 2) till Week 8 
(Visit 3). 
To correctly evaluate the additional effect of the combination therapy, the number of patients 
with uncontrolled BP on NEB 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 (ie, NEB 
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. 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. A total number of 290 patients will be 
screened considering 25% of drop-out rate, to obtain approximately 216 completed patients at 
the end of the study. 
Blood pressure and heart rate will be measured at all visits using a calibrated, fully automated 
machine with a cuff that is appropriate to the size of the upper arm. If a fully automated machine 
is not available, BP may be measured manually. The same method (either automated or 
manual) and the same arm (right or left) must be used throughout the study. The patient should 
be in a seated position with feet touching the floor. Patients should be seated quietly for several 
minutes in a chair with their backs supported, their feet flat on the ground, and their arms bared 
and supported at heart level. At each clinic visit, 3 BP measurements will be collected 24 hours 
(±3 hours) after the last study drug intake and the mean values will be recorded. Each BP 
measure must be recorded within ±2 mmHg. Patients will be instructed to take study medication 
at the same time each day except on the days of study visits when study medication will be 
taken after all visit evaluations have been performed. 
The patients will attend an End of Treatment at Visit 3 (Week 8) at the end of assessment 
period. Safety (AEs, SAEs) will be measured at all visits. In case of any abnormality of clinically 
relevant safety finding at any of the visits according to the Investigator, the patient will be 


 
 
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CONFIDENTIAL                                                                                                                                                31 
 
contacted over phone within 24 hours ensuring their safety measures. Any patient having an 
ongoing AE or SAE at the End of Treatment (Visit 3), will be followed for further 2 weeks over 
phone. 
Patients included in the study should follow the diet and lifestyle counselling. 
At the End of Treatment Visit patients will be advised to maintain the recommended diet and 
physical activity/exercise pattern as per local standards of care. 
 
7.1 
Procedures and Study Visits 
Patients will attend a total of 3 visits during the study. The description of the activities, 
procedures and tests to be performed at each visit is detailed below: 
 
1. Screening and Start of Run-in period (Visit 1, Week -4): 
The following procedures/assessments must be completed during the Screening on the same 
day prior to the run-in period (Visit 1): 
● Obtaining informed consent 
● Checking inclusion and exclusion criteria 
● Recording of medical history 
● Recording of prior and concomitant medications 
● Collection of demographic data 
● Recording concurrent diseases and medical conditions 
● Antihypertensive treatment with NEB or ZOF monotherapy  
● Physical and vital signs examination 
● BP measurement 
● Electrocardiogram (ECG) 
● Laboratory tests (see Section 10.2) (A follow-up phone call will be made within 24 hours 
in case of any abnormality and clinically relevant results from the laboratory tests 
according to the Investigator)  
● Urine pregnancy test 
● AEs and serious adverse events (SAEs) assessment 


 
 
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The subjects meeting all inclusion criteria and none of the exclusion criteria will enter into the 
run-in period on the same day and will receive monotherapy of ZOF 30 mg or NEB 5 mg. 
 
Patients who are already on therapy with ZOF 30 mg or NEB 5 mg will be provided with 
the same medication  
● Patients taking any other BBs will be provided with NEB 5 mg, and patients taking any 
other ACE-i will be provided with ZOF 30 mg 
 
2. Start of the assessment period (Visit 2, Week 0): 
At the end of the run-in period (treatment with monotherapies for 4 weeks ±2 days), only the 
patients with uncontrolled BP (SBP/DBP >130/80 mmHg), who tolerated the treatment and 
whose adherence to the therapy ranges from 80% to 120%, will enter the assessment period. 
The starting of extemporaneous combination ZOF 30 mg /NEB 5mg dosing is noted as Week 0. 
The following procedures/assessments must be completed: 
 
Recording of concurrent diseases and medical conditions  
 
Study drug dispensing (Patients will be provided with the extemporaneous combination 
ZOF 30 mg/NEB 5 mg) 
 
Recording of concomitant medications 
 
Physical examination and vital signs  
 
BP measurement 
 
ECG 
 
Urine pregnancy test (UPT) 
 
Compliance assessment by return of ZOF and NEB tablets (also empty blisters) and 
accountability 
 
AEs and serious adverse events (SAEs) assessment 
 
3. End of the Assessment Period (Visit 3, Week 8): 
The end of assessment period will be considered as end of 8 week ±3 days treatment with the 
extemporaneous combination ZOF 30 mg/NEB 5mg. 


 
 
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The following procedures/assessments must be completed: 
● Recording of concurrent diseases and medical conditions  
● Recording of concomitant medications 
● Physical examination and vital signs 
● BP measurement  
● ECG 
● Laboratory test (A follow-up phone call after will be performed within 24 hours from 
results in case of any abnormality and clinically relevant results from the laboratory tests 
according to the Investigator) 
● Urine pregnancy test (UPT) 
● Compliance assessment by study drug (extemporaneous combination of ZOF 30 mg 
and NEB 5 mg) return (also empty blisters) and accountability 
● AE and SAE assessment 
● In case of any patients having an ongoing AE or SAE at the end of the treatment, there 
will be a follow-up telephone call after 2 weeks to ensure patient safety 
 
Note: Patients will be counselled to follow a heart healthy diet as per local or regional 
guidelines and should be encouraged (as able) to participate in a regular exercise 
programme throughout the study. 
 
8. SELECTION OF PATIENTS 
Informed Consent Process 
Prior to the patient’s enrolment into the study and before performing any study related 
procedures, the Investigator or his/her authorized delegate, shall obtain the patient’s written, 
dated, and signed informed consent to participate into the study and to the confidential 
disclosure, processing and transferring of necessary documentation of the patient’s health and 
personal data to the contract research organization (CRO), Sponsor, and its Affiliates, the 
competent health authorities (HA), and any other institutions, as legally required and in 


 
 
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CONFIDENTIAL                                                                                                                                                34 
 
accordance with the local applicable privacy laws (for the privacy information to be reported on 
the informed consent form [ICF] refer to Section 19). 
The institution and Investigator undertake to duly inform patients about personal data 
processing and the relevant applicable privacy rights before their participation into the study. 
After being duly informed and interviewed by the Investigator, the patient has to freely date and 
sign the ICF before being enrolled into the study and before undergoing any study procedure. 
The Investigator must store the original of the signed ICF in the Investigator’s File, and the 
patient will be provided with a copy of it. If a protocol amendment affects the terms of the ICF, it 
will be revised to reflect the protocol change and submitted to Ethics Committee (EC) and the 
HA for approval. The Investigator will ensure that this new consent form is signed by all patients 
subsequently entered in the study and those currently in the study, if affected by the 
amendment. 
8.1 
Inclusion and Exclusion Criteria 
A patient will be considered eligible to be enrolled in the study only if he/she meets all of the 
inclusion criteria and none of the exclusion criteria. 
8.1.1. Inclusion Criteria 
1. Male or female Caucasian uncontrolled hypertensive patients ≥18 and <65 years of age 
(see definition in criterion 3), in monotherapy either with ACE-i or BBs since at least 1 
month, at Screening 
2. Patients are able to understand and have freely given written informed consent at 
Screening 
3. Patients with mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean sitting DBP 
≥ 90 mmHg and ≤109 mmHg at Screening 
4. Patients who are able to comply with all study procedures and who are available for the 
duration of the study 
5. Ability to take oral medication and willing to adhere to the drug regimen 
6. A female patient of childbearing potential is eligible to participate if she is not pregnant, 
or not breastfeeding. A woman is considered fertile following menarche and until 
becoming postmenopausal unless permanently sterile. Women of childbearing potential 


 
 
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must agree to use of highly effective contraception (eg, method of birth control 
throughout the study period and for 4 weeks after study completion defined as a method 
which results in a failure rate of less than 1% per year) and also must refrain from 
donating or storing eggs during this time. Highly effective contraception methods can be: 
● 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 (provided that partner is the sole sexual partner of the trial 
participant and that the vasectomized partner has received medical assessment 
of the surgical success) 
7. A male patient with female partner 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.  
8.1.2 
Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the study: 
1. Known contraindications, allergies, or hypersensitivities to any of the study medications 
or excipient as outlined in the investigators brochures IBs, summary of product 
characteristics (SmPCs) or local package inserts for NEB and ZOF13,14 
2. Patients with serious disorders (in the opinion of the Investigator) which may limit the 
ability to evaluate the efficacy or safety of the tested medications, including 
cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine 
or metabolic, hematological, or oncological, neurological, and psychiatric diseases. The 
same applies for immunocompromised and/or neutropenic patients 
3. Patients having a history of the following within the last 6 months: myocardial infarction, 
unstable angina pectoris, percutaneous coronary intervention, bypass surgery, heart 


 
 
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failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient 
ischemic attack  
4. Patients with secondary hypertension of any etiology such as renal diseases, 
pheochromocytoma, or Cushing’s syndrome 
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. History of angioneurotic edema 
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. History of bronchospasm and bronchial asthma 
12. Patients with bradycardia (heart rate <60 bpm) 
13. Patient with metabolic acidosis 
14. Patients with severe peripheral circulatory disturbances 
15. Participation in another study within the last 4 weeks 
16. Patients with diseases that, in the opinion of the Investigator, prevent a careful 
adherence to the protocol 
17. Pregnant and breastfeeding women. NOTE: a pregnancy test will be performed on all 
women of childbearing potential at each study visit 
8.1.3 
Screening Failures 
Screening failures are defined as patients who consented to participate in the clinical trial, but 
do not meet one or more criteria required for participation in the trial during the screening 
procedures (Visit 1). There will be no rescreening of screening failure patients in this study. 
 


 
 
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9. STUDY TREATMENT 
The treatments administered during the run-in period of the study are NEB 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 
NEB 5 mg and ZOF 30 mg. Details on the study design is provided in Section 7. 
Further details on study treatment is provided below in Table 9.1. 


 
 
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Table 9.1 
Study Treatment Details 
Study Treatment Name: 
Nebivolol  
Marketing Authorisation Holder: 
A. Menarini Industrie 
Farmaceutiche Riunite srl, Via 
Sette Santi n. 3, 50131 Florence 
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 
Dosage Formulation: 
Tablet 
Film-coated tablet 
Unit Dose 
Strength(s)/Dosage Level(s): 
5 mg once daily 
30 mg once daily 
Route of Administration:  
Oral 
Oral 
Dosing Instructions*: 
1 tablet of study medication will be 
administered with a glass of water 
once daily 
1 tablet of study medication will be 
administered with a glass of water 
once daily 
Packaging and Labelling: 
Study medication will be provided 
in a PVC//Aluminium blister 
Study medication will be provided in 
a PVC/PVDC//Aluminium blister 
Storage Conditions:  
All study treatment must be stored 
in its original packaging and kept in 
a secure area (in a dry place and 
protected from light and in 
accordance with the label’s 
instructions) with access limited to 
the Investigator and authorized site 
staff. No other special precautions 
are needed.  
All study treatment must be stored in 
its original packaging and kept in a 
secure area (in a dry place and 
protected from light and in 
accordance with the label’s 
instructions) with access limited to 
the Investigator and authorized site 
staff. No other special precautions 
are needed. 
*The patients will take the monotherapy tablets or the extemporaneous combination of NEB and ZOF in the morning 
between 6 am to 10 am except on the visit days. On the visit days, the patients will take the  monotherapy tablets or 
the extemporaneous combination of NEB and ZOF after the study assessments. It is important to keep the 
medication intake on the same time every day throughout the study period. NO restriction will be there concerning 
food intake and both the monotherapies, or the extemporaneous combination can be given with or without meals. 


 
 
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9.1 
Study Treatment Formulation, Appearance, Packaging, and Labelling 
Study treatment dosage form, strength, formulation 
Nebivolol 5 mg: NEB 5 mg is white, round, cross-scored tablet with one-sided dividing cross 
score 
Zofenopril calcium 30 mg: ZOF 30 mg is white, oblong film-coated tablet with break marks on 
both sides. 
Study treatment manufacturing 
The NEB 5 mg 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 are reported in relative SmPC.13,14 
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 NEB 5 mg will be provided in dedicated treatment boxes/kits to be 
dispensed at Visit 1 (beginning of the run-in period) and at Visit 2 (start of the assessment 
period). 
 
Visit 1 (run-in period) 
o ZOF 30 mg: each trial participant is provided with one labelled box (blue label) 
containing 42 film-coated tablets (3 blisters of 14 tablets each) of zofenopril 
calcium 30 mg. 


 
 
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o NEB 30 mg: each trial participant is provided with one labelled box (yellow label) 
containing 42 tablets (3 blisters of 14 tablets each) of nebivolol 5 mg. 
Trial participant must be instructed by Investigator to take one tablet of ZOF 30 mg or NEB 5 
mg, according to Study Protocol. 
 
Visit 2 (assessment period) 
Each trial participant is provided with one treatment kit made up by 
o ZOF 30 mg: one labelled box (blue label) containing 70 film-coated tablets (5 blisters 
with 14 film-coated tablets each) of zofenopril calcium 30 mg 
o NEB 5 mg: one labelled box (yellow label) containing 70 tablets (5 blisters with 14 tablets 
each) of nebivolol 5 mg. 
The two labelled boxes are then sealed together into a transparent plastic film in order 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 NEB 5 mg 
(nebivolol 5 mg) as one round tablet, according to Study Protocol. 
9.2 
Study Treatment Distribution and Return/Destruction 
The Principal Investigator (PI) will be responsible for the management of all study medications 
to be used for the clinical trial. An inventory will be maintained by the PI (or designee) to include 
a signed account of all medications received, dispensed to, and returned by each patient at the 
planned visits. An explanation will be given for any discrepancies. At the conclusion of the 
study, the Drug Accountability Form will be completed after a final medication supply inventory. 
All supplied (used or unused) study treatment must be accounted for and provided with relative 
return documentation duly filled in, signed, and dated as appropriate. Any discrepancy (if any) 
must be investigated and satisfactorily explained. Destruction of study medications will be 
carried out by Manufacturer after written authorization of the Sponsor. 
9.3 
Product Storage and Stability 
No special storage conditions are required. 


 
 
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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. 
9.4 
Study Product Compliance 
Compliance with study treatment will be assessed at Visit 2 for monotherapy and Visit 3 for the 
combination therapy. The PI must instruct patients to return the medications at each visit. The 
amount of study medication taken by the patient will be derived by counting the number of 
tablets in the blister returned and will be recorded in the source document and in the electronic 
case report form (eCRF). 
Adherence to treatment will be measured through treatment compliance which 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. 
9.5 
Concomitant Therapies 
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. Patients should remain on the same concomitant medication at a 
stable dose throughout the study. 
9.6 
Non-Permitted Medications 
The patients will not be permitted to use any of the following medications from Screening till the 
end of treatment. Blood pressure modifying drugs including alpha receptor blockers and 
agonists, beta receptor blockers and agonists, calcium antagonists, ACE-i, diuretics, centrally 
acting antihypertensives (eg, clonidine, methyldopa, guanfacine), reserpine, moxonidine, 
chronic nitrate treatment (eg, isosorbide dinitrate or isosorbide mononitrate) and angiotensin II 
antagonists are not permitted, even if used for other indications. 
9.7 
Rescue Medication 
Not applicable. 


 
 
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10. 
STUDY ASSESSMENT AND PROCEDURES 
10.1 
Assessment of Efficacy 
The efficacy variable is to assess the antihypertensive effect of the extemporaneous 
combination of NEB/ZOF (5 mg/30 mg) in grade 1 to 2 hypertensive patients versus each 
monotherapy after 8 weeks of treatment. Data for this variable will be collected from BP 
measurements. 
BP measurements: 
Blood pressure will be measured at all visits. The arm with the higher mean DBP will be 
identified at Screening and will be used in all subsequent visits for BP monitoring. Blood 
pressure measurements should be performed as nearly as possible at the same time of the day 
(between 7:00 AM to 12:00 noon), on the same arm, by the same personnel, and using the 
same calibrated equipment at each visit. 
All BP measurements will be performed after at least 10 minutes of rest; in sitting position in 
triplicate (spaced by at least 1 minute), and once in standing position using a calibrated and 
validated automated sphygmomanometer. The mean of the 3 recordings in the 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 period will be performed as through readings 
(ie, 24+3 hours after the last study treatment intake). 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. 
10.2 
Assessment of Safety 
Safety will be assessed through collection of treatment-emergent AEs, serious AEs (SAE), AEs 
of special interest (AEOSI), that started after the first dose of study treatments (incidence, 
severity, seriousness, treatment causality), and physical examination (body weight, height, vital 
signs, BP, and heart rate). Safety assessments will be performed at time points as described in 
Section 4.1. 


 
 
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10.2.1 Physical Examination: 
Physical examination will be performed according to the local practice. Physical examination will 
consist of the following body systems: eyes, ears, nose, throat, cardiovascular system, 
respiratory system, gastrointestinal system, dermatologic system, extremities, musculoskeletal 
system, nervous system, and lymph nodes. Height and weight will also be recorded at 
Screening. Any new finding, or worsening of a previous finding, should be reported as a new 
AE. 
10.2.2 Vital Signs 
Vital signs will include body temperature (tympanic measurement), respiratory rate, sitting BP 
(see Section 10.1), and pulse (bpm). All BP measurements will be performed after at least 
10 minutes of rest; in sitting position in triplicate (spaced by at least 1 minute), and once in 
standing position. The mean of the 3 BP readings in sitting position will be recorded on the 
eCRF. Blood pressure and pulse measurements will be assessed with a completely automated 
device. 
10.2.3 Clinical Laboratory Tests 
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood is approximately 40 mL, which will be the total blood collected during 
the study. 
A follow-up phone call after each visit will be performed within 24 hours from results only in case 
of abnormality and clinically relevant laboratory test according to the Investigator judgement. 
The local laboratory will perform laboratory tests for hematology and serum chemistry as listed 
below. The results of laboratory tests will be returned to the Investigator, who is responsible for 
reviewing and filing these results. 


 
 
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Hematology 
Serum Chemistry 
Red blood cell 
White blood cell 
Hemoglobin 
Hematocrit 
Platelets 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Neutrophils absolute, Lymphocytes 
absolute, Monocytes absolute, 
Eosinophils absolute, Basophils absolute 
 
 
ALT 
Albumin 
Alkaline phosphatase 
AST  
Total protein 
Direct bilirubin 
Total bilirubin 
Creatinine 
Blood urea nitrogen 
Creatine kinase 
GGT 
Triglycerides 
Cholesterol 
High- and low-density lipoprotein 
Chloride 
Blood glucose 
Serum potassium 
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 
10.2.4 Electrocardiograms 
A single 12-lead resting ECG will be recorded after the patient has been supine for at least 
5 minutes to calculate the heart rate and measure PR, QRS, QT, and QTc intervals. The results 
will be recorded in the eCRF. A trained clinical site physician will perform the clinical 
assessment of each 12-lead ECG. Additional 12-lead ECGs will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more detailed 
assessment of ECGs is required. 


 
 
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11. 
SAFETY DATA MANAGEMENT 
11.1 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
trial patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
11.2 
Drug Relationship 
The relationship between an AE and study treatment will be judged according to the following 
categories: 
1. 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 
2. Probable: The AE occurs in a reasonable time relation to the administration of the 
drug, it is unlikely to be attributed to a concurrent disease or other drugs or chemicals 
and it follows a clinically reasonable response on withdrawal (dechallenge). 
Rechallenge information (AE reappearance after drug reintroduction) is not required 
to fulfil this definition 
3. 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 
4. Unassessable: The relationship cannot be judged, because the information is 
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5. 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 
6. 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. 
11.3 
Adverse Drug Reaction 
An adverse drug reaction (ADR) is any untoward and unintended response to a study treatment 
related to any dose administered. 
The definition implies a reasonable possibility of a causal relationship between the event and 
the study treatment. 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. Unassessable 
An AE is not considered an ADR when the relationship is judged as: 
1. Unlikely 
2. Not related 
11.4 
Seriousness 
An AE/ADR is considered serious when: 


 
 
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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. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization; 
4. Results in persistent or significant disability/incapacity; 
5. Is a congenital anomaly/birth defect; 
6. Is a medically important condition that may jeopardize the patient or may require 
intervention to prevent one of the outcomes listed above. Any suspected transmission 
of an infectious agent via a medicinal product is considered serious and should be 
assessed under the category of medically important events in the absence of other 
seriousness criteria. 
An AE/ADR is considered nonserious when it does not fulfil the conditions for the definition of a 
serious AE/ADR. 
11.5 
Adverse Event/Adverse Drug Reaction Intensity 
The intensity level of a serious or a nonserious AE (NSAE) 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 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 
11.6 
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 ZOF and NEB).13, 14 


 
 
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11.7 
Serious Unexpected Adverse Drug Reaction 
Any SAE judged by the Investigator or the Sponsor as drug-related (see Section 11.3) and 
considered as unexpected qualifies as a serious unexpected adverse drug reaction (SUSAR). 
Suspected unexpected serious adverse drug reactions are subjected to expedited reporting, as 
specified in Section 11.10, as having a “Reasonable Possibility” of relationship with the IMP. 
11.8 
Individual Case Safety Report 
Format and content provided to describe one or several AEs or a disease experience that occur 
to an individual patient at a particular point of time. 
11.9 
Collection, Recording, and Reporting of AEs 
At each visit the Investigator will collect and assess any AEs that have occurred in each patient 
since he/she had signed the informed consent. 
Any laboratory test abnormality (newly occurring after the study treatment administration or 
worsening of previously known abnormalities) that the Investigator considers as clinically 
relevant: ie, values significantly above or under normal range or which require an intervention or 
diagnostic tests or may result in the study treatment discontinuation will be reported as an AE. 
Any AE communicated by the patient or by the patient’s relatives or delegates through phone 
calls, letters, or emails will also be collected and assessed. 
The Investigator shall record on the respective eCRF AE recording pages/AE form any 
recognised AE identifying an individual case safety report (ICSR), both serious and nonserious, 
whether or not thought to be drug-related, observed in or reported by the patient (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. 
The Investigator is expected to record also 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. 


 
 
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In case AE was ongoing, the Investigator is expected to follow-up until the outcome of the AE 
has been determined. 
The Investigator must report all the collected information on any ICSR including seriousness 
(whether or not thought to be related to the investigational drug), providing the concerned eCRF 
AE pages by alert e-mail, after the first knowledge of the occurrence of the case, to: 
CRO Pharmacovigilance Officer: Will be reported through CRO’s Pharmacovigilance group 
(ZoNe_SO@IQVIA.com) for which its details will be provided via study guidelines  
 
When relevant, the eCRF pages concerning medical history, concomitant medication, and 
laboratory tests should also be sent to the Sponsor by e-mail. 
11.10 Management 
of 
Serious 
AEs 
(SAEs) 
Including 
Laboratory 
Abnormalities 
Reporting Duties of the Investigator 
If the investigator becomes aware of a serious adverse event with a suspected causal 
relationship to the investigational medicinal product that occurs after the end of the clinical 
trial in a subject treated by him or her, the investigator shall, without undue delay, report the 
serious adverse event to the sponsor 
The Investigator must report all the collected information on any serious ICSR (whether or not 
thought to be related to the investigational drug), as specified above, no later than 24 hours 
after the first knowledge of the occurrence of the case. 
Any further information and supporting documentation that becomes available (copies of 
laboratory reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be 
provided no later than 24 hours after first knowledge, by the Investigator, to the CRO by alert 
e-mail, to be forwarded to the Sponsor. 
The Investigator must also comply with the local applicable obligation(s) on the reporting of 
ADRs to the local concerned regulatory authority/EC. 


 
 
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CONFIDENTIAL                                                                                                                                                50 
 
Reporting Duties of the Sponsor 
The Sponsor shall ensure that all relevant information about any SUSAR, is expeditiously 
reported to the competent authorities and ECs as required, with these deadlines after the first 
knowledge, intended as the day when the CRO receives the notification of the SUSAR: 
– Fatal and life-threatening unexpected cases, no later than 7 days 
– Other unexpected serious cases, no later than 15 days 
The Sponsor shall ensure that all relevant information and supporting documentation that 
subsequently becomes available, is also expeditiously reported as follow-up information 
according to the above-mentioned deadlines. 
Furthermore, the following safety issues will be patented to expedited management for the 
identification of possible necessary actions: 
– SAEs associated with the trial procedures 
– Potential clinically significant findings emerging from non-clinical studies 
– An anticipated end or suspension for safety reasons of another trial with the same 
study treatment. 
When appropriate and applicable, the Sponsor will arrange for adequate information to be 
communicated to the Investigators. 
For trials in high morbidity and/or mortality disease, where the efficacy endpoint could also be a 
serious unexpected ADR or when a fatal or other serious outcome is the primary efficacy 
endpoint, agreement with the competent authority will be reached to treat the SAE as disease-
related and not subject to expedited reporting. 
11.11 Management of Nonserious AEs Including Laboratory Abnormalities 
Reporting Duties of the Investigator 
The Investigator must report all the collected information on any NSAE ICSR (whether or not 
thought to be related to the investigational drug), as specified above, no later than 5 calendar 
days after the first knowledge of the occurrence of the case. 


 
 
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CONFIDENTIAL                                                                                                                                                51 
 
Any further information and supporting documentation that become available (copies of 
laboratory reports, tests, procedures, etc.) shall be provided no later than 24 hours after the 
Investigator first becomes aware, to the CRO by e-mail or fax, to be forwarded to the Sponsor. 
11.12 Management of Any Laboratory Abnormality 
Any laboratory test abnormality which is considered by the Investigator as an AE, is to be 
managed as detailed above (refer to Section 10.2). However, all “out of range” values should be 
collected and reviewed periodically (modality to be established) by the CRO and the Sponsor. 
11.13 Management of Pregnancy Exposure Cases 
The Investigator is expected to record in the provided form any case of pregnancy exposure 
occurring in a female patient or in a male patient’s partner during the treatment, sending it within 
5 days after being made aware of the pregnancy, to the CRO by e-mail or fax, to be forwarded 
to the Sponsor. 
The Investigator is requested to follow each case of pregnancy exposure until the outcome. 
If the pregnancy results in an abnormal outcome, this will be recorded in the eCRF as an SAE 
and managed as described above. 
Eligibility of a woman of childbearing potential (WOCBP) will be considered as described in 
Section 8.1. 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 center personnel’s: review of the patient’s 
medical records, medical examination, or medical history interview. 


 
 
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CONFIDENTIAL                                                                                                                                                52 
 
 
Postmenopausal female: A postmenopausal state is defined as no menses for 12 
months without an alternative medical cause. A high follicle stimulating hormone (FSH) 
level to 30 mIU/mL or higher may be used to confirm a postmenopausal state in women 
not using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrolment. 
12. 
WITHDRAWAL CRITERIA 
Withdrawal of monotherapies or the study drug 
Withdrawal from the monotherapies or study drug refers to any patient who does not receive the 
complete course, ie, when no further planned dose is administered from the date of withdrawal. 
A patient withdrawn from the monotherapies or study drug may continue further study 
procedures (safety) planned in the study protocol, as deemed appropriate by the Investigator 
once the safety of the patient is recovered/reassured. 
A patient’s study drug or monotherapies may be discontinued for any of the reasons below. In 
addition to the scheduled visits, patient who have been withdrawn from study drug or 
monotherapies may also undergo additional medical follow-up at the discretion of the 
Investigator. 
 
Any AE, which required treatment termination according to the Investigator's judgement 
 
Clinically significant intercurrent illness or laboratory results which could compromise the 
safety of the patient or the scientific value of the study 
 
Investigator deems it to be in the best interest of the patient to discontinue 
 
Requirement to use prohibited medication that could compromise the safety of the 
patient or the scientific value of the study 
 


 
 
Corporate Medical Department 
 
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Previous Doc Number: 
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CONFIDENTIAL                                                                                                                                                53 
 
Withdrawal of patient from the study 
The patient may withdraw from the study at any time without explanation, without losing the right 
to future medical care. The participation of the patient may, at any moment, be terminated by 
the Investigator, if considered appropriate. 
A patient can be withdrawn during the study for any of the following reasons: 
● Any AE, which required treatment and study termination for the patient according to 
the Investigator’s judgement 
● Abnormal renal function or liver enzyme parameters as described in Section 10.2 
● Patient becomes pregnant during the study 
● Request of the patient (without giving any reason) 
● Investigator deems it to be in the best interest of the patient to discontinue 
● Failure to adequately comply with the dosing, evaluations, or other requirements of 
the study 
● If the patient meets an exclusion criterion (newly developed or not previously 
recognized) that precludes further study participation 
● Use of any prohibited medication (eg, concomitant use of aliskiren-containing 
products and ACE-i with sacubitril/valsartan or any other drug as specified per 
SmPCs of ZOF or NEB) that in the opinion of the Investigator or Sponsor 
necessitates the patient being withdrawn 
The reason for the withdrawal of monotherapies or study drug, or withdrawal from the study 
must be well documented in the eCRF page and should capture the date and the specific 
underlying reason for discontinuation of study treatment or patient discontinuation/withdrawal. 
Patients who discontinue from the study early will be asked, anyway, to complete all the 
assessments of Visit 3. Patients may discontinue the study product, but remain in the study for 
follow-up, especially for safety study endpoints (if applicable). 
If a patient has been discontinued/withdrawn due to an AE, the Investigator must immediately 
notify the relevant pharmacovigilance contact (see Section 11.9) and should be followed-up until 


 
 
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CONFIDENTIAL                                                                                                                                                54 
 
the AE is resolved or the Investigator deems further observations or examinations as no longer 
medically indicated. 
13. 
LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he or she fails to return for the scheduled visits 
and is unable to be contacted by the study site staff. 
The site will attempt to contact the patient and reschedule the missed visit. The site will also 
counsel the patient on the importance of maintaining the assigned visit schedule and ascertain if 
the patient wishes to and/or should continue in the study. 
Before a patient is deemed lost to follow-up, the Investigator, or designee will make every effort 
to regain contact with the patient. These contact attempts should be documented in the patient’s 
medical record or study file. 
14. 
STATISTICS 
14.1 
Statistical Methods (Blinding and Randomization) 
This is an open-label study. In this study all the patients are receiving monotherapy in the 
run-in period and combination therapy at the study treatment phase and no randomization is 
required. 
14.2 
Determination of Sample Size 
Considering a screen failure and a drop-out rate of 25% from Visit 1 and Visit 3, the number of 
patients to be screened is 290. Two-hundred and sixteen with uncontrolled hypertension, are 
planned to be included at Screening in the assessment period lasting for 8 weeks. A total 
sample size of 216 patients is required to achieve 90% power at 5% significance level assuming 
a difference in mean DBP from baseline to 8 weeks of 4 mmHg and a standard deviation (SD) 
for this difference of 10 mmHg. The mean change in DBP for null hypothesis is set at 2 mmHg. 
14.3 
Analysis Populations 
In this study, 3 types of analysis population will be used. 


 
 
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● Enrolled population: Patients who are enrolled into the study and may or may not receive 
the study drug (extemporaneous combination) 
● Intent-to-Treat population: Patients who are in the Enrolled population and receive at 
least 1 dose of study drug (combination therapy) and have at least 1 post baseline 
safety assessment 
● Safety population: Patients who are in the Enrolled population and receive at least 
1 dose of study drug (combination therapy) 
● Per protocol population: All patients included in the safety population who do not have 
any major protocol deviations will be included in this population 
 
14.4 
Analysis Variables 
Analysis of Variables and Populations Used 
Efficacy 
 
Analysis Variables 
Population Used 
Primary efficacy 
Change in mean sitting DBP between Week 0 (Visit 2) and Week 8 
(Visit 3)  
ITT population, 
PP population 
Secondary efficacy 
Change in mean sitting SBP between Week 0 (Visit 2) and Week 8 
(Visit 3)  
ITT population, 
PP Population 
 
Number and proportion of patients achieving the BP goal (sitting BP 
≤130/80 mmHg) at Week 0 (Visit 2) and Week 8 (Visit 3) 
ITT population 
 
Adherence to treatment will be measured through treatment 
compliance which is 100 × (actual doses taken/ planned doses) 
Enrolled population, 
Safety population 
Exploratory efficacy 
 
Change in mean sitting SBP and DBP between Visit 1 and Visit 
2 in the group of patients on ZOF 30 and NEB 5 mg and in the 
group of patients switched to ZOF 30 mg or NEB 5 mg from 
any other ACE-I and BB 
 
Change in mean sitting SBP and DBP between Visit 1 and Visit 
3 in the group of patients on ZOF 30 mg and NEB 5 mg or in 
the group of patients switched to ZOF 30 mg or NEB 5 mg from 
any other ACE-i and BB 
 
Number and proportion of patients in the group of patients on 
Enrolled Population 


 
 
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CONFIDENTIAL                                                                                                                                                56 
 
ZOF 30 and NEB 5 mg and in the group of patients switched to 
ZOF 30 mg or NEB 5 mg from any other ACE-I and BB 
achieving the BP goal (sitting BP ≤130/80 mmHg) at Visit 2 and 
Visit 3 suggested in Section 6 
Safety  
Safety and tolerability of the extemporaneous combination between 
NEB 5 mg and ZOF 30 mg measured by AEs, SAEs, AEOSI, vital 
signs, physical examination, ECG, and concomitant medications at 
Week 0 (Visit 2) and Week 8 (Visit 3) 
Safety population 
AE: adverse event; AEOSI: adverse event of special interest; BP: blood pressure; DBP: diastolic blood pressure; ECG: 
electrocardiogram; ITT: Intent-to-treat; SAE: serious adverse event; NEB: nebivolol; SBP: systolic blood pressure; ZOF: zofenopril 
calcium 
 
14.5 
STATISTICAL ANALYSIS 
14.5.1 Descriptive Statistics 
Patient disposition, demographics and baseline characteristics, medical history, and prior and 
concomitant medication will be summarized by treatment group as well as overall. 
Continuous variables will be summarized with the number of non-missing observations, 
mean, SD, standard error of the mean, minimum, median, and maximum. Categorical 
variables will be presented with the number of non-missing observations and column 
percentages (n, %). 
14.5.2 Primary (efficacy) Analysis 
The primary efficacy analysis will be conducted on the intent-to-treat (ITT) population. The 
interpretation of results will be based on ITT population. The PP population will be used to 
assess the robustness of the results obtained using the ITT population. 
The primary endpoint is the mean change from baseline in sitting DBP at Week 8 (Visit 3) for 
patients who are receiving combination therapy. 
The statistical hypothesis will be defined as below: 
H0: There is no change in the sitting DBP prior or post combination therapy 
H1: There is a difference in the sitting DBP prior or post combination therapy 


 
 
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The above hypothesis will be tested as following- 
 
Change from baseline in sitting DBP from prior and post combination therapy will be 
compared using paired t-test. The p-value will be presented using paired t-test. 
 
The primary endpoint will be presented in a descriptive manner using n, mean, 
median, SD, Q1, Q3, and minimum and maximum. 
 
Assumption of normality will be investigated using Wilk-Shapiro test. If violation is 
observed, then paired t-test will be replaced by Wilcoxon signed rank test. 
14.5.3  Sensitivity Analysis 
The primary analysis will be conducted using the PP population. 
14.5.4 Secondary (efficacy) Analysis 
Secondary efficacy variables will be summarized in a descriptive manner using both ITT and 
PP population. 
 
Change in mean sitting SBP between Week 0 (Visit 2) and Week 8 (Visit 3): 
o Change from baseline in sitting SBP from prior and post combination therapy 
will be compared using paired t-test. The p-value will be presented using a 
paired t-test comparing mean at baseline and mean at Week 8. 
o The secondary endpoint will be presented in a descriptive manner using n, 
mean, median, SD, Q1, Q3, and minimum and maximum. 
Assumption of normality will be investigated using Wilk-Shapiro test. If violation is observed, 
then paired t-test will be replaced by Wilcoxon signed rank test. 
The number of patients achieving BP goal (sitting BP ≤130/80 mmHg) will be summarized for 
Visit 2 and Visit 3, along with percentage. A p-value using McNemar’s test will be presented to 
compare the proportion of patients achieving the BP goal (sitting BP ≤130/80 mmHg) between 
Visit 2 and Visit 3. 
14.5.5 Exploratory (Efficacy) Analysis 
Exploratory efficacy variables will be summarized in a descriptive manner using safety 
population for Visits 1, 2 and 3. 


 
 
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CONFIDENTIAL                                                                                                                                                58 
 
 
Change in mean sitting SBP and sitting DBP between Visit 1 and Visit 3 will be 
analyze as following 
o Change from baseline in sitting SBP and DBP from prior (Visit 1) and post 
(Visit 3) combination therapy will be compared using paired t-test. The p-value 
will be presented using a paired t-test comparing mean at baseline and mean 
at Week 8. 
o The exploratory endpoint will be presented in a descriptive manner using n, 
mean, median, SD, Q1, Q3, and minimum and maximum. 
Assumption of normality will be investigated using Wilk-Shapiro test. If violation is 
observed, then paired t-test will be replaced by Wilcoxon signed rank test. 
The number of patients achieving BP goal (sitting BP ≤130/80 mmHg) will be summarized for 
Visit 1 and Visit 3, along with percentage. A p-value using McNemar’s test will be presented to 
compare the proportion of patients achieving the BP goal (sitting BP ≤130/80 mmHg) between 
Visit 1 and Visit 3. 
 
14.5.6 Subgroup Analysis 
Subgroup analysis will be conducted using ITT and PP population based on the following 
parameters. 
 
Country/Site 
 
Age (<40 years and ≥40 years) 
 
Gender (Male, Female, Other) 
 
Presence of diabetes (patients with or without diabetes) 
 
Presence of hypercholesterolemia (patients with or without hypercholesterolemia) 
 
Screening therapy (ACE-i, Beta blocker) 
 
Run-in period therapy (Monotherapies of ZOF 30 mg or NEB 5 mg) 
 


 
 
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14.5.7 Safety Analysis 
Adverse Events: 
Adverse events recorded during the study will be mapped to a system organ class (SOC) 
and preferred term (PT) using the current Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent adverse events are defined as new AEs that occur on or 
after the date/time of the first administration of study medication or worsen if an AE started 
prior to the start of first administration of study medication. 
All the AEs will be presented with the following: 
● Number of cases 
● Number of patients with AE 
● Percentage of patients with AE 
Laboratory: 
Laboratory parameters will be summarized descriptively using the safety population by visit. 
All laboratory data will be listed. 
ECG: 
Electrocardiogram parameters will be summarized descriptively using the safety population 
by visit. All ECG data will be listed. 
Physical Examination (PE): 
Physical examination parameters will be summarized descriptively using the safety 
population by visit. All PE data will be listed. 
14.5.8 Interim Analysis and Stopping Rules 
Not applicable. 


 
 
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14.5.9 Data Imputations 
As a part of missing data analysis Multiple Imputation (MI) simulation method for imputing 
missing data will be conducted on the primary efficacy endpoint using ITT population. This will 
help to assess the impact of missing data on the primary analysis. 
The SAS procedure MI will be used, and the details of MI procedure will be stated in the dataset 
specification document. If the data is monotone missing, an imputation model with regression 
baseline parameters (age, gender, country/site, monotherapy and baseline values) will be 
applied, otherwise Markov Chain Monte Carlo (MCMC) will be applied. All variables included in 
the analysis model and values at Week 0 for the primary endpoint will be included in the 
imputation model. To reduce the sampling variability from the imputation process, 50 datasets 
will be generated. 
In the estimation step, separate analysis will be performed using the paired t-test. 
After the completion of the estimation step SAS procedure MIANALYZE will be used to pool the 
estimates. 
14.6 
Protocol Deviations and Protocol Amendments 
No deviations from the protocol should be initiated without prior approval by the 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, ie, are likely to have an impact on the safety of the patients, 
or to change the interpretation of the scientific documents in support of the conduct of the 
study, or if they are otherwise significant, the ECs and the country authorities (CAs) in the 
participating countries have to approve these amendments before implementation, according 
to applicable regulatory requirements. 


 
 
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Changes which have no significant impact on the medical or scientific validity of the study will 
be agreed upon and approved in writing by all signatories of the protocol and the EC, CAs 
(where applicable) will be notified of this protocol amendment. 
Any substantial amendments of the protocol will be integrated in an updated study protocol. 
The PI must ensure full compliance with the updated study protocol. 
14.7 
Statistical Analysis Plan 
This study is an open-label study and statistical analysis plan (SAP) will be finalized prior to 
first patient in. However, in case of any protocol amendment or any modification which may 
not affect the integrity of data or primary analysis but may lead to modification of SAP 
version, will be finalized prior to database lock. The SAP will describe in detail study 
endpoints and statistical analyses, including the analysis of the primary as well as additional 
endpoints. In case changes to the original primary endpoint or of the original primary 
analyses occurs during the study, these changes will be the subject of a substantial protocol 
amendment. 
All statistical analyses not prespecified and run after database lock will be considered 
additional/exploratory analyses. 
15. 
STUDY DISCONTINUATION AND CLOSURE 
In case this study is temporarily suspended or prematurely terminated, written notification, 
documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to study patients, Investigators, ECs, Sponsor, and 
regulatory authorities with the reason(s) for the termination or suspension. The study patients 
will be contacted, as applicable, and be informed of changes to study visit schedule. 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must permit study related monitoring, audits, EC review, and regulatory 
authorities’ inspections and provide direct access to source data/documents. The 
Investigator/institution should maintain adequate and accurate source documents and study 


 
 
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CONFIDENTIAL                                                                                                                                                62 
 
records that include all pertinent observations on each of the study site patients. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Source 
documents are filed at the Investigator’s study site. 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE 
17.1 
Study Monitoring/Data Quality Control 
Site monitoring is conducted to ensure that the rights and well-being of trial patients are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
ICH-GCP, and with applicable regulatory requirement(s). 
The Investigator will be contacted by the study monitor on a regular basis. The monitor will 
have the responsibility of reviewing the ongoing study with the Investigator to verify 
adherence to the protocol and to deal with any problems. 
The Investigator agrees to allow access to all study materials 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. 
17.2 
Case Report Forms 
Data collected during the study will be recorded in the eCRF. Data reported on the eCRF 
have to be consistent with the source documents. The Investigator must ensure the 
accuracy, the completeness, and the consistency of the data entered in the eCRF. 
On the eCRF, patients will be identified by the patient number/code, assigned at the 
Screening Visit. The patient number/code will be a number composed of numeric values. 
During the conduct of the clinical part of the study, the eCRF must be available and up-to-
date, so that it always reflects the latest observations on the respective patient. 
The Investigator will be responsible for entering study data into the eCRF in accordance with 
the eCRF user guidelines. 


 
 
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17.3 
Quality Assurance 
All clinical activities conducted under this protocol are subject to GCP regulations. This 
includes audits/inspections by the Sponsor, and/or by national/international HA 
representatives at any time. Principal Investigators must agree to the inspection of the study 
site, facilities, and of study related records by HA representatives and/or by the Sponsor, 
and/or its delegates, which must be performed in accordance with national laws concerning 
personal data protection. 
18. 
ETHICAL ASPECTS 
The study will be carried out in compliance with the study protocol, the recommendations on 
biomedical research on human patients of the Declaration of Helsinki, International Council 
for Harmonisation – Good Clinical Practices (ICH-GCP) guidelines, EU-Directives and 
Regulations and national requirements of the participating countries. 
18.1 
Ethics Committees 
Before starting the study in a study site, the study protocol and relevant documentation 
(Patient information leaflet, ICF, the Investigator’s Brochure, and other documents, according 
to National Regulations) must be submitted to and approved by the ECs and the HAs of the 
participating countries. 
In addition, all local national legal requirements for the conduct of a clinical study must 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. 
18.2 
Patient’s Insurance 
For patients participating in the study, the Sponsor will issue an insurance policy in 
accordance with local regulatory requirements. 


 
 
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CONFIDENTIAL                                                                                                                                                64 
 
Details on the insurance company, the insurance number and conditions will be made 
available to patients in the ICF and/or provided as a separate document, in accordance with 
national requirements. The insurance policy will be submitted for approval to the ECs along 
with the other study documents. 
A copy of the insurance certificate will be provided to each Investigator and will be filed in the 
Investigator’s File at the sites and in the study’s Trial Master File (TMF). 
The Investigator must notify the Sponsor immediately upon notice of any claims or lawsuits. 
19. 
DATA PROTECTION LAWS COMPLIANCE 
All clinical trial information shall be recorded, processed, handled, and stored in such a way 
that it can be accurately reported, interpreted, and verified; at the same time, the 
confidentiality of records and of the personal data of the patients shall remain protected in 
accordance with the applicable law on personal data protection such as the EU General Data 
Protection Regulation 679/2016 and the EU Regulation on clinical trials on medicinal 
products for human use 536/2014. This section defines the appropriate technical and 
organizational measures that shall be implemented to protect information and personal data 
processed against unauthorized or unlawful access, disclosure, dissemination, alteration, or 
destruction or accidental loss as well as to assure the fulfilment of patients’ privacy rights. 
19.1 
Acknowledgement 
The site, the PI, the local laboratory, the CRO as well as their appointed staff and service 
providers acknowledge that: (a) the performance of the study will imply processing of 
sensitive personal data; (b) personal data processing is regulated by the applicable 
European and local laws (ie, the laws of the country where the study is conducted) as well as 
by the Sponsor’s national legislation. 
In particular, it is hereby acknowledged that the Sponsor being a company incorporated 
under Italian law, it has to mandatorily comply with Italian legal provisions on data protection: 
therefore the site, the PI, the local laboratory, and the CRO shall cooperate with the Sponsor 
to allow the fulfilment of such obligations; (c) strict compliance with the applicable data 


 
 
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CONFIDENTIAL                                                                                                                                                65 
 
protection laws and this section of the protocol is deemed by the Sponsor as an essential 
condition of collaboration with the site, the PI, the local laboratory, and the CRO. 
19.2 
Data Controllers and Data Processors 
The Sponsor, the site, the PI, and the CRO acknowledges that according to the applicable 
privacy laws, the Sponsor and site will act as independent data controllers while the CRO 
and the PI will act as data processors respectively of the Sponsor and of site. Before 
beginning of the study, the site will instruct in writing the PI as its data processor*. However, 
if specific local laws or regulations mandate a different definition of the privacy roles, the 
Sponsor, the site, the PI, and the CRO will implement the relevant legal instruments (eg, if 
pursuant to the local laws the site is a data processor of the Sponsor, a Data Processing 
Agreement will be finalized; if pursuant to the local laws the Sponsor and Site are join 
controllers, a Joint Controllership Agreement will be finalized). 
*For clinical trials where the PIs are the owners of the site, this provision may not apply. In such cases, the PI might be 
considered as a Data Controller 
19.3 
Duties of the Parties Involved in the Performance of the Study 
 
Collection and use of patients’ personal data including their biological samples, will be 
carried out in full respect of the provisions of the information notices submitted to patients, as 
well as the privacy rights, the fundamental freedoms, and the dignity of data patients. All the 
parties involved in this study undertake to adopt adequate measures to warrant that data will 
always be processed securely and in compliance with privacy laws. The site, the PI, the 
Sponsor, the CRO, and the local laboratory as well as their appointed staff and service 
providers, each in its respective remit and within the limits of their specific role in the study, 
shall implement the following safety measures (physical, logical, organizational, technical, 
electronic, IT, etc.) to ensure adequate protection of the personal data of the patients 
involved in the study. In particular: 
(i) DATA SAFETY. The Site and/or the PI shall adopt all the necessary measures to prevent 
or minimize the risks of theft, fire, flooding, partial or total loss, accidental disclosure or 
illegal/unauthorized access to patient’s data or Sponsor’s proprietary confidential information; 


 
 
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CONFIDENTIAL                                                                                                                                                66 
 
to this extent, before the beginning of the study, the Site and/or the PI shall ensure that the 
actual measures they have implemented are fit-for purpose and law-compliant, and in 
particular: - in order to minimize the risk of unauthorized access and theft, the hardware on 
which patients’ personal data are stored shall be placed in a restricted-access area, 
accessible only to those individuals who need to retrieve the patients’ personal data included 
in the database for professional purposes; the same safeguards shall be put in place for non-
electronic databases; 
- any electronic database containing the patients’ personal data shall be password-protected 
by means of a strong password. Systems shall be set so that passwords must be updated at 
least every 3 months and feature at least 8 characters, with upper-case and lower-case 
recognition, containing at least 3 "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 (eg, 
“johnbrown80”) or easily predictable strings of characters (eg, “qwerty”, “12345”, “admin”, 
“user”, etc.); 
 - adequate cryptographic protection measures shall be put in place for data “at rest” and “in 
transit” (these include, eg, file system or database cryptography, or any other equivalent IT 
measure which renders data unintelligible to those who are not authorized to access them); 
-high level security measures shall also be implemented on the files or databases which 
contain the “key” to match the patients’ personal data (ie, name, surname, etc.) with their 
respective “Patient IDs” (as defined at point [iv] below); 
- Backup processes and other measures that ensure rapid restoration of business-critical 
systems shall be implemented; 
- Updated antivirus and firewall programs shall be installed on IT devices. 
The site shall regularly test and update the measures listed above. The site shall, at the 
Sponsor’s request 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. 


 
 
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CONFIDENTIAL                                                                                                                                                67 
 
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to the 
centralized database(s) used to process study data or to generate statistical analyses shall 
implement secure protocols based on cryptographic standards which make data unintelligible 
to unauthorized individuals. 
(iii) SECURITY OF THE CENTRALIZED DATABASE. The centralized database held by the 
Sponsor shall have the following safeguards in place: appropriate authentication methods, 
which differentiate between different users according to their respective roles so as to ensure 
that access to a specific set of patients’ data is permitted exclusively to those for whom 
access to such data is essential in the context of their work for the study; - appropriate 
measures to ensure that the authentication credentials are periodically updated (ie, password 
change). 
(iv) PSEUDONYMIZATION. All personal data that may allow identification of the patients 
involved in the study shall be adequately dissociated from the other data pertaining to the 
study (“pseudo-anonymization” process). The PI shall adequately dissociate the identification 
data of patients from the data pertaining to the study by linking results to a an alphanumerical 
code [“Patient ID”], whose format shall not make it possible to identify the patient directly or 
indirectly, so as to ensure that only anonymous data are transmitted to the Sponsor, the local 
laboratory and /or the CRO. The site/PI shall securely store a separate list (eg: identification 
log) with the identification code, together with all signed informed consents, in accordance 
with the security measures as defined above. 
The patient code pairing list (ie, the list where the Patient ID is linked to the patients’ 
identification data such as name and surname), shall be archived by the PI. 
As outlined below, samples shall only be stored for as long as strictly necessary for the 
study’s performance and should be destroyed after the analysis. Biological samples and any 
other examination (eg, X-ray, ECG) shall bear Patient ID, and in no case will they bear other 
information that may lead to the direct or indirect identification of the patient, especially when, 
in accordance with this protocol, samples shall be forwarded and shared outside the clinical 
site (eg, in case of centralized reading or local laboratory analysis). 


 
 
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CONFIDENTIAL                                                                                                                                                68 
 
(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 site and/or the CRO 
to the competent authorities (including data protection authorities) and ECs if and when 
requested. If such authorities or the Sponsor consider the implementation of the afore 
mentioned measures insufficient to guarantee an adequate level of protection of the patients’ 
personal data, the site, the PI, the CRO and the local laboratory undertake to adopt all the 
necessary activities to overcome such remarks to assure full compliance with data protection 
laws. 


 
 
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19.4 
Data Breach 
Data Breach is an incident regarding personal data security and leading to the accidental or 
unlawful destruction, loss, alteration, unauthorized disclosure, or access to personal data 
transmitted, stored or otherwise processed. In particular: destruction of personal data is 
where the data no longer exists, or no longer exists in a form that is of any use to the site, 
Sponsor, CRO, PI etc.; data loss is when the data may still exist, but the site, Sponsor, CRO, 
PI etc. has lost control or access to it, or no longer has it in its possession; damage is where 
personal data has been altered, corrupted, or is no longer complete; data unavailability is 
where, following a data incident (such as a network outage, a natural or manmade disaster, 
etc.), personal data become temporarily inaccessible to the site, Sponsor, CRO, PI etc. An 
anomalous event is an event that is not part of the standard operational scope of an 
infrastructure, network or service and which affects, or is likely to affect, personal data; this 
may include theft or loss of IT devices and other physical events (eg, an unauthorized access 
to a locked storage room containing paper files with personal data), and/or electronic/IT 
anomalies (eg, cyber-attacks, default or hacking of cloud services), which may in any way 
entail loss, unavailability, alteration, theft, copy or dissemination of personal data. Whoever 
becomes aware in any way of an anomalous event and/or of a Data Breach (see definitions 
above) affecting the patients’ personal data and/or personal data collected in the context of 
the study, shall, as appropriate, immediately (and in any case no later than 24 hours from the 
knowledge of an anomalous event and/or of a Data Breach) inform the Clinical Operations 
Director, the Sponsor’s Data Protection Officer, the site and the CRO (CRO responsible 
persons for Data Breach incidents management) and shall provide the following information: 
(i) 
Anomalous Event / Data Breach Type (eg, 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) 


 
 
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(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 (eg, 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 has 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 EU, the Sponsor and 
Site autonomously or jointly -depending on the circumstances and their privacy 
responsibilities as defined by the Regulation 679/2016- shall: 
1. Collect the necessary evidence and information 
2. Categorize the breach 
3. Determine the risk probability and level to the rights and freedom of the 
concerned patients 
4. Identify and put in place appropriate remedies to minimize the impact of the Data 
Breach 
5. Determine the notification and communication duties vis à vis the competent 
supervisory authority and/or the concerned patients 


 
 
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19.5 
Information 
notice 
on 
personal 
data 
protection 
and 
pseudo-anonymization 
Prior to patients’ enrolment in the study, the PI and/or the site (including their personnel) shall 
provide each patient with adequate, law-compliant “information notices and consent forms to 
process personal data” as included in the ICF (or, as the case may be, through a separate, 
specific form) provided by the Sponsor or delegated CRO and shall collect his/her written 
consent to the processing of personal data according to the actual performance conditions in 
which the study is carried out. The PI is responsible to archive the signed ICF in accordance 
with the security measures described above. Among other things, the ICF (or the separate 
form) shall inform 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 (eg, performance of the study, pharmacovigilance) 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 pseudonymization procedure and scope 
(vii) who can access patients’ data and under what circumstances 
(viii) the period of data retention/storage as defined in Paragraph 19, including the storage of 
the biological sample 
(ix) to which entities/countries outside the EU patients’ data will be transmitted (if applicable), 
as per Paragraph 18.7 
(x) patients’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016 
(xi) Data Controllers / Data Processors and the relevant contact details 
(xii) Sponsor’s Data Protection Officer contacts (DPO) 


 
 
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(xiii) in case of genetic data processing the possible findings, also with regard to unexpected 
findings that might be disclosed on account of the processing of the genetic data 
19.6 
Genetic Data 
Genetic data will not be collected for this study. 
19.7 
Transfer of patient’s data outside the European Union 
The study performance entails transferring patients ‘personal data (coded data) outside the 
EU. To this extent, the Sponsor, the site, the PI, the local laboratory, the CRO, undertake to 
export such data in compliance with adequate safeguards/legal basis as required by the 
Regulation 679/2016 including the Commission Decisions, the Standard Contract Clauses, 
the Privacy Shield, patients’ specific consent. 
19.8 
Exercise of patients’ data privacy rights 
Each study patient has the right to contact the Sponsor, the site, the PI, the local laboratory, 
the CRO to exercise the rights afforded to the patient by the law, including the afforded ones 
under articles 15 to 22 of Regulation (EU) 2016/679, namely: knowing whether or not any 
data referring to his/her is being processed in the context of the study; access his/her data; 
verify the data’s content, origin, exactness, location (including, where applicable, the non-EU 
countries where the data might be); obtain a copy of the data including their transmission to 
another entity indicated by the [patient- use the same protocol terminology/definitions]; ask 
that the data are supplemented, updated, amended; in the circumstances set forth by the 
law, ask that the processing of data is restricted, that data are anonymized or frozen; oppose 
to the processing of his/her data for legitimate reasons. Each patient has the right to lodge a 
complaint with his/her local supervisory authority and/or to notify to the DPO any use of 
his/her personal data. Each patient is free to withdraw at any time from the study. In such 
case, each study patient may ask the site staff and the Investigator to destroy/delete his/her 
personal data (IF APPLICABLE: including his/her biological samples, unless they have been 
permanently anonymized), thus preventing any further processing or analysis of his/her data. 
However, data and results of tests that may have been used to determine the results of the 
study shall not be deleted, to avoid altering or impairing altogether the results of the study. If 


 
 
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CONFIDENTIAL                                                                                                                                                73 
 
the site, the PI, the local laboratory, the CRO receive a request for data privacy rights 
exercise, the concerned recipient shall immediately inform the Sponsor DPO by e-mail at 
dpo@menarini.com. The request shall be fulfilled within the term set forth by the applicable 
privacy laws (normally 30 days). The Sponsor, the site, the PI, the local laboratory, the CRO 
shall implement adequate organizational measures to reply to patients within the above-
mentioned deadline. 
19.9 
Future research 
With patients’ optional and additional consent, the Sponsor and/or the site may use the data 
collected during the course of the study for further medical and scientific research purposes. 
These may include, eg, retrospective clinical studies; clinical studies pertaining to the 
patients’ pathology/medical condition(s)or similar conditions; studies which compare the data 
of this study with those from other sources to identify the factors involved in a disease; 
registration of new drugs 
In the context of these additional research activities, patients’ data will be processed, 
pseudonymized and transferred abroad and may be shared with future research partners. 
In the context of these additional research activities, patients’ data will be processed, 
anonymized and transferred abroad, and may be shared with future research partners –in 
most cases this will prevent patient’s identification; however, in the unlikely event patients full 
identity really needs to be disclosed, the same precautions and safeguards as those 
described in this protocol will be implemented. 
20. 
DATA HANDLING AND RECORDS KEEPING 
Unless other laws require archiving for a longer period, the site and the PI shall archive the 
content of the clinical trial file, including the relevant patients’ personal data, for at least 
25 years after the end of the clinical trial. However, medical records shall be archived in 
accordance with the national laws of the country where the study is performed. 
The Investigator should keep all study related documents, as specified in ICH E6 (GCP) 
Section 8 and by the applicable regulatory requirement(s), in the Investigator's File. 


 
 
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The media used to archive the content of the clinical trial file shall be such that the content 
remains complete and legible throughout the period referred to in the first paragraph. Any 
modification to the content of the clinical TMF shall be traceable 
The content of the Investigator’s File shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. 
The Sponsor must be notified in writing of the name and address of the new custodian. 
21. 
PUBLICATION POLICY AND RESULTS 
By signing the study protocol, the Investigator (and his/her appointed staff) ensures that any 
information and all the study documents provided by the Sponsor will be maintained strictly 
confidential. 
None of this material may be disclosed to any party not directly involved in the study without 
written permission from Sponsor. 
All information concerning the study, the drug as well as data and results of the study are 
confidential and property of the Sponsor. 
The Sponsor will prepare the final report, including the statistical and clinical evaluations, and 
trial results will be posted and made public, according to applicable Regulatory Regulations. 
The Investigator’s agreement and signature will be obtained, and a copy will be provided to 
the Investigator. 
Sponsor reserves the exclusive right to publish and present data and results of the present 
study at scientific meetings, or to submit these clinical trial data to national and international 
regulatory authorities. The Investigator may not use the results of this study for publication or 
presentation without written authorization from Sponsor. 


 
 
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CONFIDENTIAL                                                                                                                                                75 
 
22. 
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. Weber MA, Basile J, Stapff M, Khan B, Zhou D. Blood pressure effects of combined β-
blocker and angiotensin converting enzyme inhibitor therapy compared with the individual 
agents: a placebo-controlled study with nebivolol and lisinopril. J Clin Hypertens 
(Greenwich) 2012;14(9):588-92. 
8. Nilsson P. Antihypertensive efficacy of zofenopril compared with atenolol in patients with 
mild to moderate hypertension. Blood Press Suppl. 2007;2:25-30. 
9. Cicero AFG, Kuwabara M, Borghi C. A Critical review of nebivolol and its fixed-dose 
combinations in the treatment of hypertension. Drugs. 2018;78(17):1783-1790. 
10. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose 
combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399-
407. 


 
 
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CONFIDENTIAL                                                                                                                                                76 
 
11. Vogel Anderson KL. Combination therapy in hypertension management. US Pharm. 
2012;37(6)(Generic suppl):46-50. 
12. Taylor BC, Wilt TJ, Welch HG. Impact of Diastolic and Systolic Blood Pressure on Mortality: 
Implications for the Definition of “Normal”. J Gen Intern Med. 2011;26(7):685–90. 
13. Summary of product characteristics, Zofenil. 
14. Summary of product characteristics, Labelling and Package Leaflet, v 3.0, Apr 2013, 
Nebivolol. 




 
 
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FORM-000050125 
Previous Doc Number: 
CTWI10A 
Version Number: 
1.0, CURRENT 
Protocol Template 
 
Sponsor: Menarini Pharmaceutical 
Study Code: MEIN/19/ZoNe-HYP/001 
Protocol Version_1 of 16/07/2020 
  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                                78 
 
24. 
Investigator’s Approval Page  
I understand that all information concerning the product Menarini Pharmaceutical supplied 
............................. in connection with this study protocol are confidential information. This 
information includes: Protocol, Investigator’s Brochure, Case Report Form, Other documents 
_________________. 
I understand that any change in this study protocol must be approved in writing by Menarini 
Pharmaceutical and the Coordinating 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 
Pharmaceutical. 
I confirm that I will transfer adequate ownership of my responsibilities for the trial and will inform 
the Sponsor, in case I retire from my PI role. 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly inform 
the Sponsor and declare it to the Competent Authorities. 
 
 
Principal Investigator: ____________________________________________________ 
Signature & Date: _________________________________________________________  


 
 
Corporate Medical Department 
 
Identification Number: 
FORM-000050125 
Previous Doc Number: 
CTWI10A 
Version Number: 
1.0, CURRENT 
Protocol Template 
 
Sponsor: Menarini Pharmaceutical 
Study Code: MEIN/19/ZoNe-HYP/001 
Protocol Version_1 of 16/07/2020 
  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                                79 
 
 
25. 
APPENDICES 
25.1 
Appendix 1: Declaration of Helsinki 
  

SAP_001.pdf: 
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Version Date:  
[14Dec2021] 
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Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
STATISTICAL ANALYSIS PLAN 
 
MEIN/19/ZoNe­HYP/001 
 
Open­label, multicenter, multinational interventional clinical trial to 
assess effectiveness and safety of the extemporaneous combination 
of nebivolol and zofenopril calcium in grade 1 to 2 hypertensive 
patients versus each monotherapy 
 
 
 
 
 
 
AUTHOR: ASWIN NAIR 
VERSION NUMBER AND DATE: FINAL V1.0 14DEC2021 
 
 
 
NCT05257148


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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan Final (Dated 14Dec2021) for Protocol MEIN/19/ZoNe­HYP/001. 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Author: 
Aswin Nair 
Refer to eSignature 
 
 
Position: 
Biostatistician 2 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing that 
the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMYYYY) 
Reviewed By: 
Jisho Jose 
Refer to eSignature 
 
Position: 
Assoc Dir, Biostatistics 
Company: 
IQVIA 
 
Approved By: 
Jean Dorothee Müller 
Refer to eSignature 
 
Position: 
Sr Clin Project Mgr 
Company: 
IQVIA 
 
Approved By: 
Dr. Giorgio Reggiardo 
Refer to eSignature 
 
Position: 
Biostatistician 
Company: 
Menarini International Operations­ external consultant. 
 
Approved By: 
Paolo Fabrizzi 
Refer to eSignature 
 


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Position: 
Clinical Operations Director 
Company: 
Menarini International Operations 


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MODIFICATION HISTORY 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
V1.0 
14Dec2021 
Aswin Nair 
Not Applicable. First version 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACE­i   
angiotensin converting enzyme­inhibitors 
ACS   
Abnormal, Clinically Significant 
ADaM  
analysis data model 
ADR   
adverse drug reaction 
AE 
 
adverse Event 
AEOSI 
adverse event of special interest 
ANCS  
abnormal, not clinically significant 
ATC    
anatomical therapeutic chemical 
BB  
 
beta blocker 
BP  
 
blood pressure 
BMI 
 
body mass index 
CTMS  
clinical trials management system 
DBL   
data base lock 
DBP    
diastolic BP 
DMC   
data monitoring committee 
ECG    
electrocardiogram 
eCRF    
electronic case report form 
EOT    
end of treatment 
ENR   
enrolled 
ITT  
 
Intent­to­treat 
MCMC 
markov chain monte carlo 
MedDRA 
medical dictionary for regulatory activities 
MI 
 
multiple imputation 
NEB    
Nebivolol 
PD 
 
protocol deviation 
PP  
 
per protocol 
PT  
 
preferred term 
SAE    
serious adverse event 
SAF 
 
safety 
SAP    
statistical analysis plan 
SBP    
systolic BP 
SD  
 
standard deviation 
SDTM  
study data tabulation model 
SOC    
system organ class 
TEAE   
treatment emergent adverse events 
WHO   
world health organization 
ZOF    
zofenopril calcium 


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TABLE OF CONTENTS 
 
Table of Contents 
1. 
Introduction ................................................................................................................................................. 11 
2. 
Study Objectives and Estimands ................................................................................................................ 11 
2.1. 
Primary Objective ....................................................................................................................................... 11 
2.2. 
Secondary Objectives .................................................................................................................................. 11 
2.3. 
Exploratory Objectives ............................................................................................................................... 11 
2.4. 
Estimands ..................................................................................................................................................... 12 
3. 
Study Design ................................................................................................................................................ 13 
3.1. 
General Description .................................................................................................................................... 13 
3.2. 
Schedule of Events ....................................................................................................................................... 14 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 15 
4. 
Planned Analyses ......................................................................................................................................... 16 
4.1. 
Data Monitoring Committee (DMC) ......................................................................................................... 16 
4.2. 
Final Analysis............................................................................................................................................... 16 
5. 
Analysis Population ..................................................................................................................................... 17 
5.1. 
Enrolled [ENR] Population ........................................................................................................................ 17 
5.2. 
Intent­to­Treat [ITT] Population ............................................................................................................... 17 
5.3. 
Safety [SAF] Population ............................................................................................................................. 17 
5.4. 
Per Protocol [PP] Population ..................................................................................................................... 17 
6. 
General Considerations .............................................................................................................................. 18 
6.1. 
Reference Start Date and Study Day ......................................................................................................... 18 


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6.2. 
Baseline ......................................................................................................................................................... 18 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ....................................................................... 18 
6.4. 
Windowing Conventions ............................................................................................................................. 19 
6.5. 
Statistical Tests ............................................................................................................................................ 19 
6.6. 
Common Calculations ................................................................................................................................. 19 
6.7. 
Software Version ......................................................................................................................................... 19 
7. 
Statistical Considerations ........................................................................................................................... 20 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses ..................................................... 20 
7.2. 
Multicenter Studies ..................................................................................................................................... 20 
7.3. 
Missing data ................................................................................................................................................. 20 
7.4. 
Multiple Comparisons/ Multiplicity .......................................................................................................... 20 
7.5. 
Examination of Subgroups ......................................................................................................................... 21 
8. 
Output Presentations .................................................................................................................................. 21 
9. 
Disposition and Withdrawals ..................................................................................................................... 22 
9.1. 
Disposition .................................................................................................................................................... 22 
9.2. 
Protocol Deviations ..................................................................................................................................... 22 
9.3. 
Covid­19 Impact .......................................................................................................................................... 22 
10. 
Demographic and other Baseline Characteristics .................................................................................... 22 
10.1. 
Derivations ................................................................................................................................................... 23 
11. 
Medical History ........................................................................................................................................... 23 
12. 
Concurrent Diseases .................................................................................................................................... 23 
13. 
Medications .................................................................................................................................................. 23 
14. 
Study Medication Exposure ....................................................................................................................... 24 
14.1. 
Derivations ................................................................................................................................................... 24 


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15. 
Study Medication Compliance ................................................................................................................... 24 
15.1. 
Derivations ................................................................................................................................................... 25 
16. 
Efficacy Outcomes ....................................................................................................................................... 25 
16.1. 
Primary Efficacy ......................................................................................................................................... 25 
16.1.1. Primary Efficacy Variable & Derivation .................................................................................................. 25 
16.1.2. Missing Data Methods for Primary Efficacy Variable(s) ........................................................................ 25 
16.1.3. Primary Analysis of Primary Efficacy Variable ....................................................................................... 25 
16.1.4. Sensitivity Analysis of Primary Efficacy Variable(s) ............................................................................... 26 
16.2. 
Secondary Efficacy ...................................................................................................................................... 26 
16.2.1. Secondary Efficacy Variables & Derivations ............................................................................................ 26 
16.2.2. Analysis of Secondary Efficacy Variables ................................................................................................. 26 
16.2.3. Sensitivity Analysis of Secondary Efficacy Variable(s) ............................................................................ 27 
16.3. 
Exploratory Efficacy ................................................................................................................................... 27 
16.3.1. Exploratory Efficacy Variables & Derivations ......................................................................................... 27 
16.3.2. Analysis of Exploratory Efficacy Variables .............................................................................................. 27 
17. 
Quality of Life Analysis .............................................................................................................................. 28 
18. 
Safety Outcomes .......................................................................................................................................... 28 
18.1. 
Adverse Events ............................................................................................................................................ 28 
18.1.1. All TEAEs .................................................................................................................................................... 28 
18.1.3. Serious Adverse Events ............................................................................................................................... 29 
18.1.4. Adverse Events Leading to Death .............................................................................................................. 29 
18.2. 
Deaths ........................................................................................................................................................... 29 
18.3. 
Laboratory Evaluations .............................................................................................................................. 29 
18.4. 
ECG Evaluations ......................................................................................................................................... 30 


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18.5. 
Vital Signs .................................................................................................................................................... 30 
18.6. 
Physical Examination .................................................................................................................................. 31 
18.7. 
Other Safety Assessments ........................................................................................................................... 31 
19. 
Data Not Summarized or Presented .......................................................................................................... 31 
20. 
References .................................................................................................................................................... 32 
APPENDIX 1. 
Programming Conventions for Outputs ..................................................................................... 33 
APPENDIX 2. 
Partial Date Conventions ............................................................................................................. 35 
 
 
 


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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of efficacy and safety 
data for Protocol MEIN/19/ZoNe­HYP/001. It describes the data to be summarized and analyzed, including specifics 
of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 1.0 dated 16JUL2020 and addendum version 1.0 dated 
29OCT2020. 
2. STUDY OBJECTIVES AND ESTIMANDS 
2.1.  PRIMARY OBJECTIVE 
To  assess  the  antihypertensive  effect  of  the  extemporaneous  combination  of  zofenopril  calcium(ZOF)  30  mg  or 
nebivolol(NEB) 5 mg in lowering sitting diastolic blood pressure(DBP) after 8 weeks of treatment, in patients with 
uncontrolled blood pressure(BP) who were previously treated with NEB or ZOF monotherapies for at least 4 weeks 
2.2.  SECONDARY OBJECTIVES 
The secondary objectives are, 
• 
To assess the antihypertensive effect of the extemporaneous combination of NEB 5 mg and ZOF 30 mg in 
lowering sitting systolic blood pressure (SBP) after 8 weeks of treatment in patients with uncontrolled BP, after 
at least 4 weeks of treatment with NEB or ZOF monotherapies 
• 
To evaluate the total number and percentage of patients who achieved the BP goal (sitting BP ≤130/80 mmHg) 
at Visit 2 and Visit 3 
• 
To assess compliance to the monotherapy and extemporaneous combination (actual doses taken versus planned 
doses to be taken) 
• 
To evaluate the safety and tolerability of the ZOF and NEB monotherapies, and the extemporaneous combination 
of NEB 5 mg and ZOF 30 mg after 8 weeks of treatment 
2.3.  EXPLORATORY OBJECTIVES 
The exploratory objectives are, 


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• 
To assess the antihypertensive efficacy at different time points in patients who  
1.  received NEB or ZOF monotherapies before the run­in period,  
2.  received any other ACE­i or BB monotherapies before the run­in period 
• 
To assess the antihypertensive effect on patients, based on their hypertension grade, presence or absence of 
hypercholesterolemia, presence or absence of diabetes at Visit 2 and Visit 3 
2.4.  ESTIMANDS 
Estimand 
Definition 
Attributes 
Population 
Variable/Endpoint 
Intercurrent event 
handling strategy 
Population­
level 
summary 
measure 
Primary 
Estimand 
  
Intent­To­
Treat (ITT) 
Change in mean sitting 
DBP between Week 0 
(Visit 2) and Week 8 
The patients will not 
be permitted to use 
any of the Blood 
pressure modifying 
medications from 
Screening till the end 
of treatment. 
Difference 
in mean 
DBP with 
P­value 
Secondary 
Estimand 1 
  
Intent­To­
Treat (ITT) 
Change in mean sitting 
SBP between Week 0 
(Visit 2) and Week 8 
The patients will not 
be permitted to use 
any of the Blood 
pressure modifying 
medications from 
Screening till the end 
of treatment. 
Difference 
in mean 
SBP with P­
value 
Secondary 
Estimand 2 
 
Intent­To­
Treat (ITT) 
The number of patients 
achieving BP goal 
(sitting BP ≤130/80 
mmHg) 
The patients will not 
be permitted to use 
any of the Blood 
pressure modifying 
medications from 
Screening till the end 
of treatment. 
Difference 
in 
proportion 
of patients 
achieving 
BP goal 
between 
Week 0 
(Visit 2) and 
Week 8 
with P­
value 
 
 
 


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Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
3. STUDY DESIGN 
3.1.  GENERAL DESCRIPTION 
This is a phase IV, open­label, multicenter, multinational study with 2 study periods (a run­in period of 4 weeks and 
an assessment period of 8 weeks). Grade 1­2 hypertensive patients (blood pressure [BP] ranging from ≥140/90 mmHg 
to ≤179/109 mmHg) on treatment with any angiotensin converting enzyme­inhibitors (ACE­i) or beta blockers (BBs) 
including ZOF 30 mg or NEB 5 mg respectively will be screened for eligibility (Visit 1). On the same day, the eligible 
patients will enter into a run­in period after Screening, during which:  
• 
Patients on ZOF 30 mg or NEB 5 mg will continue the same therapy for 4 weeks  
• 
Patients on any other ACE­i will be assigned to monotherapy with ZOF 30 mg while patients on any other BB 
will be assigned to monotherapy with NEB 5 mg, respectively, for 4 weeks.  
After the 4 weeks of monotherapy in the run­in period, if BP at Visit 2, remains uncontrolled (sitting SBP/DBP 
>130/80 mmHg) despite an adherence to the treatments ranging from 80% to 120%, the patients will start treatment 
(Week 0, Visit 2) with the extemporaneous combination of NEB 5 mg/ZOF 30 mg (NEB/ZOF) and will be assessed 
for further 8 weeks (assessment period). If the patients, at Visit 2 after the Run­In period, have controlled BP (sitting 
SBP/DBP ≤130/80 mmHg), and/or do not tolerate the treatment, and/or do not maintain the adherence to the therapy 
(range from 80% to 120%), these patients will not be continued further in the study. At the end of the assessment 
period (Visit 3) the antihypertensive effect of the extemporaneous combination of NEB 5 mg and ZOF 30 mg will be 
evaluated. A total number of 290 patients will be screened considering 25% of drop­out rate, to obtain approximately 
216 completed patients at the end of the study. 
 
 
 
 
 
 
 
 
 
 
 
 


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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Figure 1: Study Scheme 
 
 
3.2.  SCHEDULE OF EVENTS 
 
Study Procedures/ Assessments 
Visit 1 (Week ­4) 
Visit 2 (Week 0)a 
Visit 3 (Week 8) 
  
Screening  +  Start  of 
Run­in Periodb 
Start of Assessment 
Period 
End of Assessment 
Period 
Informed consent 
 X 
  
  
Inclusion/exclusion criteria 
X 
  
  
Medical history 
X 
  
  
Prior medication 
X 
  
  
Demography (age, sex, race) 
X 
  
  
Concurrent diseases and medical conditions 
X 
X 
X 
Antihypertensive  treatment  with  NEB  or 
ZOF monotherapyc 
X 
  
  
Study drug dispensingd 
  
X 
  
Study  drug  return  and  accountability 
(Compliance assessment) 
  
Xe 
Xf 


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Concomitant medications 
X 
X 
X 
Urine pregnancy test 
X 
X 
X 
Physical examination 
X 
X 
X 
Vital signs 
X 
X 
X 
Laboratory testg 
X 
  
X 
Blood pressure 
X 
X 
X 
ECG 
X 
X 
X 
AE/SAE assessment 
X 
X 
Xh 
ACE­i: Angiotensin converting enzyme­inhibitors; AE: Adverse event; BB: Beta blockers; ECG: electrocardiogram; 
EOT: End of treatment; NEB: nebivolol; SAE: serious adverse event; ZOF: zofenopril 
calcium 
a: For Visit 2, a window of ±2 days will be allowed at Week 0; and for Visit 3, a window of ±3 days will be 
allowed at Week 8 
b: Patients meeting the eligibility criteria at Screening, will enter the run­in period on the same day 
c: Patients on ZOF 30 mg or NEB 5 mg at Screening will continue the same therapy. Patients on any other 
ACE­i or BBs at Screening will be assigned to monotherapy with ZOF 30 mg or NEB 5 mg, respectively 
d: Patients will be provided with the extemporaneous combination of NEB 5 mg with ZOF 30 mg 
e: Adherence to monotherapies will be checked at the beginning of Visit 2 
f: Adherence to the extemporaneous combination of NEB 5 mg with ZOF 30 mg will be checked at the end 
of Visit 3 
g: 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 
h: Patients having any ongoing AE/SAE at the end of the treatment, will be followed for further 2 weeks via a phone 
call to check about the status of the AE/SAE 
3.3.  CHANGES TO ANALYSIS FROM PROTOCOL 
• 
As per protocol, the definition of Per Protocol Population is “All patients included in the safety population who 
do not have any major protocol deviations will be included in this population”. In SAP, this has been updated to,  


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“The per­protocol (PP) population will contain all patients in the SAF population who have not experienced major 
protocol violations that could affect the efficacy analyses”. 
The primary endpoint analysis includes only 2 two consecutive visits, i.e. Baseline (week 0) and one post baseline 
(Week 8). The protocol suggested multiple imputation (MI) simulation method for imputing missing  data is not 
applicable in this scenario. MI method may not be appropriate for a longitudinal study with only two time­points 
data. Thus, it has been agreed not to perform multiple imputation, and the primary analysis will be performed 
only on the observed data. 
• 
The secondary and exploratory analysis use McNemar’s test to analyze proportion of patients achieving BP goal 
(SBP/DBP <=130/80 mmHg) between visit 2 and visit 3. As per the entry criteria to the combination therapy, 
only those patients with uncontrolled BP (SBP/DBP > 130/80 mmHg) at visit 2 are eligible. So, the proportion of 
patients achieving the BP goal at visit 2 will be always zero. Thus, SAP has been updated with exact McNemar’s 
test instead of McNemar’s test. 
• 
The products involved in this study are well established in the market for many years with an excellent safety 
profile. The term AEOSI is mentioned in the study protocol by error and no adverse events of special interest 
(AEOSI) have been identified which require special monitoring during the study. Thus, no analysis is performed 
on AEOSIs in the study. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
• 
Final Analysis  
4.1.  DATA MONITORING COMMITTEE (DMC)  
There will be no DMC for this study. 
4.2.  FINAL ANALYSIS 
All  final,  planned  analyses  identified  in  this  SAP  will  be  performed  by  IQVIA  Biostatistics  following  Sponsor 
Authorization of this Statistical Analysis Plan, Database Lock, Sponsor Authorization of Analysis Populations.  
 


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5. ANALYSIS POPULATION 
Agreement and authorization of patients included/excluded from each analysis population will be conducted prior to 
database lock of the study.  A data review meeting will be conducted prior to database lock and confirm the patients 
in each analysis set population. Impact of Covid­19 pandemic on the missed data, missed visits or dropouts will be 
assessed during this meeting and appropriate decisions on population counts will be taken. 
5.1.  ENROLLED [ENR] POPULATION 
The enrolled (ENR) population will contain all patients who are enrolled into the study and may or may not receive 
the study drug (extemporaneous combination) 
5.2.  INTENT­TO­TREAT [ITT] POPULATION 
The intent­to­treat (ITT) population will contain all patients in the ENR population and receive at least 1 dose of study 
drug (combination therapy) and have at least 1 post baseline safety assessment 
5.3.  SAFETY [SAF] POPULATION 
The safety (SAF) population will contain all patients who are in the ENR population and receive at least 1 dose of 
study drug (combination therapy) 
5.4.  PER PROTOCOL [PP] POPULATION 
The per­protocol (PP) population will contain all patients in the SAF population who have not experienced major 
protocol violations that could affect the efficacy analyses. Patients with major protocol deviations which can affect 
the primary endpoint of the study, failure to satisfy inclusion or exclusion criteria, taking any prohibited medications 
affecting blood pressure during the study, serious non­compliance to dose regimen and visit schedule are excluded. 
Whether to include or exclude the patients from PP set will be finalized in the data review meeting prior to database 
lock. 


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6. GENERAL CONSIDERATIONS 
6.1.  REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the first dose of study drug (combination therapy) (Visit 2), (Day 
1 is the day of the first dose of study drug ) and will appear in every listing where an assessment date or event date 
appears.  
• 
If the date of the event is on or after the reference date, then:  
• 
Study Day = (date of event – reference date) + 1. If the date of the event is prior to the reference date, then:  
Study Day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will appear 
partial or missing in the listings. 
6.2.  BASELINE 
Unless  otherwise  specified,  baseline  is  defined  as  the  last  non­missing  measurement  taken  same day or  prior  to 
reference start date (including unscheduled assessments) before first dose of study medication (combination therapy). 
Adverse Events (AEs) and medications commencing on the reference start date/time will be considered post­baseline, 
unless the start time of the AE is known to be prior to the first dosing of the  study drug. Since there is no Lab 
assessment in Visit 2, Lab values collected at Visit 1 will be considered baseline for Lab data. 
6.3.  RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
In general, for by­visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will  not  be  included  in  by­visit  summaries.  Listings  will  include  scheduled,  unscheduled,  retest  and  early 
discontinuation data. 


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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
6.4.  WINDOWING CONVENTIONS  
The following table describes assignment of visit windows for the purposes of analysis: 
Table A: 
Visit Window 
Assigned Study Day (Inclusive) 
Visit Assigned 
Week Assigned 
From 
To 
 
 
 
­29 
Visit 1 
Week ­4 
­2 
2 
Visit 2 
Week 0 
53 
59 
Visit 3 
Week 8 
 
6.5.  STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be two­sided, unless 
otherwise specified in the description of the analyses. 
 
6.6.  COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
• 
Test Value at Visit X – Baseline Value 
 
And for change from Visit 1 will be calculated as: 
• 
Test Value at Visit X – Visit 1 Value 
6.7.  SOFTWARE VERSION 
All analyses will be conducted using SAS Enterprise Guide 7.1. 


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7. STATISTICAL CONSIDERATIONS 
Summaries will include descriptive statistics for continuous variables (sample size [n], mean, standard deviation [SD], 
median, minimum and maximum) and for categorical variables (frequency [n] and percentage), unless otherwise stated 
in the relevant section. Percentages will be based on the number of patients within the relevant analysis population 
and treatment arm, or the number of patients with data available where relevant.  
 
If the original data has N decimal places, then the summary statistics will have the following decimal places: 
Minimum and maximum: N 
Mean, median, Q1, Q3, confidence intervals, ratios: N + 1 
SD: N + 2 
 
Percentages will be reported to one decimal place. P­values should be reported to three decimal places, except values 
<1.000 but >0.999 will be presented as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be 
presented as ‘<0.001’ (e.g., 0.0009 is presented as <0.001) 
7.1.  ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
No adjustment for covariates will be performed for this study. 
7.2.  MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally. Center pooling will not be 
carried out for use in analyses for this study. 
7.3.  MISSING DATA 
Missing efficacy and safety data will not be imputed.   
7.4.  MULTIPLE COMPARISONS/ MULTIPLICITY 
Not Applicable 


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7.5. 
 EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections. It should be noted that the study 
was not designed to detect treatment differences with high statistical power within subgroups. 
The following subgroups will be assessed  and described within the exploratory analysis sections on ITT and PP 
populations. 
• 
Country/Site  
• 
Age (<40 years and ≥40 years)  
• 
Gender (Male, Female, Other)  
• 
Hypertension grade at screening (grade 1 and grade 2) 
• 
Presence of diabetes (patients with or without diabetes)  
• 
Presence of hypercholesterolemia (patients with or without hypercholesterolemia)  
• 
Screening therapy (ACE­i, Beta blocker)  
• 
Run­in period therapy (Monotherapies of ZOF 30 mg or NEB 5 mg)  
 
Hypertension grade at screening is derived as follows; 
­ 
Grade 1 – 140 <= SBP < 160 or 90 <= DBP <100 
­ 
Grade 2 – 160 <= SBP < 180 or 100 <= DBP <110 
Patients with presence of diabetes and hypercholesterolemia will be identified from the medical history data using the 
preferred terms. Presence of diabetes can be identified with the preferred terms “Diabetes  mellitus" Or “Type  2 
diabetes 
mellitus" 
and 
hypercholesterolemia 
with 
“Dyslipidaemia” 
or 
“Hypercholesterolaemia” 
or 
“Hyperlipidaemia”. Patients under ACE­i and beta blocker can be identified from the concomitant medication data 
with  anatomical  therapeutic  chemical  (ATC)  class  “Ace  inhibitors,  plain" and “Beta  blocking  agents,  selective" 
respectively. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 


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9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
9.1.  DISPOSITION 
All patients who provided informed consent will be considered for this study. Patient disposition and withdrawals, 
and reasons for exclusion from each analysis population, including inclusion and exclusion criteria will be presented 
for the ENR population. 
9.2.  PROTOCOL DEVIATIONS 
All  protocol  deviations  (PD)  will  be  discussed  and  reviewed  on  a  case­by­case  basis  before  the  DBL.  All  PDs 
authorized by Sponsor will be documented. 
Individual PDs will be presented in a data listing. The number and percentage of patients with PDs will be summarized 
by deviation on ENR population. Additional Major and Minor PDs may be identified during data review and will be 
reflected in the Table and Listing as appropriate. 
All PDs will be recorded and classified in Clinical Trial Management System (CTMS). 
9.3.  COVID­19 IMPACT 
The impact of COVID­19 on study related procedures are collected on ‘COVID­19 Impact Form’ in eCRF.  Impact 
information will be presented in a summary table and a data listing. 
10.  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the ENR. No statistical testing will be carried 
out for demographic or other baseline characteristics. The following demographic and other baseline characteristics 
will be reported for this study  
• 
Age (years)  
• 
Sex 
• 
Race  
• 
Childbearing potential 


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• 
Weight (kg) 
• 
Height (cm) 
10.1.  DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
11.  MEDICAL HISTORY 
Medical History information will be presented for the ENR.  
• 
Medical  History  data  captured  on  eCRF  will  be  coded  using  Medical  Dictionary  for  Regulatory  Activities 
(MedDRA, Version 23.1 or latest) dictionary 
o 
Medical History conditions are defined as those conditions which stop prior to or at Screening.  
o 
Presented by SOC and PT.  
12.  CONCURRENT DISEASES 
Concurrent Diseases will be presented for the SAF by combination therapy. 
• 
Concurrent Diseases will be coded using Medical Dictionary for Regulatory Activities (MedDRA, Version 23.1) 
dictionary 
o 
Concurrent  Diseases  are  conditions  started  prior  to  or  at  Screening  and  are  ongoing  at  the  date  of 
Screening.  
o 
Presented by SOC and PT.  
o 
Concurrent Diseases conditions are defined as those conditions recorded in the eCRF form “Concurrent 
Diseases and Medical Conditions”. 
13.  MEDICATIONS 
Medications will be presented for the SAF and coded using WHO Drug dictionary Version 01SEP2020 or latest. See 
Appendix 2 for handling of partial dates for medications, in the case where it is not possible to define a medication as 
prior, concomitant, the medication will be classified by the worst case, i.e. concomitant.  
Frequency tabulations will be presented for prior and concomitant medications by primary therapeutic subgroup (3rd 


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level ATC code) and preferred name. 
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study medication.  
• 
‘Concomitant’ medications are medications which:  
o 
started prior to, on or after the first dose of study medication,  
o 
AND ended on or after the date of first dose of study medication or were ongoing at the end of the study. 
14.  STUDY MEDICATION EXPOSURE 
Exposure to study medication for both Monotherapy and Combination therapy in days will be presented for the ENR 
and SAF respectively. 
The date of first study medication administration will be taken from the eCRF “Exposure” form. The date of last study 
medication will be taken from the eCRF “End of Study Treatment” form. 
Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
14.1.  DERIVATIONS 
Duration  of  exposure  (days)  =  date  of  last  study  medication  administration  –  date  of  first  study  medication 
administration + 1.  
15.  STUDY MEDICATION COMPLIANCE  
Compliance to study medication will be presented for the ENR and SAF. 
A table consisting of summary statistics for percent compliance along with the number and percent of patients with 
compliance in each of the following groups: 
Low: percentage of compliance <80% 
Normal: percentage of compliance =>80% ­ <=120%  
High: percentage of compliance >120%  
on ENR population for Monotherapy and SAF population for Combination therapy. 
A listing of drug accountability will be presented on ENR population by phase to account for all drug distributed to 
each patient, including the box number, total number tablets dispensed, returned, consumed, lost (if any), percentage 
compliance and compliant (yes/no). 


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15.1.  DERIVATIONS 
Compliance with study medication—based on the drug accountability data will be calculated as the number of tablets 
taken (total dispensed – total returned) divided by the prescribed number of tablets expressed as a percentage, see 
calculations below.  
Mono/Combination Therapy and overall Compliance with study drug based on the drug accountability data will be 
calculated as the number of tablets taken x 100 / expected number of tablets which should have been taken expressed 
as a percentage. 
For patients who permanently stop the study medication, the expected number of tablets will be calculated up­to the 
date of study withdrawal. 
16.  EFFICACY OUTCOMES  
16.1.  PRIMARY EFFICACY 
16.1.1.  PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is Change in mean sitting DBP between Week 0 (Visit 2) and Week 8 
(Visit 3). 
16.1.2.  MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
Not Applicable. 
16.1.3.  PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE 
The primary objective of this study is to test the hypothesis that  
• 
H0: There is no change in the sitting DBP prior or post combination therapy 
• 
H1: There is a difference in the sitting DBP prior or post combination therapy.  
The primary efficacy analysis will be performed for the  ITT population. The above hypothesis will be tested as 
following­ 
• 
Change from baseline in sitting DBP from prior and post combination therapy will be compared using paired 
t­test. The p­value will be presented using paired t­test. 


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• 
The  primary  endpoint  will  be  presented  in  a  descriptive  manner  using  n,  mean,  median,  SD,  Q1,  Q3, 
minimum and maximum. 
• 
Assumption of normality will be investigated using Wilk­Shapiro test. If violation is observed, then paired t­
test will be replaced by Wilcoxon signed rank test. 
 
16.1.4.  SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary sensitivity analysis will be conducted using the PP population. 
16.2.  SECONDARY EFFICACY 
16.2.1.  SECONDARY EFFICACY VARIABLES & DERIVATIONS 
• 
Change in mean sitting SBP  
 
Change in mean sitting SBP between Week 0 (Visit 2) and Week 8 (Visit 3) 
• 
Number and proportion of patients achieving the BP goal 
Number and proportion of patients achieving the BP goal (sitting BP ≤130/80 mmHg) at Week 0 (Visit 2) 
and Week 8 (Visit 3). 
16.2.2.  ANALYSIS OF SECONDARY EFFICACY VARIABLES 
Secondary efficacy variables will be summarized in a descriptive manner using ITT population. 
• 
Change in mean sitting SBP between Week 0 (Visit 2) and Week 8 (Visit 3): 
Change from baseline in sitting SBP from prior and post combination therapy will be compared using paired t­
test. The p­value will be presented using a paired t­test comparing mean at baseline and mean at Week 8.  The 
secondary endpoint will be presented in a descriptive manner using n, mean, median, SD, Q1, Q3, and minimum 
and maximum. 
Assumption of normality will be investigated using Wilk­Shapiro test. If violation is observed, then paired t­test 
will be replaced by Wilcoxon signed rank test.  
• 
The number of patients achieving BP goal (sitting BP ≤130/80 mmHg) will be summarized for Visit 2 and Visit 
3, along with percentage. A p­value using exact McNemar’s test will be presented to compare the proportion of 
patients achieving the BP goal (sitting BP ≤130/80 mmHg) between Visit 2 and Visit 3. 


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16.2.3. 
SENSITIVITY ANALYSIS OF SECONDARY EFFICACY VARIABLE(S) 
The secondary sensitivity analysis will be conducted using the PP population for change in mean sitting SBP between 
Week 0 (Visit 2) and Week 8 (Visit 3). 
16.3.  EXPLORATORY EFFICACY  
16.3.1.  EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
• 
Change in mean sitting SBP and DBP between Visit 1 and Visit 2 in the group of patients on ZOF 30 mg and 
NEB 5 mg and in the group of patients switched to ZOF 30 mg or NEB 5 mg from any other ACE­I and BB 
• 
Change in mean sitting SBP and DBP between Visit 1 and Visit 3 in the group of patients on ZOF 30 mg and 
NEB 5 mg or in the group of patients switched to ZOF 30 mg or NEB 5 mg from any other ACE­i and BB 
• 
Number and proportion of patients in the group of patients on ZOF 30 and NEB 5 mg and in the group of patients 
switched to ZOF 30 mg or NEB 5 mg from any other ACE­I and BB achieving the BP goal (sitting BP ≤130/80 
mmHg) at Visit 2 and Visit 3 
• 
Number and proportion of patients on combination therapy, divided into subgroups specified under section 7.5, 
achieving the BP goal (sitting BP ≤130/80 mmHg) at Visit 2 and Visit 3 
16.3.2.  ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
Exploratory efficacy variables will be summarized in a descriptive manner using safety population for Visits 1, 2 and 
3.  
• 
Change in mean sitting SBP and sitting DBP between Visit 1 and Visit 3 will be analyzed as following:  
• 
Change from baseline in sitting SBP and DBP from prior (Visit 1) and post (Visit 3) combination therapy will be 
compared using paired t­test. The p­value will be presented using a paired t­test comparing mean at baseline and 
mean at Week 8.  The exploratory endpoint will be presented in a descriptive manner using n, mean, median, SD, 
Q1, Q3, and minimum and maximum. Assumption of normality will be investigated using Wilk­Shapiro test. If 
violation is observed, then paired t­test will be replaced by Wilcoxon signed rank test. 
• 
The number of patients achieving BP goal (sitting BP ≤130/80 mmHg) will be summarized for Visit 2 and Visit 
3, along with percentage. A p­value using exact McNemar’s test will be presented to compare the proportion of 
patients achieving the BP goal (sitting BP ≤130/80 mmHg) between Visit 2 and Visit 3. 
• 
The number of patients achieving BP goal (sitting BP ≤130/80 mmHg) will be summarized for Visit 2 and Visit 
3, along with percentage for each of the subgroup specified under section 7.5 of the SAP. 


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17.  QUALITY OF LIFE ANALYSIS  
Not Applicable 
18.  SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Population.  
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified with 
the relevant section.  
18.1.  ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) central coding 
dictionary, Version 23.1.  
Treatment emergent adverse events (TEAEs) are defined as AEs that started or worsened in severity on or after the 
first dose of study medication (Combination therapy). 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an AE as treatment 
emergent or not, the AE will be classified by the worst case; i.e. treatment emergent.  
An overall summary of number of patients within each of the categories described in the sub­section below, will be 
provided as specified in the templates. Listings will include TEAEs and Non­TEAEs. 
18.1.1.  ALL TEAES 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and broken down 
further by maximum severity and relationship to study medication. 
18.1.1.1. 
Severity 
Severity  is  classed  as  mild/  moderate/  severe  (increasing  severity).  TEAEs  starting  after  the  first  dose  of  study 
medication with a missing severity will be classified as severe. If a patient reports a TEAE more than once within that 
SOC/ PT, the AE with the worst­case severity will be used in the corresponding severity summaries. 
18.1.1.2. 
Adverse Drug Reaction  
An adverse drug reaction (ADR) is any untoward and unintended response to a study treatment related to any dose 
administered. The definition implies a reasonable possibility of a causal relationship between the event and the study 


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treatment. In eCRF, if related, as indicated by the Investigator, is classed as “Certain Related”, “Probable Related”, 
“Possible Related”, “Un­assessable”, and if unrelated then classed as “Unlikely related”, “Not related”. TEAEs with 
a missing relationship to study medication will be regarded as “Probable Related” to study medication. If a patient 
reports the same AE more than once within that SOC/ PT, the AE with the worst­case relationship to study medication 
will be used in the corresponding relationship summaries.  
18.1.2.  TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
Treatment­emergent  Adverse  Events  leading  to  discontinuation  of  study  medication  are  those  events  where  for 
‘Reason treatment not completed’ recorded as ‘Adverse event’. 
For  TEAEs  leading  to  discontinuation  of  study  medication,  summaries  of  incidence  rates  (frequencies  and 
percentages) by SOC and PT will be prepared.  
18.1.3.  SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as ”Serious” on the Adverse Events page of the (e)CRF. A 
summary of serious TEAEs by SOC and PT will be prepared. 
18.1.4.  ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as ”Fatal” on the Adverse Events page of the (e)CRF. A 
summary of TEAEs leading to death by SOC and PT will be prepared. 
18.2.  DEATHS 
If any patients die during the study the information will be presented in a summary table and a data listing. 
18.3.  LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, Blood Chemistry 
and Pregnancy test. A list of laboratory assessments to be included in the outputs is included in protocol Section 
10.2.3. Laboratory evaluations will be summarized for Combination therapy by SAF population. Presentations will 
use SI Units.  
The following summaries will be provided for laboratory data: 


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Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• 
A descriptive summary of lab parameters by visit. 
• 
The Shift from screening (visit 1)according to the lab result summary will be provided for laboratory data 
• 
A by­patient listing of all laboratory data and pregnancy test data will be presented. 
18.4.  ECG EVALUATIONS 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of this study.  
The following ECG parameters will be reported for this study: 
• 
PQ Interval (PR) (msec) 
• 
QRS Interval (msec) 
• 
QT Interval (msec) 
• 
QTc Interval (msec) 
• 
HR (bpm) 
• 
Overall assessment of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (ANCS) 
o 
Abnormal, Clinically Significant (ACS) 
ECG parameters will be summarized descriptively using the safety population for the Combination therapy. All ECG 
data will be listed.  
 
18.5.  VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Sitting [/ Standing/ Supine] Systolic Blood Pressure (mmHg) 
• 
Sitting [/Standing/ Supine] Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (bpm) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (⁰C) 
 
 
The following summaries for both Monotherapy and Combination therapy, will be provided for vital signs data: 
• 
Actual and change from baseline by visit. 


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Version Date:  
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18.6.  PHYSICAL EXAMINATION  
The following summaries will be provided for physical examination data for combination therapy by visit on SAF: 
• 
Summary of Physical examination 
• 
Shift from baseline according to the physical examination findings. 
18.7.  OTHER SAFETY ASSESSMENTS 
No other safety assessment will be collected for this study. 
19.  DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
• 
Comments 
• 
Contacts 
• 
These domains and/or variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. 


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20.  REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
EMA. (n.d.). Guideline on Missing Data in Confirmatory Clinical Trials. Retrieved December 15, 2011, from 
European Medicines Agency: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500096793.pdf 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. Biometrics , vol 52, 
1324-1333. 
 
 
 
 
 


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APPENDIX 1.  PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following Global Bios > Processes > GBIOS Processes ­ Implementation 
Guidelines and Templates > General Guidelines and Templates > Output Conventions.   
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy­mm­ddThh:mm:ss. 
 
SPELLING FORMAT 
English US  
PRESENTATION OF TREATMENT GROUPS 
 
 
 
For outputs, treatment groups will be represented as follows and in the given order: 
Therapy 
Treatment Group 
For Tables and Graphs 
For Listings (include if different to 
tables) 
Monotherapy 
NEB 5mg 
NEB 5mg 
NEB 5mg 
Monotherapy 
ZOF 30mg 
ZOF 30mg 
ZOF 30mg 
Combination 
therapy 
NEB+ZOF 
NEB+ZOF 
NEB+ZOF 
 
 
 


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Aswin Nair 
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Version Date:  
[14Dec2021] 
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Effective Date: 02Dec2019 
 
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PRESENTATION OF VISITS 
Visit 1  Week ­4 
Visit 2  Week 0 
Visit 3  Week 8 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening (Visit 1) 
Scr (V1) 
Baseline (Week 0) or Week 0 (Visit 2) 
BL(W0) or W0(V2) 
Week 8 (Visit 3) 
W4 (V3) 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Treatment group (Monotherapy and Combination therapy)  
• 
Center­patient ID,  
• 
Date (where applicable) 
 
 


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APPENDIX 2.  PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, but known components 
show  that  it  cannot  be  on  or 
after study med start date 
Known/Partial/ 
Missing 
Not TEAE 
 
 
 
Partial,  could  be  on  or  after 
study 
med 
start 
date 
OR Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if  day  unknown  or  31st  December  if  day  and  month  are 
unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
 


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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, assign 
as concomitant  
If stop date >= study med start date and start date > end of treatment, assign 
as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, assign 
as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute  start  date  as  earliest  possible  date  (i.e.  first  day  of  month  if  day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, assign 
as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 


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START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute  start  date  as  earliest  possible  date  (i.e.  first  day  of  month  if  day 
unknown or 1st January if day and month are unknown) and impute stop date 
as latest possible date (i.e. last day of month if day unknown or 31st December 
if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, assign 
as concomitant 
If stop date >= study med start date and start date > end of treatment, assign 
as post treatment 
 
Missing 
Impute  start  date  as  earliest  possible  date  (i.e.  first  day  of  month  if  day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 


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