Post-Marketing Clinical Follow-Up Trial to Evaluate the Performance and Safety of the Medical Device PROCTOeze® PLUS in the Relief of Haemorrhoidal Disease and Anal Irritation Symptoms
Phase: NA
Conditions: Haemorrhoidal Disease
Sponsor: Biokosmes Srl

 
 
 
 
Sponsor: 
 
BIOKOSMES S.r.l. 
Via dei Livelli 1 
 23842 Bosisio Parini, Lecco (Italy) 
 
Coordinating Centre 
 
Unități medicale:Specializare: Medicină de familie  
 Principal Investigator: 
C.M.I. Dr. Sisu Lucia-Cristina  
 
Protocol Title: 
Post-Marketing Clinical Follow-Up trial to evaluate the performance and safety of 
the medical device PROCTOeze® PLUS in the relief of haemorrhoidal disease and 
anal irritation symptoms 
 
Final report: OpBio/0123/MD 
Version: 1.0 20250513 
Any and all information presented here is confidential and it shall remain the exclusive property of BIOKOSMES 
S.r.l. Such confidential information must not be disclosed to anyone without written authorisation from 
BIOKOSMES S.r.l., except for possible discussions with regulatory authorities, Ethical Committees or persons 
involved in the conduct of the study who need to know, with the obligation not to further disseminate this 
information. 
 
 

 
 
 
 
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1. COVER 
Clinical Investigation Plan Title 
Post-Marketing Clinical Follow-Up trial to evaluate the 
performance and safety of the medical device PROCTOeze® PLUS 
in the relief of haemorrhoidal disease and anal irritation 
symptoms 
Study Product  
OpBio/0123/MD 
ClinicalTrials.gov Identifier 
NCT 06944951 
Sponsor/Manufacturer 
BIOKOSMES S.r.l. 
Via Besana 10,  
20122 Milano, Italy  
Clinical Research Organization 
Solaris Healthcare SA 
Via Favre 3 
6830 Chiasso 
Study Geography and Site  
Unități medicale Specializare: Medicină de familie  
Str.Eustatiu Stoenescu 200443 
CRAIOVA  
C.I. C.M.I. Dr. Sisu Lucia-Cristina 
Patient Population 
The sample size for this study is 50 patients 
Actual study population: 50 patients  
Document Version 
Version 1.0  
Date 
20250513 
This Final Report has been prepared in accordance with current regulatory standards (ISO 14155:2020, 
MDR 2017/745, ICH GCP)  
Any and all information presented here is confidential and it shall remain the exclusive property of 
BIOKOSMES S.r.l. Such confidential information must not be disclosed to anyone without written 
authorization from BIOKOSMES S.r.l., except for possible discussions with regulatory authorities, Ethical 
Committees or persons involved in the conduct of the study who need to know, with the obligation not 
to further disseminate this information. 
 
 

 
 
 
 
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2. TABLE OF CONTENT 
 
1. 
COVER .................................................................................................................................... 2 
2. 
TABLE OF CONTENT ................................................................................................................ 4 
3. 
SUMMARY .............................................................................................................................. 5 
4. 
PROTOCOL .............................................................................................................................. 9 
5. 
PATIENT DIARY ..................................................................................................................... 60 
6. 
CRF ....................................................................................................................................... 62 
7. 
LABELLING AND INSTRUCTIONS FOR USE .............................................................................. 70 
8. 
INFORMED CONSENT FORM .................................................................................................. 77 
9. 
STATISTICAL ANALYSIS .......................................................................................................... 82 
 
 
 
 
 
Index of Figures 
Figure 1 ................................................................................................................................................ 83 
Figure 2 ................................................................................................................................................ 88 
Figure 3 ................................................................................................................................................ 89 
Figure 4 ................................................................................................................................................ 90 
 
 
Index of Tables 
Table 1 ................................................................................................................................................. 82 
Table 2 ................................................................................................................................................. 82 
Table 3 ................................................................................................................................................. 83 
Table 4 ................................................................................................................................................. 84 
Table 4.1 .............................................................................................................................................. 89 
Table 5 – 5.1 – 5.2 -5.3 ........................................................................................................................ 91 
Table 6 – 5.1 - 6.2 -6.3  ........................................................................................................................ 92 
Table 7 –  7.1 -7.2 -7.3 ......................................................................................................................... 93 
 
 
 
 

 
 
 
 
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3. SUMMARY  
Title 
Post-Marketing Clinical Follow-Up trial to evaluate the performance and safety of the 
medical device PROCTOeze® PLUS in the relief of haemorrhoidal disease and anal 
irritation symptoms 
Study Start Date 
28th October 2024 
Study Stop Date 
27th January 2025 
Sponsor  
BIOKOSMES S.r.l. 
Via Besana 10,  
20122 Milano,  
Italy 
Product/medical 
device description 
PROCTOeze® PLUS is a soft and light hydrophilic emulsion, adjuvant for the 
symptomatic relief of internal and external haemorrhoids and anal irritation. 
PROCTOeze® PLUS key ingredients are mainly paraffinum liquidum, petrolatum, 
dimethicone, and hydroxyethyl cellulose. 
Intended use 
PROCTOeze® PLUS creates a physical barrier that protects the peri-anal tissue, 
minimizing the possibility of bacterial colonization and contact with local and 
environmental agents, which may exacerbate haemorrhoid condition. It has a 
protective, lubricating and refreshing action and emollient properties, which help to 
prevent irritation and discomfort of the perianal area, providing relief from pain, 
burning, itching and other related complaints, contributing to the physiological 
restoration of the anal and perianal tissues. Its application leaves the treated area soft 
and moisturized, avoiding the onset of irritation and cracking of the skin. The 
lubricating action helps to facilitate bowel movement, thus minimising the trauma and 
pain sensation associated with defecation.  
Dosage form and 
Route of 
Administration  
PROCTOeze® PLUS is a soft and light hydrophilic emulsion it is applied, throughout 
the anal orifice and on the surrounding perianal area to relieve symptoms associated 
to hemorrhoids and anal irritation, when required up to three/four times per day. To 
prevent anal irritation and cracking of the skin, it is possible to apply PROCTOeze® 
PLUS once a day. 
Regulatory Status 
This product is a substance-based medical device, CE marked, Class IIb rule 21 
according to the Regulation (EU) 2017/745 
Study Design 
Open, non-comparative, multicenters, prospective, interventional trial. 
Study Geography 
and Site Numbers 
Three centers in Craiova, Romania 
Introduction 
Haemorrhoids are present universally in healthy individuals as cushions surrounding 
the anastomoses between the superior rectal artery and the superior, middle, and 
inferior rectal veins. Nonetheless, the term “haemorrhoid” is commonly invoked to 
characterise the pathologic process of symptomatic haemorrhoid disease instead of 
the normal anatomic structure.  Haemorrhoids play a signiﬁcant physiologic role in 
protecting the anal sphincter muscles and augment closure of the anal canal during 
moments of increased abdominal pressure (e.g., coughing, sneezing) to prevent 
incontinence and contribute 15 to 20% of the resting anal canal pressure. Increases 
in abdominal pressure increase the pressure in the inferior vena cava that cause 
these vascular cushions to engorge and prevent leakage. PROCTOeze® PLUS, a soft 
and light hydrophilic emulsion able to provide symptomatic relief of haemorrhoids 
and anal irritation thanks to its formulation (s). Moreover, due to its formulation, 
the product contributes to the physiological restoration of anal and perianal 
tissues. 

 
 
 
 
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Study 
Rationale/Purpose 
The Research Question of the present trial is the following: in a population of adult 
patients, men and women, suffering from symptomatic haemorrhoids, will the 
administration for 4 weeks of the IMD PROCTOeze® PLUS improve the haemorrhoidal 
symptomatology, giving results assessed at the end of the treatment by means of 
validated questionnaires? 
Study Objective 
This trial aims to evaluate the overall performance and safety of the MD PROCTOeze® 
PLUS in relieving symptomatology of haemorrhoidal disease and anal irritation in adult 
patients affected by Grade I-II (Goligher classification) haemorrhoids as assessed by 
the patient and the Investigator at the end of the treatment period. 
The primary objective is the assessment of performance by the improvement in the 
quality of life (QoL). Secondary objectives are the assessment of performance by 
validated scales completed by the Investigator and by the patient at the end of the 
treatment period. 
The safety of the MD will be evaluated through AE and ADE incidence assessed by 
Investigators and reported according to the current legislation. 
Study Primary 
endpoints: 
● 
The Short Health Scale for Haemorrhoidal Disease (SHSHD) (Annex 3 “Collected 
variables”) (5,16,17) will be used to evaluate the QoL. The questionnaire will be 
administered by the Investigator to each patient during the study visit, at baseline 
and on day 30, in PAPI mode (Paper and Pen Interview) 
Secondary 
endpoints: 
● The Haemorrhoid Severity Score (HSS) (Annex 3 “Collected variables”) (6), a 
physician-reported outcome, will be completed by Investigator at baseline and 
day 30, at the end of the treatment with the MD 
● The Haemorrhoidal Disease Symptom Score (HDSS) (Annex 3 “Collected 
variables”) (5,19) is a patient-reported outcome. The questionnaire will be 
administered by Investigator to each patient at baseline and on day 30, at the end 
of the treatment with the MD. 
● Evaluation of AE, SAE, ADE, SADE, ASADE, USADE incidence assessed by 
Investigator and reported according to the current legislation for the whole study 
period. Device Deficiencies (DD) will be also evaluated. 
Study Population 
Adult patients affected by Grade I-II (Goligher classification) haemorrhoids that did not 
need hospitalization and treated as outpatients (the treatment will be self-
administered at home). 
Selection criteria 
● Men and women ≥ 18 years old. 
● Patients diagnosed with Grade I – II symptomatic haemorrhoids (according to 
Goligher classification) confirmed by clinical and anoscopic or proctoscopic 
examination performed within 3 months before baseline.  
● Patients able to do self-administration at home of the MD, for 30 days, to treat 
symptoms of haemorrhoids and anal irritation. 
● Patient free from the following treatments for haemorrhoids for at least 4 weeks: 
laser treatments for haemorrhoids, steroidal or non-steroidal anti-inflammatory 
drugs, analgesics, any anti-haemorrhoidal treatment, anticoagulants, and 
antiplatelet agents. 
● Patients able to communicate adequately with the Investigator and understand 
the trial questionnaire.  
● Patients able to understand and who can provide valid informed consent to the 
trial. 
Study sites 
Unități medicale Specializare: Medicină de familie  
Str.Eustatiu Stoenescu 200443 - CRAIOVA  
PI  C.M.I. Dr. Sisu Lucia-Cristina 
PI  C.M.I. Dr. Paulina Brezoi  
PI  C.M.I. Dr.  Sanda Petcu 

 
 
 
 
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Executive 
summary 
This report summarizes the results of the post-marketing clinical investigation 
conducted in Romania to evaluate the efficacy and safety of PROCTOeze® PLUS in 
treating hemorrhoidal symptoms and anal irritation. This open-label, non-
comparative, prospective study enrolled 50 patients (68% females and 32% males) 
with Grade I-II hemorrhoids.   
The primary endpoint was assessed using the Short Health Scale for Hemorrhoidal 
Disease (SHSHD) to evaluate quality of life, while secondary endpoints were 
measured via the Hemorrhoidal Disease Symptom Score (HDSS) and Hemorrhoid 
Severity Score (HSS).   
Statistically significant reductions (P < 0.0001) were observed for SHSHD, HDSS, and 
HSS scores from baseline to the end of treatment. Notably, a significant interaction 
was observed in the HSS between genders. The device demonstrated good 
tolerability and an acceptable safety profile  
Sample Size 
Calculation and 
Statistical 
Methods 
 
A total of 50 subjects was be enrolled. 
Simple size estimation was based on the primary endpoint. 
By employing a one-tailed Wilcoxon signed-rank test for matched pairs at a 
significant level of 2.5 % and a power of 80 % we derived a sample size of 50 
evaluable patients to prove PROCTOeze® PLUS performance.   
Considering a possible screen failure rate of 10% we require 55 enrollable patients. 
In addition, 5 patients should account for a possible 10% moderate drop-out rate, so 
60 patients should be screened for enrolment in the clinical investigation. 
Descriptive statistics (mean, standard deviation - SD- median, first and third quartile -
Q1-Q3, min-max) have been calculated for quantitative variables.  
Absolute and percent frequencies have been calculated for qualitative variables. 
Comparison between gender on quantitative variables normally/symmetrically 
distributed have been carried out by means of the Student's t test. 
The change of the total of the SHSDH (primary objective of the study), on the total of 
the HSS and HDSS (secondary objectives of the study) between baseline and the end 
of the study has been assessed, according to the protocol, by means of the Wilcoxon 
signed-rank test. 
In addition, the change between Visit 1 and Visit 2 of SHSDH, HSS, and HDSS has 
been modeled between the two genders by means of the repeated measurement 
ANOVA with gender as a fixed factor between patients, time as a fixed factor within 
patients and their interaction. 
The detailed statistical tables and figures are included below. 
Discussion 
The findings of this PMCF study confirm that PROCTOeze® PLUS is effective and safe 
in relieving the symptoms of haemorrhoidal disease and anal irritation. The 
significant reduction in pain, itching, burning, and swelling highlights the product’s 
efficacy, while the absence of adverse events demonstrates good tolerability.  
The statistical analyses demonstrate a significant improvement in quality of life and 
symptom relief.   
• 
The SHSHD score decreased markedly, indicating enhanced quality of life.   
• 
Both the HDSS and HSS scores showed significant reductions, confirming the 
device’s efficacy in alleviating symptom severity.   
• 
The significant interaction in the HSS suggests a gender-related difference in 
response, which may require further study.   
• 
Overall, the safety data were reassuring, with no adverse events reported. 
The integrated tables and figures from the statistical analysis clearly support the 
robustness of these findings. 

 
 
 
 
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Results 
Demographics and Baseline Characteristics   
• 
Number of Patients: 50   
• 
Gender Distribution 68% female, 32% male   
• 
Mean Age Approximately 50 years (SD 13.90)  
with no significant difference between genders (see Table 1 ). 
 
Outcome Assessments   
SHSHD 
• 
Baseline: 14.04 (SD 7.79)   
• 
End-of-Treatment: 7.80 (SD 3.69)   
• 
Mean Reduction: 6.24 points (P < 0.0001)   
(See Table 5 and Figure 2 for detailed analysis.) 
 
HDSS   
• 
Baseline: 10.12 (SD 3.60)   
• 
End-of-Treatment: 7.20 (SD 2.47)   
• 
Mean Reduction: 2.92 points (P < 0.0001)   
(See Table 6 and Figure 3 for detailed analysis.) 
 
HSS   
• 
Baseline: 8.50 (SD 2.11)   
• 
End-of-Treatment: 6.48 (SD 2.17)   
• 
Mean Reduction: 2.02 points (P < 0.0001)   
• 
A significant Visit x Gender interaction was found (P = 0.0272).   
(See Table 7 and Figure 4 for detailed analysis.) 
 
Device Usage   
Patient diaries indicated a mean usage of approximately 34 cream applications over 
the 14-day monitoring period, with daily consumption remaining relatively 
consistent and a slight decrease observed in the later study days. 
 
Safety   
No serious adverse events (SAEs) were reported. No, AE was reported.  
Conclusions 
This post-marketing clinical investigation demonstrates that PROCTOeze® PLUS is 
effective in improving quality of life and reducing the symptoms associated with 
hemorrhoidal disease and anal irritation in adult patients with Grade I-II 
hemorrhoids.  
The significant reductions in SHSHD, HDSS, and HSS scores (all P < 0.0001), combined 
with an acceptable safety profile, support the continued clinical use of PROCTOeze® 
PLUS.   
Ongoing post-marketing surveillance is recommended to further confirm the long-
term safety of the device.  
 
Timing 
Approval by National Bioethics 
Committee for Medicines and Medical 
Devices 
18th October, 2024 
Start of enrolment (FPI) 
8th November 2024 
End of enrolment (LPI)  
17th December 2024 
End of treatment (LPO) 
16th January 2025 
Final Report of trial  
 03th April 2025 

 
 
 
 
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4. PROTOCOL 
 
 
Sponsor: 
 
BIOKOSMES S.r.l. 
Via dei Livelli 1 
 23842 Bosisio Parini, Lecco (Italy) 
 
Unități medicale: ; Specializare: Medicină de familie  
Coordinating Centre:  
 
 C.M.I. Dr. Sisu Lucia-Cristina  
Principal Investigator:  
 
 
 
Protocol Title: 
Post-Marketing Clinical Follow-Up trial to evaluate the performance and safety of 
the medical device PROCTOeze® PLUS in the relief of haemorrhoidal disease and 
anal irritation symptoms 
 
 
Protocol Code: OpBio/0123/MD 
Version: 1.0 – 20241201 
Type: PMCF 
Register: www.ClinicalTrials.gov  
Contract Research Organization: 
Solaris Healthcare SA 
Via Favre 3 
CH 6830 Chiasso 
Any and all information presented here is confidential and it shall remain the exclusive property of BIOKOSMES 
S.r.l. Such confidential information must not be disclosed to anyone without written authorisation from 
BIOKOSMES S.r.l., except for possible discussions with regulatory authorities, Ethical Committees or persons 
involved in the conduct of the study who need to know, with the obligation not to further disseminate this 
information. 

 
 
 
 
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PROTOCOL APPROVAL - SPONSOR 
 
Sponsor 
I declare that our company has sent all information related to the Investigational Medical Device to 
the CRO to elaborate the clinical investigation plan code OPBIO/0123/MD (Version: 1.0– 20231201).  
Name: 
Dr Lodovico Braguti 
Date: 
_____/_____/_____ 
Signature: 
______________________________ 
Professional position:  
CEO and Legal Representative 
Company: 
 
BIOKOSMES S.r.l. 
Via Besana 10, 20122 Milano (Italy) (Registered Office) 
 
 

 
 
 
 
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PROTOCOL APPROVAL  
Site No. 01 –Principal Investigator  
 
I have carefully read the protocol trial plan code OpBio/0123/MD (Version: 1.0  – 20231201) and, on behalf of 
the study staff and myself, I agree to maintain the procedures required by the BIOKOSMES S.r.l. and CRO, to 
conduct this trial in accordance with Good Clinical Practice, Declaration of Helsinki, local laws and regulations. 
It is understood that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. I agree that BIOKOSMES S.r.l., its delegates, 
CRO, and National Competent Authorities have direct access to all study documentation. I agree to obtain 
written Informed Consent from all participating patients. 
Name: 
C.M.I. Dr. Sisu Lucia-Cristina 
Date: 
_____/_____/_____ 
Signature: 
______________________________ 
Professional position:  
Medical Doctor 
Site: 
Unități medicale Specializare: Medicină de familie Str.Eustatiu 
Stoenescu 200443 
CRAIOVA 
 
EMERGENCY CONTACTS 
Role 
Contact Name 
Phone/fax/e-mail 
SPONSOR 
BIOKOSMES S.r.l. 
Andrea Turconi 
Quality Assurance Director 
Diana Koprivec 
Clinical and Safety 
Phone: +39 0313581085 
e-mail: andrea.turconi@biokosmes.it  
Phone +41 79 220 10 94 
diana.koprivec@kbcompany.ch 
CRO 
SOLARIS Healthcare SA 
Donatella Mariani 
Project Director and QPPV 
Mobile: +41 79 844 2600 
e-mail: pv@solarishc.ch 
 

 
 
 
 
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RESPONSIBILITIES 
SPONSOR 
 
 
 
 
 
 
 
 
BIOKOSMES S.r.l. 
Via dei Livelli 1, 23842 Bosisio Parini, Lecco (Italy) (Headquarters) 
Via Besana 10, 20122 Milano (Italy) (Registered Office) 
Telephone: +39 0313581085 
Fax +39 0313581082 
e-mail: biokosmes@biokosmes.it  
 
Represented by: 
 
Dr Lodovico Braguti 
Phone: + 39 0313581085 
e-mail: biokosmes@biokosmes.it  
CRO 
 
Represented by: 
 
Donatella Mariani 
Phone +41 79 8442600 
e-mail info@solarishc.ch 
 
 

 
 
 
 
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TABLE OF CONTENTS 
 
PROTOCOL APPROVAL - SPONSOR 
2 
PROTOCOL APPROVAL 
3 
EMERGENCY CONTACTS 
4 
RESPONSIBILITIES 
5 
TABLE OF CONTENTS 
6 
LIST OF ABBREVIATIONS 
8 
SYNOPSIS 
9 
SCHEDULE OF ASSESSMENTS 
15 
1. 
GENERAL INFORMATION 
16 
1.1. 
TITLE 
16 
1.2. 
STUDY REGISTRATION 
16 
1.3. 
PROTOCOL VERSION 
16 
1.6. 
CURRENT LEGISLATION AND GUIDELINES 
17 
1.7. 
TIMING 
18 
2. 
INTRODUCTION 
18 
2.1.  
BACKGROUND AND RATIONALE 
18 
2.2. 
RESEARCH HYPOTHESIS 
20 
2.3. 
STUDY OBJECTIVES 
20 
J 
USTIFICATION FOR THE TRIA 
20 
3. 
PROCEDURES 
21 
3.1.     DESIGN 
21 
3.2. 
STUDY SETTING 
21 
3.3. 
SELECTION OF POPULATION 
21 
3.4. 
MEDICAL DEVICE DESCRIPTION 
22 
3.5. 
STUDY PROCEDURES AND COLLECTED VARIABLES 
23 
3.6. 
DEFINITIONS AND PROCEDURE FOR REPORTING OF ADVERSE EVENTS 
25 
3.6.1. 
DEFINITIONS 
25 
3.6.2. 
CLASSIFICATION OF AN ADVERSE EVENT 
27 
3.7. 
DATA COLLECTION 
31 
SCHEDULE OF ASSESSMENTS 
32 
4. 
DATA MANAGEMENT AND ANALYSIS 
35 
4.2. 
DATA MANAGEMENT 
35 
4.3. 
STATISTICAL ANALYSIS 
36 
5. 
DEVIATIONS FROM THE PROTOCOL 
38 
6. 
TERMINATION OF THE STUDY 
38 
6.1. 
END OF THE TRIAL AND ITS DURATION 
38 
6.2. 
PREMATURE TERMINATION/SUSPENSION OF THE TRIAL 
38 
7. 
COMPLIANCE TO ETHICS AND REGULATORY 
39 
7.1. 
GUIDELINE AND LEGISLATION 
39 
7.2. 
ETHICS COMMITTEE APPROVAL 
39 
7.3. 
INFORMED CONSENT AND PATIENT INFORMATION 
39 
7.4. 
VULNERABLE POPULATION 
39 
7.5. 
PATIENT’S DATA PROTECTION 
39 

 
 
 
 
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7.6. 
ETHICAL PRINCIPLES 
40 
7.7.  
INSURANCE 
40 
7.8. 
DECLARATION OF INTERESTS 
40 
8. 
QUALITY ASSURANCE 
41 
8.1. 
QUALITY CONTROL PROCEDURES 
41 
8.2. 
AUDITS AND INSPECTIONS 
41 
8.3. 
STAFF TRAINING 
41 
9. 
REFERENCES 
42 
10. 
ANNEX 1 Medical Device Composition 
44 
11. 
ANNEX 2 Goligher Classification 
46 
12. 
ANNEX 3 Collected Variables 
47 
13. 
ANNEX 4 Adverse Event Classification 
49 
14. 
ANNEX 5 Declaration of Helsinki 
51 
 
 

 
 
 
 
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LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
CRO 
Contract Research Organization 
DB 
Data Base 
DD 
Device Deficiency 
DPS 
Data Privacy Sheet 
EC 
Ethics Committee 
CRF 
Case Report Form 
EMA 
European Medicines Agency 
FPI 
First Patient In 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HDSS 
Haemorrhoidal Disease Symptom Score 
HSS 
Haemorrhoid Severity Score 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
IFU 
Instructions For Use 
IMD 
Investigational Medical Device 
ISF 
Investigator Site File 
LPI 
Last Patient In 
LPO 
Last Patient Out 
CRO 
Contract Research Organization S.r.l. 
PMCF 
Post-marketing Clinical Follow-Up 
QC 
Quality Control 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SHSHD 
Short Health Scale for Haemorrhoidal Disease 
SR 
Study Report 
TMF 
Trial Master File 
USADE 
Unanticipated Serious Adverse Device Effect 

 
 
 
 
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SYNOPSIS 
Title 
Post-Marketing Clinical Follow-Up trial to evaluate the 
performance and safety of the medical device PROCTOeze® 
PLUS in the relief of haemorrhoidal disease and anal 
irritation symptoms 
Protocol code 
OpBio/0123/MD 
Version 
1.0  – 20241201 
Registry 
www.ClinicalTrials.gov   
Type 
Post-Marketing Clinical Follow-Up   
MD class 
Medical Device of Class IIb, according to the classification rules of Regulation (EU) 
2017/745 of the European Parliament and of the Council of 5 April 2017 on 
medical devices (Rule 21).  
Sponsor 
BIOKOSMES S.r.l. 
Via Besana 10, 20122 Milano, Italy (Registered Office) 
CRO 
Solaris Healthcare SA 
Via Favre 3 
6830 Chiasso 
The Sponsor authorised and delegated the CRO to perform: 
 
● Support to define the rationale and research hypothesis. 
● Protocol writing. 
● CRF and work instructions preparation. 
● ICF and other study documents preparation. 
● Elaboration of study documents in the Romanian language. 
● Preparation and updating of Trial Master File (TMF) and Investigator Study 
File (ISF). 
● 
Ethics Committees and Competent Authority issues and submissions in 
Romania. 
● Supporting the procedures for the financial agreement between the Sponsor 
and administrations of involved Centres in Romania. 
● Monitoring 
● Data Management. 
● Safety Management. 
● Statistical Analysis. 
● Preparation of the Final Report. 
Introduction and 
Rationale 
 
 
Haemorrhoids are variceal dilatations of the anal and perianal venous plexus 
and often develop secondary to the persistently elevated venous pressure 
within the haemorrhoidal plexus (1,2).  
Haemorrhoids may be present in three classical positions: the right anterior, 
right posterior and left lateral areas of the anal canal. External haemorrhoids are 

 
 
 
 
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covered with skin and internal haemorrhoids are covered with anal mucous 
membranes. Goligher introduced the most widely accepted classification (3,4). 
Most symptoms and signs that patients present with arise from internal 
haemorrhoids, derive from structural changes of the normal anatomic padding 
(enlarged internal haemorrhoids) and are generally associated with chronic 
straining either due to constipation, diarrhoea or prolonged periods trying to 
defecate. Symptoms are also common during pregnancy and childbirth.   
The acute clinical manifestation of the haemorrhoidal disease is commonly 
known as haemorrhoidal crisis and it is characterized by rectal bleeding, 
prolapse, pruritus (itching), pain, oedema, often thrombosis, and less frequently 
soiling or mucoid discharge (1,2). The most common sign is rectal bleeding that 
appears bright red for the high blood oxygen content within the arteriovenous 
anastomosis. The bleeding is usually described as red spotting on the toilet 
tissue or dripping in the toilet bowl at the end of defecation, separately from the 
stool. External haemorrhoids may be asymptomatic or associated with 
discomfort or with acute extreme pain in the event of a local thrombosis 
(formation of a clot). 
BIOKOSMES has developed the medical device PROCTOeze® PLUS, a soft and 
light hydrophilic emulsion, containing film-forming agents that help minimise 
the possibility of bacterial colonisation and contact with environmental dirt, 
which may exacerbate haemorrhoid condition. The ingredients responsible for 
the formation of the barrier are mainly paraffinum liquidum, petrolatum, 
dimethicone, and hydroxyethylcellulose. The film-forming (barrier) effect allows 
the retention of the product locally, at the rectal mucosa level, maintaining the 
emollient action, meanwhile the overall rheologic effect of the product 
facilitates the emptying of the rectal ampoule with a subsequent decrease of 
local discomfort. 
PROCTOeze® PLUS is registered as a Medical Device of Class IIb, rule 21 according 
to the Regulation (EU) 2017/745 and it is largely used in the clinical practice of 
thousands of medical doctors in Italy, Romania, Iceland, Bulgaria, Taiwan, and 
Israel. Following the actual medical device legislation, the manufacturer must 
routinely present to the Notified Body for each CE-registered medical device the 
results of clinical investigations performed post-marketing clinical follow-up 
(PMCF) activities. The present trial is planned to follow this requirement and it 
will be performed in Romania where the IMD PROCTOeze® PLUS is 
commercialised with the brand name PROCTINUM®.  
The Research Question of the present trial is the following: in a population of 
adult patients, men and women, suffering from symptomatic haemorrhoids, will 
the administration for 4 weeks of the IMD PROCTOeze® PLUS improve the 
haemorrhoidal symptomatology, giving favorable results assessed at the end of 
the treatment by means of validated questionnaires? 
Objectives 
This trial aims to evaluate the overall performance and safety of the MD 
PROCTOeze® PLUS in relieving symptomatology of haemorrhoidal disease and 

 
 
 
 
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anal irritation in adult patients affected by Grade I-II (Goligher classification) 
haemorrhoids as assessed by the patient and the Investigator at the end of the 
treatment period.  
The primary objective is the assessment of performance by the improvement in 
the quality of life (QoL).  
Secondary objectives are the assessment of performance by validated scales 
completed by the Investigator and by the patient at the end of the treatment 
period. 
The safety of the MD will be evaluated through Adverse Events (AE) and Adverse 
Device Effect (ADE) incidence assessed by Investigators and reported according 
to the current legislation. 
Outcomes 
Primary outcome 
● The Short Health Scale for Haemorrhoidal Disease (SHSHD) (5) will be used to 
evaluate the QoL. The questionnaire will be completed by the patient at 
baseline and day 30, at the end of the treatment with the MD. 
Secondary outcomes 
● The Haemorrhoid Severity Score (HSS) (6), a physician-reported outcome, 
will be completed by Investigator at baseline and day 30, at the end of the 
treatment with the MD. 
● The Haemorrhoidal Disease Symptom Score (HDSS) (5), a patient-reported 
outcome questionnaire, will be administered by Investigator to each patient 
at baseline and at day 30, at the end of the treatment with the MD. 
● Evaluation of AE, SAE, ADE, SADE, ASADE, USADE incidence assessed by 
Investigator and reported according to the current legislation for the whole 
study period. DD will be also evaluated. 
Design 
Open, non-comparative, prospective, interventional trial. 
Disease 
Hemoroidal disease :Grade I – II symptomatic haemorrhoids (according to 
Goligher classification) 
Population 
Adult patients affected by Grade I-II (Goligher classification) haemorrhoids that 
did not need hospitalization and treated as outpatients (the treatment will be 
self-administered at home). 
Inclusion criteria 
● Men and women ≥ 18 years old. 
● Patients diagnosed with Grade I – II symptomatic haemorrhoids (according 
to Goligher classification) confirmed by clinical and anoscopic or 
proctoscopic examination performed within 3 months before baseline.  
● Patients able to do self-administration at home of the MD, for 30 days, to 
treat symptoms of haemorrhoids and anal irritation. 
● Patient free from the following treatments for haemorrhoids for at least 4 
weeks: laser treatments for haemorrhoids, steroidal or non-steroidal anti-
inflammatory drugs, analgesics, any anti-haemorrhoidal treatment, 
anticoagulants, and antiplatelet agents. 

 
 
 
 
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● Patients able to communicate adequately with the Investigator and 
understand the trial questionnaire.  
● Patients able to understand and who can provide valid informed consent to 
the trial. 
Exclusion criteria 
● Inflammatory and infectious disease of the digestive tract (e.g., IBD – 
Inflammatory Bowel Disease). 
● Frequent hemorraidal bleeding 
● Severe, uncontrolled hypertension, renal failure, cirrhosis, colorectal cancer, 
anal fissure or fistula. 
● Patients with known sensitivity to the tested medical device or its 
components. 
● Patients with any other medical condition that, in the opinion of the 
Investigator, would compromise participation or be likely to lead to 
hospitalisation during the study. 
● Participation in an interventional clinical study or administration of any 
investigational agents in the previous 30 days. 
Countries  
Romania. 
Number of patients 
The number of evaluable patients will be 50.  
Sample size 
calculation 
The Short Health Scale for Haemorrhoidal Disease (SHSHD), the primary outcome 
of this clinical investigation, was used as the basis for the calculation of the 
required sample size. In a study published by Renato Pietroletti et al. (2022) (7), 
the researchers assessed the performance of a rectal ointment based on Zn-L-
carnosine in the treatment of haemorrhoidal disease by using the SHSHD 
following 4 weeks of treatment with the medical device.  
Their results showed an SHSHD mean ± SD score of 7.90 ± 4.17 before treatment 
and 4.05 ± 0.22 after 4 weeks of treatment with Proctilor® rectal ointment.  
Lacking the results of a similar emulsion (PROCTOeze® PLUS) we assumed a mean 
± SD SHSHD score of 6.20 ± 0.25 after 4 weeks of treatment for the haemorrhoidal 
disease, resulting in a moderate effect size of around 0.42. 
By employing a one-tailed Wilcoxon signed-rank test for matched pairs at a 
significant level of 2.5 % and a power of 80 % we derived a sample size of 50 
evaluable patients to prove PROCTOeze® PLUS performance.   
Considering a possible screen failure rate of 10% we require 55 enrollable 
patients. In addition, 5 patients should account for a possible 10% moderate 
drop-out rate, so 60 patients should be screened for enrolment in the clinical 
investigation. 
Medical device 
PROCTOeze® PLUS is a soft and light hydrophilic emulsion, adjuvant for the 
symptomatic relief of internal and external haemorrhoids and anal irritation. 
PROCTOeze® PLUS creates a physical barrier that protects the peri-anal tissue, 
minimizing the possibility of bacterial colonization and contact with local and 
environmental agents, which may exacerbate haemorrhoid condition. It has a 
protective, lubricating and refreshing action and emollient properties, which 
help to prevent irritation and discomfort of the perianal area, providing relief 

 
 
 
 
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from pain, burning, itching and other related complaints, contributing to the 
physiological restoration of the anal and perianal tissues. Its application leaves 
the treated area soft and moisturised, avoiding the onset of irritation and 
cracking of the skin. The lubricating action helps to facilitate bowel movement, 
thus minimising the trauma and pain sensation associated with defecation.  
PROCTOeze® PLUS key ingredients are mainly paraffinum liquidum, petrolatum, 
dimethicone, and hydroxyethylcellulose. 
All the patients will use the MD PROCTOeze® PLUS during the whole study 
according to Instruction for Use of the MD and to standard clinical practice. 
Chronogram of visits 
The study envisages the following visits and phone follow up per patient: 
● Visit 1, day 0: Screening / Baseline visit. 
● Visit 2, day 14 (± 2 days):  
● Phone follow up, day 30 (± 1 day).  
Study duration 
The study will last 30 days for each patient. 
Procedures 
Visit 1 Screening / Baseline visit (day 0)  
• 
Informed consent / Eligibility Criteria  
• 
Demographics / Medical History / Physical examination and vital signs 
(including haemorrhoids evaluation and confirmation of diagnosis) 
• 
Concomitant treatments and medications assessment 
• 
Quality of life assessment by means of the Short Health Scale for 
Haemorrhoidal Disease (SHSHD) by patient 
• 
Haemorrhoid Severity Score (HSS) by Investigator 
• 
Haemorrhoidal Disease Symptom Score (HDSS) by patient 
• 
Diary supply 
• 
MD supply 
Visit 2 End of Study visit (day 14 ± 2 days)  
• 
Treatment adherence  
• 
Diary's maintenance 
• 
Physical examination and vital signs (including haemorrhoids 
evaluation) 
• 
Concomitant treatments and medications assessment 
• 
Quality of life assessment by means of the Short Health Scale for 
Haemorrhoidal Disease (SHSHD) by patient 
• 
Haemorrhoid Severity Score (HSS) by Investigator 
• 
Haemorrhoidal Disease Symptom Score (HDSS) by patient 
• 
Diary collection 
• 
MD collection 
• 
Safety assessment by AE / ADE / DD collection 
Phone call (day 30 ± 1 day)  
• 
Treatment adherence  
• 
Diary's maintenance 
• 
Safety assessment by AE / ADE / DD collection 
Not allowed 
concomitant 
treatment or 
Any drug or treatment mentioned in the eligibility criteria as not allowed will be 
forbidden during the study and its use will have to be avoided by patients, 
otherwise they are excluded from the participation: use of laser treatment, 

 
 
 
 
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medications 
 
 
steroidal or non-steroidal anti-inflammatory drugs, analgesics, any anti-
haemorrhoidal treatment (both drugs and dietary supplements), anticoagulants, 
and antiplatelet agents will be not allowed during the whole study. 
No restriction on treatments taken previously by patients for medical conditions 
not related to this study protocol will be envisaged. 
Patients will be advised to note any concomitant treatment or medications or 
any major modification to their diet and / or lifestyle in the diary. 
Statistical analysis 
Statistical analyses will be conducted on all patients who have successfully 
completed the study without a protocol deviation that is regarded as impacting 
the assessment of the key variables (as per protocol). The quality and 
completeness of the collected data will be evaluated preliminarily compared to 
data analysis. If a patient is missing information for one or more variables, even 
after the resolution of its query, the missing data will not be replaced. If a patient 
has been involved in violation of inclusion/exclusion criteria, the respective data 
will be excluded from the analysis. Quantitative variables (i.e., demographic) if 
normally distributed will be described through media, and standard deviation 
(SD); non-normally distributed variables will be described using median and 
range of interquartile. The Student's t-test and the Mann-Whitney U will be 
employed to perform comparative analysis in accordance with the distribution 
of these variables. Factorial variance analysis can also be used to evaluate any 
interactions between quantitative variables and linear progression models to 
relate possible confounding bias with independent variables. Categorical 
variables will be finally described using frequencies and percentages and 
comparative analysis will use the χ2 test. 
The overall type I error rate will be preserved at 5%. All tests will be two-sided. 
Data from unscheduled visits will not be included in the analysis. 
GCP Statement, 
Guidelines and 
legislation 
The protocol is developed in accordance with the following: 
● International Standard ISO 14155:2020 (10). 
● Regulation (EU) 2017/745 of the European Parliament and of the Council of 
5 April 2017 on medical devices (11). 
● ICH 6 Harmonized Tripartite guidelines for Good Clinical Practice (ICH GCP) 
requirements (12). 
● Local legislation. 
 
 
 
Timing 
Submission to Competent Authority 
January, 2024 
Approval by Competent Authority/EC 
February, 2024 
Start of enrolment (FPI) 
February, 2024 
End of enrolment (LPI)  
September, 2024 
End of treatment (LPO) 
October, 2024 
Final Report of trial  
December, 2024 

 
 
 
 
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SCHEDULE OF ASSESSMENTS 
Procedures 
Visit 1 
Visit 2 
Follow up 
call 
Screening 
Baseline 
 visit 
Follow up 
Day 0 
Day 14 (± 2)  
Day 30 (± 1)  
Informed consent 
X 
 
 
Inclusion Criteria 
X 
 
 
Exclusion Criteria 
X 
 
 
Demographics and Medical History 
X 
 
 
Physical examination and Vital signs1 
X 
X 
 
Concomitant treatments and medications assessment 
X 
X 
X 
Short Health Scale for Haemorrhoidal Disease (SHSHD) 
(by patient) 
X 
X 
 
Haemorrhoid Severity Score (HSS) (by Investigator) 
X 
X 
 
Haemorrhoidal Disease Symptom Score (HDSS) (by 
patient) 
X 
X 
 
Compliance  
 
X 
X 
Patient Diary supply 
X 
 
 
Patient Diary collection 
 
X 
 
MD supply 
X 
 
 
MD collection 
 
X 
 
AE / ADE / DD assessment  
X 
X 
X 
1Patients diagnosed with Grade I – II symptomatic haemorrhoids (according to Goligher classification) confirmed by clinical and 
anoscopic or proctoscopic examination performed within 3 months before baseline will be enrolled. Haemorrhoids evaluation, 
pulse, blood pressure (diastolic and systolic), weight / height and BMI (kg/m2) will be collected. 
 
 

 
 
 
 
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1. 
GENERAL INFORMATION 
1.1. 
TITLE 
Post-Marketing Clinical Follow-Up trial to evaluate the performance and safety of the medical device 
PROCTOeze® PLUS in the relief from haemorrhoidal disease and anal irritation. 
1.2. 
STUDY REGISTRATION 
Following 
the 
WHO 
statement 
on 
public 
disclosure 
of 
clinical 
study 
results 
in 
https://www.who.int/ictrp/results/WHO_Statement_results_reporting_clinical_trials.pdf, before a clinical 
study is initiated, its details must be registered in a publicly available, free to access, searchable clinical study 
registry complying with WHO’s international agreed standards. The final version of this clinical study protocol 
will be registered on www.clinicaltrials.gov. 
1.3. 
PROTOCOL VERSION 
Issue Date: 1.0  – 20231201. 
1.5.2. Sponsor 
Sponsor 
BIOKOSMES S.r.l. 
Contact Name 
Andrea Turconi, QA 
Address 
Via Besana 10, 20122 Milano (Italy)  
Phone 
+39 0313581085 
e-mail 
andrea.turconi@biokosmes.it 
Contact Name 
Diana Koprivec, MD PhD 
Clinical and Safety Consultant for Biokosmes S.r.l. 
Address 
KB Company SAGL 
Via San Gottardo 80 
CH-6900 Massagno Lugano 
Phone 
+41 79 2201094 
e-mail 
diana.koprivec@kbcompany.ch 
 
1.5.3. Centres 
Sites located in Romania (i.e., the clinical centres), with all the necessary equipment required by the protocol, 
were selected for the trial. 
 
 
 

 
 
 
 
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1.5.5. Principal Investigator Roles 
● General coordination of the site. 
● Collection and reporting data with respect to International Standard ISO 14155:202, Romanian 
legislation and GDPR. 
1.5.6. CRO 
BIOKOSMES S.r.l., as Sponsor of the trial, has designated Contract Research Organization to perform the 
following activities:  
● Support to define the rationale and research hypothesis. 
● Protocol writing. 
● CRF and work instructions preparation. 
● ICF and other study documents preparation. 
● Elaboration of study documents in the Romanian language. 
● Preparation and updating of Trial Master File (TMF) and Investigator Study File (ISF). 
● Ethics Committees and Competent Authority issues and submissions in Romania. 
● Supporting the procedures for the financial agreement between the Sponsor and administrations of 
involved Centres in Romania. 
● Data Management. 
● Safety Management. 
● Statistical Analysis. 
● Preparation of the Final Report. 
The extent of the delegation has been specified in a contract between the involved parties. During the study 
period, the CRO should implement quality assurance and quality control procedures, but the Sponsor will have 
the right to supervise the implementation of the methods in order to ensure quality. 
1.6. 
CURRENT LEGISLATION AND GUIDELINES 
The protocol of the present trial is developed in accordance with the following: 
● International Standard ISO 14155:2020 (10). 
● Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical 
devices (11). 
● ICH Harmonized Tripartite guidelines for Good Clinical Practice (ICH GCP) requirements (12). 
● Local Romanian legislation. 
1.7. 
TIMING 
 
Timing 
Submission to Competent Authority 
January, 2024 
Approval by Competent Authority/EC 
February, 2024 
Start of enrolment (FPI) 
February, 2024 
End of enrolment (LPI)  
September, 2024 
End of treatment (LPO) 
October, 2024 
Final Report of trial  
December, 2024 

 
 
 
 
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2. 
INTRODUCTION 
2.1.  
BACKGROUND AND RATIONALE 
Haemorrhoids are present universally in healthy individuals as cushions surrounding the anastomoses between 
the superior rectal artery and the superior, middle, and inferior rectal veins. Nonetheless, the term 
“haemorrhoid” is commonly invoked to characterise the pathologic process of symptomatic haemorrhoid 
disease instead of the normal anatomic structure.  Haemorrhoids play a signiﬁcant physiologic role in 
protecting the anal sphincter muscles and augment closure of the anal canal during moments of increased 
abdominal pressure (e.g., coughing, sneezing) to prevent incontinence and contribute 15 to 20% of the resting 
anal canal pressure. Increases in abdominal pressure increase the pressure in the inferior vena cava that cause 
these vascular cushions to engorge and prevent leakage. 
Haemorrhoids are a very common anorectal condition defined as the symptomatic enlargement and distal 
displacement of the normal anal cushions. The abnormal dilatation and distortion of the vascular channel, 
together with destructive changes in the supporting connective tissue within the anal cushion, is a paramount 
finding of haemorrhoidal disease (13). 
 
External haemorrhoids are located below the dentate line, internal haemorrhoids lie above the dentate line. 
Vascular outﬂows of internal haemorrhoids include the middle and superior rectal veins, which subsequently 
drain into the internal iliac vessels. 
The most widely accepted classification for haemorrhoids was introduced by Goligher (3,4) (Annex 2). 
The exact pathophysiology of symptomatic haemorrhoid disease is poorly understood. Currently, the theory 
of sliding anal canal lining, which proposes that haemorrhoids occur when the supporting tissues of the anal 
cushions deteriorate, is more widely accepted. Advancing age and activities such as strenuous lifting, straining 
with defecation, and prolonged sitting are thought to contribute to this process. Haemorrhoids is therefore 
the pathological term to describe the abnormal downward displacement of the anal cushions causing venous 
dilatation. On histopathological examination, changes seen in the anal cushions include abnormal venous 
dilatation, vascular thrombosis, degenerative process in the collagen ﬁbres and ﬁbroelastic tissues, and 
distortion and rupture of the anal subepithelial muscle (1,2). 
The most common symptom is painless fresh rectal bleeding, but patients may also experience pruritus, 
swelling, prolapse, discharge, or soiling. For internal haemorrhoids, bleeding is the most commonly reported 

 
 
 
 
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symptom. The occurrence of bleeding is usually associated with defecation and is almost always painless (1,2).  
The blood is bright red and coats the stool at the end of the defecation. Prolapsed internal haemorrhoids may 
accompany mild faecal incontinence, mucus discharge, sensation of perianal fullness, and irritation and 
pruritus of perianal skin. Pain is signiﬁcantly less common with internal haemorrhoids than with external 
haemorrhoids, but can occur in the setting of prolapsed, strangulated internal haemorrhoids that develop 
gangrenous changes due to the associated ischemia. In contrast, external haemorrhoids are more likely to be 
associated with pain, due to activation of perianal innervations associated with thrombosis. Patients typically 
describe a painful perianal mass that is tender to palpation. This painful mass may be initially increasing in size 
and severity over time. Pruritis and “burning” can result from discharges or difficulty with hygiene (1,2). 
The natural history of most cases of haemorrhoidal disease is self-limited. For a symptomatic haemorrhoidal 
disease that presents to the clinic or emergency room, treatments range from nonoperative medical 
interventions and office-based procedures to surgery.  
One general guiding principle is that the least-invasive approaches should be considered first, except in cases 
of acute thrombosis. Specific choices of treatments depend on patients' age, severity of symptoms, and 
comorbidities (13). For symptomatic control, topical treatments containing various local anaesthetics, 
corticosteroids, or anti-inflammatory drugs are available. Notable topical drugs include 0.2% glyceryl trinitrate, 
which has been studied to relieve grade I or II haemorrhoids with high resting anal canal pressures but is 
associated with headaches in 43% of patients (14).  
Pharmaceutical topical preparations containing steroids, anaesthetics, astringents, and/or antiseptics are 
often recommended for all grades of haemorrhoidal disease. However, no randomised studies support their 
use. Steroid-containing creams should not be used for prolonged periods because of their atrophic effects on 
skin and their efficacy remains unproven. 
Except in the case of thrombosis, both internal and external haemorrhoids respond readily to conservative 
medical therapy.  
BIOKOSMES has developed the medical device PROCTOeze® PLUS, a soft and light hydrophilic emulsion able to 
provide symptomatic relief of haemorrhoids and anal irritation thanks to its formulation (see in Annex 1 
“Product composition” the composition of the product and the function of its components).  
The product creates a physical barrier that protects the peri-anal tissue, minimising the possibility of bacterial 
colonisation and contact with environmental agents, which may exacerbate haemorrhoid conditions. The key 
ingredients responsible for the barrier film are the film-forming agents paraffinum liquidum, petrolatum, 
dimethicone and hydroxyethylcellulose.  
The MD has a protective, lubricating and refreshing action; its emollient properties help to prevent irritation 
and discomfort of the perianal area, providing relief from pain, burning, itching and other haemorrhoidal-
related complaints. Its application leaves the treated area soft and moisturised, avoiding the onset of irritation 
and cracking of the skin. The emollient and lubricating action helps to facilitate the emptying of the rectal 
ampoule with a subsequent decrease of local discomfort, minimising the trauma and pain associated with 
defecation. Moreover, due to its formulation, the product contributes to the physiological restoration of anal 
and perianal tissues. 
 
PROCTOeze® PLUS is registered as a Medical Device of Class IIb, rule 21 according to the Regulation (EU) 
2017/745 and it is largely used in the clinical practice of thousands of medical doctors in Italy, Romania, Iceland, 
Bulgaria, Taiwan, and Israel. Following the actual medical device legislation, the manufacturer must routinely 
present to the Notified Body, for each CE-registered medical device, the results of clinical investigations 

 
 
 
 
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performed as post-marketing clinical follow-up (PMCF) activities. The present trial is planned to follow this 
requirement and it will be performed in Romania where the IMD PROCTOeze® PLUS is commercialised with the 
brand name PROCTINUM®. 
2.2. 
RESEARCH HYPOTHESIS 
The Research Question of the present trial is the following: in a population of adult patients, men and women, 
suffering from symptomatic haemorrhoids, will the administration for 4 weeks of the IMD PROCTOeze® PLUS 
improve the haemorrhoidal symptomatology, giving results assessed at the end of the treatment by means of 
validated questionnaires? 
2.3. 
STUDY OBJECTIVES 
This trial aims to evaluate the overall performance and safety of the MD PROCTOeze® PLUS in relieving 
symptomatology of haemorrhoidal disease and anal irritation in adult patients affected by Grade I-II (Goligher 
classification) haemorrhoids as assessed by the patient and the Investigator at the end of the treatment period.  
The primary objective is the assessment of performance by the improvement in the quality of life (QoL). 
Secondary objectives are the assessment of performance by validated scales completed by the Investigator 
and by the patient at the end of the treatment period. 
The safety of the MD will be evaluated through AE and ADE incidence assessed by Investigators and reported 
according to the current legislation. 
JUSTIFICATION FOR THE TRIAL 
The protocol is based on what is already known on both the topic object of the study, i.e., the symptomatic 
treatment of haemorrhoids, and the investigational medical device, according to which is shortly summarized 
in section 2.1. MD PROCTOeze® PLUS is a specific adjuvant for the symptomatic relief of internal and external 
haemorrhoids and anal irritation. Due to its formulation, it contributes to the physiological restoration of the 
anal and perianal tissues.   
The tool used in this research is a PMCF, a procedure which, through a scientific method of detection (one or 
more questionnaires to be submitted to a representative sample of patients related to the issue of the 
research), allows to collect, and subsequently analyse, the data needed to study the relationships between 
different variables.  
3. 
PROCEDURES 
3.1.     DESIGN 
Open, non-comparative, multicentre, prospective, interventional trial. 
3.2. 
STUDY SETTING 
Sites located in Romania (i.e., the clinical centres), will be involved 
3.3. 
SELECTION OF POPULATION 
The study population will include 50 evaluable patients, afferent at the study Centres. These patients will be 
asked for informed consent and verified for the inclusion and exclusion criteria. 
 

 
 
 
 
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3.3.1. Inclusion criteria 
Patients will be eligible for inclusion if ALL the following criteria are respected: 
● Men and women ≥ 18 years old. 
● Patients diagnosed with Grade I – II symptomatic haemorrhoids (according to Goligher classification) 
confirmed by clinical and anoscopic or proctoscopic examination performed within 3 months before 
baseline.  
● Patients able to do self-administration at home of the MD, for 30 days, to treat symptoms of haemorrhoids 
and anal irritation. 
● Patient free from the following treatments for haemorrhoids for at least 4 weeks: laser treatments for 
haemorrhoids, steroidal or non-steroidal anti-inflammatory drugs, analgesics, any anti-haemorrhoidal 
treatment, anticoagulants, and antiplatelet agents. 
● Patients able to communicate adequately with the Investigator and understand the questionnaire. 
● Patients able to understand and who can provide valid informed consent to the trial. 
 
3.3.2. Exclusion criteria 
Patients fulfilling one or more of the following exclusion criteria will NOT be included in the study:  
• 
Inflammatory and infectious disease of the digestive tract (e.g., IBD – Inflammatory Bowel Disease). 
• 
Frequent hemorraidal bleeding 
• 
Severe, uncontrolled hypertension, renal failure, cirrhosis, colorectal cancer, anal fissure or fistula. 
• 
Patients with known sensitivity to the tested medical device or its components. 
• 
Patients with any other medical condition that, in the opinion of the Investigator, would 
compromise participation or be likely to lead to hospitalisation during the study. 
• 
Participation in an interventional clinical study or administration of any investigational agents in 
the previous 30 days. Patients considered smokers (≥10 cigarettes/day). 
• 
Energy-restricted diet for weight loss. 
• 
Pregnant woman, lactating woman, and woman of childbearing potential who is planning a 
pregnancy or is unwilling to use appropriate methods of contraception* during the study.  
*Methods of contraception: hormonal contraceptive, intrauterine device or intrauterine system, 
double barrier method (condom with spermicide/diaphragm or cervical cap with spermicide), 
surgical sterilization (vasectomy, tubal ligation, etc.). 
• 
Patients unlikely to cooperate. 
• 
Patients with any other medical condition that, in the opinion of the Investigator, would 
compromise participation or be likely to lead to hospitalisation during the study. 
• 
Participation in an interventional clinical study or administration of any investigational agents in 
the previous 30 days. 
3.3.3. Patient identification 
Each patient enrolled will be identified by the patient number, a five digits code (e.g., 01.001), which will be 
the only identification element and will be used only for the purposes of this study. This code will consist of 
the Centre number (e.g., 01/02/etc. corresponding to each Centre) and of the sequence number of the patient 
(e.g., .001, which means the 1st patient enrolled). If the patient is declared a screening failure (one or more 
eligibility criteria is not fulfilled and the patient cannot participate in the study), the identification code will not 
be reassigned to another patient. 
 
 

 
 
 
 
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3.3.4. Patient Enrolment and allocation 
Once the eligibility is established according to inclusion/exclusion criteria, ICF signed, patients will be enrolled 
3.3.5. Number of patients 
Fifty fully evaluable patients will be included in the study. 
3.3.6. Withdrawal or discontinuation criteria and procedures; patient lost to follow up 
Patients may withdraw at any time at their own request. The centre must inform the CRO personnel when a 
patient withdraws from the study.  
The Investigator will complete and sign the appropriate CRF when a patient is lost to follow-up. The date and 
type of attempted communication with the patient will also be documented. 
3.4. 
MEDICAL DEVICE DESCRIPTION 
PROCTOeze® PLUS is a soft and light hydrophilic emulsion that provides protection to irritated areas. It is a 
specific adjuvant for the symptomatic relief of internal and external haemorrhoids and anal irritation. The 
product creates a physical barrier that protects the peri-anal tissue, minimizing the possibility of bacterial 
colonization and contact with local and environmental agents, which may exacerbate haemorrhoid conditions. 
Due to its formulation, it contributes to the physiological restoration of the anal and perianal tissues. 
PROCTOeze® PLUS has a protective, lubricating and refreshing action. PROCTOeze® PLUS has emollient 
properties, which help to prevent irritation and discomfort of the perianal area, providing relief from pain, 
burning, itching and other related complaints. Its application leaves the treated area soft and moisturised, 
avoiding the onset of irritation and cracking of the skin. The lubricating action helps to facilitate bowel 
movement, thus minimising the trauma and pain sensation associated with defecation. It also supports the 
physiological repairing process. 
Key ingredients of IMD paraffinum liquidum, petrolatum, dimethicone and hydroxyethylcellulose (Annex 1 
“Product composition”), appropriately provided with study-specific labels. 
 The MD will be supplied in the same package available on the market, and with the same leaflet / IFU – 
Instructions for Use. 
3.4.1. Patient compliance monitoring 
The investigator will assess patients’ compliance (adherence to the treatment) at the end of the study; the 
compliance will be assessed by means of the information about administration contained in the diary, 
completed by the patients for the whole study.  
A patient will be declared as compliant with the treatment if he /she has used at least 75 % of the MD, 
according to Instruction for Use and to standard clinical practice. 
3.4.2. Concomitant care and interventions that are permitted or prohibited during the study 
Any drug or treatment mentioned in the eligibility criteria as not allowed will be forbidden during the study 
and its use will have to be avoided by patients, otherwise they are excluded from the participation: use of laser 
treatment, steroidal or non-steroidal anti-inflammatory drugs, analgesics, any anti-hemorrhoidal treatment 
(both drugs and dietary supplements), anticoagulants, and antiplatelet agents will be not allowed during the 
whole study. 
No restriction on treatments taken previously by patients for medical conditions not related to this study 
protocol will be envisaged. 

 
 
 
 
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Patients will be advised to note any concomitant treatment or medications or any major modification to their 
diet and / or lifestyle in the diary. 
3.5. 
STUDY PROCEDURES AND COLLECTED VARIABLES 
3.5.1. Outcomes  
The following outcomes will be evaluated: 
Primary outcome 
• 
The Short Health Scale for Haemorrhoidal Disease (SHSHD) (Annex 3 “Collected variables”) (5,16,17) will 
be used to evaluate the QoL. The questionnaire will be administered by the Investigator to each patient 
during the study visit, at baseline and on day 30, in PAPI mode (Paper and Pen Interview) (15). 
The Short Health Scale (SHS) is a patient-reported measurement instrument of subjective health originally 
developed for patients with inflammatory bowel disease (IBD) (16–18). SHS was proposed as a simplified 
HRQoL (Health-Related Quality of life) instrument with just 1 question in each of its 4 dimensions, including 
symptom burden, functional status, disease-specific worries, and general well-being. SHS was adapted for HD 
(Short Health Scale for Haemorrhoidal Disease - SHSHD) in accordance with the Consensus-Based Standards for 
the Selection of Health Measurement Instruments (COSMIN) guidelines; SHSHD has shown to be a reliable and 
responsive measure for HRQoL. Patients are asked to report overall symptom load, interference with daily 
activities, and worries caused by HD. The fourth question regarded general well-being. A 7-point Likert scale, 
giving a total score ranging from 4 to 28 is used. 
Secondary outcomes 
• 
The Haemorrhoid Severity Score (HSS) (Annex 3 “Collected variables”) (6), a physician-reported 
outcome, will be completed by Investigator at baseline and day 30, at the end of the treatment 
with the MD. 
safety outcome 
• 
Evaluation of AE, SAE, ADE, SADE, ASADE, USADE incidence assessed by Investigator and reported 
according to the current legislation for the whole study period. Device Deficiencies (DD) will be also 
evaluated. 
The HS is a physician-reported measurement instrument based on PNR-Bleed classification, that classifies and 
describes the haemorrhoids based on the four main characteristics of the hemorrhoidal disease i.e., the degree 
of hemorrhoidal Prolapse (P), Number (N) of the primary hemorrhoidal columns involved, Relation (R) of the 
haemorrhoidal tissue to the dentate line and the amount of Bleeding (B) from it. All four components in this 
classification system are graded into five grades ranging from 1 to 5. Grade 1 is the normal anal cushions and 
Grade 5 is the worst grade in a specific characteristic. HSS is the total score obtained by the sum of the 
numerical grades of all four characteristics of haemorrhoids in the PNR-Bleed classification. The minimum HSS 
score is 4 and the maximum score can be 20. The HSS score of a normal person without any signs and symptoms 
of haemorrhoids is 4. Calculation of the HSS help in the quantification of the haemorrhoidal disease for further 
reference and is helpful in post-treatment patient follow-up to grade the response to treatment and to assess 
the effectiveness or failure of any particular treatment regimen for haemorrhoids. It may also be used in 
predicting and diagnosing the recurrence after any form of treatment for the haemorrhoids. 
• 
The Haemorrhoidal Disease Symptom Score (HDSS) (Annex 3 “Collected variables”) (5,19) is a 
patient-reported outcome. The questionnaire will be administered by Investigator to each patient 
at baseline and on day 30, at the end of the treatment with the MD. 

 
 
 
 
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The HDSS is a patient-reported measurement instrument. It comprises five items. Symptoms are assessed 
using the patient-reported frequency of the 5 symptoms, including pain, itching, bleeding, soiling, and 
prolapse. Patients are instructed to answer based on their experience during the previous period. Each 
symptom is graded on a 5-point scale (0 = never, 1 = less than once a month, 2 = less than once a week, 3 = 1–
6 days per week, 4 = every day or always), giving a total score ranging from 0 to 20. 
3.6. 
DEFINITIONS AND PROCEDURE FOR REPORTING OF ADVERSE EVENTS 
3.6.1. DEFINITIONS  
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs, including an 
abnormal laboratory finding, in subjects, users or other persons, in the context of a clinical investigation, 
whether or not related to the Investigational Medical Device (IMD).  
a. This definition includes events that are anticipated as well as unanticipated events.  
b. This definition includes events occurring in the context of a clinical investigation related to the investigational 
device, the comparator or the procedures involved (for the purpose of safety reporting all activities related to 
the use of a medical device may be considered procedures). 
Serious Adverse Event (SAE) 
Any adverse event that led to any of the following:  
a) death,  
b) serious deterioration in the health of the subject, that resulted in any of the following:  
i. life-threatening illness or injury,  
ii. permanent impairment of a body structure or a body function,  
iii. hospitalization or prolongation of patient hospitalization,  
iv. medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function,  
v. chronic disease,  
c) foetal distress, foetal death or a congenital physical or mental impairment or birth defect 
Device Deficiency (DD) 
Device deficiency is any inadequacy in the identity, quality, durability, reliability, safety or performance of an 
investigational device, including malfunction, use errors or inadequacy in the information supplied by the 
manufacturer. 
Incident  

 
 
 
 
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Incident means any malfunction or deterioration in the characteristics or performance of a device made 
available on the market, including use-error due to ergonomic features, as well as any inadequacy in the 
information supplied by the manufacturer and any undesirable side-effect.  
Serious Incident 
Serious Incident means any incident that directly or indirectly led, might have led or might lead to any of the 
following: (a) the death of a patient, user or other person, (b) the temporary or permanent serious 
deterioration of a patient's, user's or other person's state of health, (c) a serious public health threat.  
Serious Public Health Threat 
Serious Public Health Threat means an event which could result in imminent risk of death, serious deterioration 
in a person's state of health, or serious illness, that may require prompt remedial action, and that may cause 
significant morbidity or mortality in humans, or that is unusual or unexpected for the given place and time.  
Corrective Action 
Corrective Action means action taken to eliminate the cause of a potential or actual non-conformity or other 
undesirable situation. 
Field Safety Corrective Action 
Field Safety Corrective Action means corrective action taken by a manufacturer for technical or medical 
reasons to prevent or reduce the risk of a serious incident in relation to a device made available on the market.  
Field Safety Notice 
Field Safety Notice means a communication sent by a manufacturer to users or customers in relation to a field 
safety corrective action. 
User 
User means any healthcare professional or layperson who uses a device. 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
This includes any adverse event resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any malfunction of the investigational 
medical device. 
This includes also any event that is a result of a use error or intentional abnormal use of the investigational 
medical device. 
Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristics of a serious adverse event. 
Unanticipated Serious Adverse Device Effect (USADE) 

 
 
 
 
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Serious adverse device effect which by its nature, incidence, severity or outcome has not been identified in the 
current version of the risk analysis report. 
Anticipated Serious Adverse Device Effect (ASADE)  
Anticipated SADE is an effect that by its nature, incidence, severity or outcome has been previously identified 
in the risk analysis report. 
3.6.2. CLASSIFICATION OF AN ADVERSE EVENT  
The Investigator is responsible for the AE classification, following Annex F of ISO 14155 (reported in Annex 4). 
The Investigator is responsible for the following assessment. 
1. SEVERITY OF ADVERSE EVENT (AE) ASSESSMENT 
The severity (Intensity) of each AE will be evaluated according to the following 3/point scale: Grade 1, 
Mild (Events require minimal or no treatment and do not interfere with the participant’s daily activities); 
Grade 2, Moderate (Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning); Grade 3, Severe (Events 
interrupt a participant’s usual daily activity and may require systemic drug therapy or other treatment. 
Severe events are usually incapacitating). 
2. CAUSALITY ASSESSMENT 
The Investigator will be responsible for assessing the causal relationship of the AE.  
The relationship between the use of the medical device (including the medical-surgical procedure) and 
the occurrence of each adverse event shall be assessed and categorized.  
The investigators (and the Sponsor) will use the following definitions to assess the relationship of the 
serious adverse event to the investigational device, the comparator or the investigation procedure.  
Each SAE will be classified according to four different levels of causality:  
1. Not related  
2. Possible  
3. Probable  
4. Causal relationship 
The sponsor and the investigators will use the following definitions to assess the relationship of the serious 
adverse event to the investigational device, the comparator or the investigation procedure: 
1. Not related: Relationship to the device, comparator or procedures can be excluded when:  
- the event has no temporal relationship with the use of the investigational device, or the procedures 
related to the application of the investigational device; 
- the serious adverse event does not follow a known response pattern to the medical device (if the 
response pattern is previously known) and is biologically implausible;  

 
 
 
 
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- the discontinuation of medical device application or the reduction of the level of activation/exposure - 
when clinically feasible - and reintroduction of its use (or increase of the level of activation/exposure), do 
not impact on the serious adverse event;  
- the event involves a body-site or an organ that cannot be affected by the device or procedure;  
- the serious adverse event can be attributed to another cause (e.g., an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors);  
- the event does not depend on a false result given by the investigational device used for diagnosis, when 
applicable;  
In order to establish the non-relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious adverse event.  
2. Possible: The relationship with the use of the investigational device or comparator, or the relationship 
with procedures, is weak but cannot be ruled out completely. Alternative causes are also possible (e.g., 
an underlying or concurrent illness/ clinical condition or/and an effect of another device, drug or 
treatment). Cases where relatedness cannot be assessed, or no information has been obtained should 
also be classified as possible.  
3. Probable: The relationship with the use of the investigational device or comparator, or the relationship 
with procedures, seems relevant and/or the event cannot be reasonably explained by another cause.  
4. Causal relationship: the serious adverse event is associated with the investigational device, comparator 
or with procedures beyond reasonable doubt when:  
- the event is a known side effect of the product category the device belongs to or of similar devices and 
procedures;  
- the event has a temporal relationship with investigational device use/application or procedures;  
- the event involves a body-site or organ that  
• 
the investigational device or procedures are applied to;  
• 
the investigational device or procedures have an effect on;  
- the serious adverse event follows a known response pattern to the medical device (if the response 
pattern is previously known);  
- the discontinuation of medical device application (or reduction of the level of activation/exposure) and 
reintroduction of its use (or increase of the level of activation/exposure), impact on the serious adverse 
event (when clinically feasible);  
- other possible causes (e.g., an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment) have been adequately ruled out;  
- harm to the subject is due to error in use;  
- the event depends on a false result given by the investigational device used for diagnosis, when 
applicable;  

 
 
 
 
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In order to establish the relatedness, not all the criteria listed above might be met at the same time, 
depending on the type of device/procedures and the serious adverse event. 
Only causality level 1 (i.e., “not related”) is excluded from reporting. If either the sponsor or the 
investigator has assigned a higher causality level than "not related", the event should be reported. 
During causality assessment activity, clinical judgement shall be used and the relevant documents, such 
as the Investigator’s Brochure, the Clinical Investigation Plan or the Risk Analysis Report shall be consulted, 
as all the foreseeable serious adverse events and the potential risks are listed and assessed there. The 
presence of confounding factors, such as concomitant medication/treatment, the natural history of the 
underlying disease, other concurrent illnesses or risk factors shall also be considered.  
The above considerations apply also to the serious adverse events occurring in the comparison group.  
3. TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care. At 
each visit/assessment, the participant should be assessed for the possible occurrence of an AE/SAE. Care 
will be taken not to introduce bias when detecting adverse events and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about adverse event 
occurrences. 
Any medical condition that is present at the time that the participant is screened will be considered a 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE. Changes in the severity of an AE will be documented to 
allow an assessment of the duration of the event at each level of severity to be performed. AEs 
characterized as intermittent require documentation of the onset and duration of each episode. 
AE/SAE can occur during any period of the study. The Investigator will record all reportable events with 
start dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days 
(for SAEs) after the last day of study participation. At each study visit, the investigator will inquire about 
the occurrence of AE/SAEs since the last visit. Each patient will receive a phone call from the investigator 
30 days after the end of the study to check if there have been AEs. Events will be followed for outcome 
information until resolution or stabilization. 
AE/SAE, as all medical occurrences, should be recorded by the Investigator in the subject’s medical records 
as source data.  
Each identified AE is assessed by the Investigator for Seriousness and Causality relationships to the 
Investigational Medical device or procedure. 
All AE/SAE will be recorded on the appropriate case report form (CRF) by the Investigator. 
4. SAE REPORTING  
The Investigator has the responsibility of reporting SAE/SADE to the Sponsor/CRO immediately and in any 
case no later than 24 hours of becoming aware by using the SAE/SADE Reporting Form, accompanied by 
the SAE/SADE Reporting Form Instructions.  

 
 
 
 
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The sponsor shall implement and maintain a system to ensure that the reporting of the reportable events, 
as above defined, is provided by the investigator to the sponsor immediately, but not later than 3 calendar 
days after the investigation site study personnel’s awareness of the event. 
The Sponsor must perform the evaluation of each SAE in order to assess of Seriousness, Expectedness and 
causality relationship to the Investigational Medical device (IMD) and/or the procedure. 
The Sponsor must report to all NCAs where the clinical investigation is authorized to start:  
a) any serious adverse event that has a causal relationship with the investigational device, the comparator 
or the investigation procedure or where a such causal relationship is reasonably possible; 
b) any device deficiency that might have led to a serious adverse event if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate;  
c) any new findings in relation to any event referred to in points a) and b).  
For all reportable events as described above which indicate an imminent risk of death, serious injury, or 
serious illness and that requires prompt remedial action for other patients/subjects, users or other 
persons or a new finding to it: Immediately, but not later than 2 calendar days after awareness by the 
sponsor of a new reportable event or new information in relation with an already reported event. This 
includes events that are of significant and unexpected nature such that they become alarming as a 
potential public health hazard. It also includes the possibility of multiple deaths occurring at short 
intervals. These concerns may be identified by either the NCA or the manufacturer.  
Any other reportable events or a new finding/update to it: Immediately, but not later than 7 calendar 
days following the date of awareness by the Sponsor of the new reportable event or new information in 
relation to the already reported event. 
According to article 80 of Regulation 745/2017/EU, the sponsor shall fully record all of the following:  
(a) any adverse event of a type identified in the clinical investigation plan as being critical to the evaluation 
of the results of that clinical investigation;  
(b) any serious adverse event;  
(c) any device deficiency that might have led to a serious adverse event if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate;  
(d) any new findings in relation to any event referred to in points (a) to (c) furthermore. 
Reporting form 
The reporting form is study specific and covers only a given clinical investigation, defined by a distinct clinical 
investigation plan. The table gives a cumulative overview of the reportable events per clinical investigation and 
will be updated and transmitted to participating NCAs each time a new reportable event or a new finding to 
an already reported event is to be reported.  
The sponsor shall report, without delay to all Member States in which the clinical investigation is being 
conducted, all of the following by means of the electronic system, if any:  

 
 
 
 
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(a)any serious adverse event that has a causal relationship with the investigational device, the comparator or 
the investigation procedure or where a such causal relationship is reasonably possible;  
(b) any device deficiency that might have led to a serious adverse event if appropriate action had not been 
taken, intervention had not occurred, or circumstances had been less fortunate;  
(c) any new findings in relation to any event referred to in points (a) and (b). 
Copies of any reports to regulatory bodies regarding serious and unexpected AEs will be provided to the 
investigators for review and submission to the EC. The communication of any SAEs to the EC and Competent 
Authority, will be done according to national requirements in Romania by the Investigator). Copies of SAEs 
correspondence with the investigators, regulatory bodies, and Sponsor must be retained with study records. 
3.7. 
DATA COLLECTION  
3.7.1. Collected variables  
The details and template of the questionnaires are reported in Annex 3 with the corresponding references. 
Moreover, the questionnaires are contained in the CRF section of the ISF/TMF, as a separate document. The 
data collected will be saved on databases corresponding to the sites. Each database will be uniquely identified 
with the name of the location; each investigator will input data only in the database allocated to his location.  
3.7.2. Schedule of assessments by visit 
SCHEDULE OF ASSESSMENTS 
Procedures 
Visit 1 
Visit 2 
Follow up 
call 
Screening 
Baseline 
 
Follow up 
visit 
Day 0 
Day 14 (± 2)  
Day 30 (± 1)  
Informed consent 
X 
 
 
Inclusion Criteria 
X 
 
 
Exclusion Criteria 
X 
 
 
Demographics and Medical History 
X 
 
 
Physical examination and Vital signs1 
X 
X 
 
Concomitant treatments and medications assessment 
X 
X 
X 
Short Health Scale for Haemorrhoidal Disease (SHSHD) 
(by patient) 
X 
X 
 
Haemorrhoid Severity Score (HSS) (by Investigator) 
X 
X 
 
Haemorrhoidal Disease Symptom Score (HDSS) (by 
patient) 
X 
X 
 
Compliance  
 
X 
X 

 
 
 
 
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Patient Diary supply 
X 
 
 
Patient Diary collection 
 
X 
 
MD supply 
X 
 
 
MD collection 
 
X 
 
AE / ADE / DD assessment  
X 
X 
X 
 
1Patients diagnosed with Grade I – II symptomatic haemorrhoids (according to Goligher classification) confirmed by clinical and 
anoscopic or proctoscopic examination performed within 3 months before baseline will be enrolled. Haemorrhoids evaluation, 
pulse, blood pressure (diastolic and systolic), weight / height and BMI (kg/m2) will be collected. 
3.7.2.1. Study visits 
Visit 1 Screening / Baseline Visit (day 0)  
At each Centre, patients will be enrolled consecutively. During this visit, patients who will meet the eligibility 
criteria (inclusion and exclusion criteria) will be enrolled after the signature of the informed consent form and 
will be informed verbally and in writing about the nature and requirements of the trial. Patients agreeing with 
the participation in the study will have to date and sign the informed consent form prior to any study-related 
procedure. All the screening procedures must be completed during this visit.  
During this visit, the Investigator will collect information regarding medical history, demography, concomitant 
treatments and medications, AE/SAE if applicable. The Investigator will report data on the appropriate eCRF 
pages. 
A physical examination will be performed, including evaluations of vital signs; pulse, blood pressure (diastolic 
and systolic), weight / height and BMI (kg/m2) data will be collected. An evaluation of the haemorrhoidal 
disease will be performed, and a confirmation of the diagnosis and of the stage of haemorrhoids will take 
place, according to inclusion criteria (patients diagnosed with Grade I – II symptomatic haemorrhoids 
(according to Goligher classification, confirmed by clinical and anoscopic or proctoscopic examination 
performed within 3 months before baseline)  
During this visit the following questionnaires will have to be completed: 
• 
HR-QoL questionnaire: SHSHD (by patient) 
• 
HSS (by Investigator) 
• 
HDSS (by patient) 
During this visit, the MD will be provided to each patient. The used, partially used and unused containers of 
the MD will have to be brought back to the centre on the last study visit. The MD will be supplied in the same 
package available on the market, and with the same leaflet / IFU – Instructions for Use. 
A patient diary will be supplied; it will have to be completed at home by patients for the whole duration of the 
study. A series of information will have to be collected related to the health status of the patient (not an 
exhaustive list): use of any treatment or OTC or prescribed medications (concomitant treatments and 
medications), start and stop dates and name/dosage of the product will be collected; AE/ADE/DD occurrence; 
self-administration of the MD (according to IFU and standard clinical practice). 
The importance of duly completing the diary will be stressed by the Investigator. The completed diary will be 
collected at the end of the study (at V2). Patients will be advised to note any major modification to their diet 

 
 
 
 
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and / or lifestyle in the diary. Moreover, patients will be informed (it will be written in the diary) that they will 
receive a phone call from the investigator 30 days after the end of the study to check if there have been AEs. 
The following visit (V2) will be scheduled 14 (± 2) days after V1; a phone call will be scheduled 30(± 1) days 
after V1. 
Visit 2 (day 14 ± 2 days)  
During this visit, the Investigator will perform the following examinations and the e-CRF will be completed 
accordingly: 
• 
Physical examination (according to what was already performed at visit 1: pulse, blood pressure, 
weight / height and BMI will be evaluated), including haemorrhoidal disease evaluation. 
• 
Concomitant treatments and medications assessment. 
• 
Evaluation of compliance (MD administration assessment by means of the patient’s diary carried out 
by Investigator).  
• 
Diary and MD (used, partially used, or unused containers) collection.  
• 
Safety assessment by AE/ADE/DD collection. 
During this visit the following questionnaires will have to be completed: 
• 
HR-QoL questionnaire: SHSHD (by patient) 
• 
HSS (by Investigator) 
• 
HDSS (by patient) 
Patients who discontinued the protocol, will be visited reporting on the last visit page all the safety 
assessments and (if possible) the examinations and questionnaires requested for the last visit. 
Patients who discontinued the protocol, will be visited reporting on the last visit page all the safety 
assessments and (if possible) the questionnaires requested for the last visit. 
Phone call (day 30 ± 1 day) 
During this phone call the following evaluations will take place: 
• 
Safety assessment by AE / ADE / DD collection 
3.7.3 
 Case Report Form  
The Case Report Form (CRF) of the study will be filled by investigator. The CRO will insert the data in the EDC 
All data collected through CRO’s EDC system will be checked for completeness and extreme values (outliers) 
presence. Any anomaly will be forwarded by the statistician/data manager to the Investigator and/or Clinical 
Research Associates. Such data queries will be solved with priority, in no more than 3 days from the query’s 
opening. The statistician decides to use/accept the revised data for the subsequent statistical analyses. 
Because of legal considerations (GDPR directive effective from 21.05.2018 in all European Union countries), 
patients or their legal surrogates may have an absolute right to request that their data are removed from the 
study database. As a result, there are potentially two datasets: the full list of enrolled patients, and the list 
containing the patients who have kept their data available. The latter is obtained after deleting the data for 
patients who withheld or withdrew their consent and did not allow their data to be submitted or maintained 
in the database. Only the latter dataset can be used in the analysis. 
It is the CROs responsibility to keep all the above-mentioned software tools to their latest and most secure 
versions. 

 
 
 
 
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Data is stored according to existing legislation and current regulation (Directive 2001/20/EC and EU Regulation 
1924/2006), and with the rules of Good Clinical Practice ICH E6 (R2). Succinctly, the Investigator Study File 
contains, among other study documents, the eCRFs printouts. The Sponsor will archive all the electronically 
collected data on DVDs. A copy of the eCRF printouts will be provided to the participating centres. 
The collected data will be subjected to multiple checks for correctness (entry errors). Every information will be 
verified by an SDV (Source Data Verification) process, performed by the study monitors. Data Clarification 
Forms will be implemented to obtain clean data. 
4. 
DATA MANAGEMENT AND ANALYSIS 
4.1. 
Record keeping and archiving 
At the end of the trial, all copies of all essential documentation will be archived securely by the Investigator for 
a minimum of 10 years starting when the last device has been put on the market. Essential documents are 
those which enable both the conduct of the trial and the quality of the data produced to be evaluated and 
show whether the site complied with all applicable regulatory requirements. Included in the records to be 
maintained are the signed protocol Trial, signed consent forms, ethics committee approval letters, 
correspondence with Sponsor/CRO and any other documents to identify the patients. 
The CRO will notify the sites when the trial documentation can be archived. All archived documents must 
continue to be available for inspection by competent authorities or Sponsor audit upon request. In addition, if 
the Investigator moves/retires, etc., he/she should provide the Sponsor with the name and address of the 
person who will look after and be responsible for the trial-related records. 
4.2. 
DATA MANAGEMENT 
4.2.1. Data review, DB cleaning, issuing, and resolving queries 
The Data Management process includes all activities related to data handling regarding:  
• 
Set-up of study-specific DB for data processing and analysis. 
• 
Supporting the Data entry / Data editing. 
• 
Export of data to R statistical software. 
• 
Creation of post-entry checks and listings. 
• 
Clean-file process. 
CRO will be responsible for all these activities. The confidentiality of records that could identify patients will 
be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory 
requirement(s). 
 
4.2.2. Procedures for data retention and retention period definition 
Electronic/physical data (study documents) will be retained by the Sponsor or other contracted third party for 
a minimum of 10 years starting when the last device has been put on the market, as required by clinical trial 
legislation. 
4.3. 
STATISTICAL ANALYSIS 
4.3.1. Sample size calculation 
The Short Health Scale for Haemorrhoidal Disease (SHSHD), the primary outcome of this clinical investigation, 
was used as the basis for the calculation of the required sample size. In a study published by Renato Pietroletti 
et al. (2022) (7), the researchers assessed the performance of a rectal ointment based on Zn-L-carnosine in the 

 
 
 
 
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treatment of haemorrhoidal disease by using the SHSHD following 4 weeks of treatment with the medical 
device.  
Their results showed an SHSHD mean ± SD score of 7.90 ± 4.17 before treatment and 4.05 ± 0.22 after 4 weeks 
of treatment with Proctilor® rectal ointment.  
Lacking the results of a similar emulsion (PROCTOeze® PLUS) we assumed a mean ± SD SHSHD score of 6.20 ± 
0.25 after 4 weeks of treatment for the haemorrhoidal disease, resulting in a moderate effect size of around 
0.42. 
By employing a one-tailed Wilcoxon signed-rank test for matched pairs at a significant level of 2.5 % and a 
power of 80 % we derived a sample size of 50 evaluable patients to prove PROCTOeze® PLUS performance.   
Considering a possible screen failure rate of 10% we require 55 enrollable patients. 
In addition, 5 patients should account for a possible 10% moderate drop-out rate, so 60 patients should be 
screened for enrolment in the clinical investigation.   
The software used in the calculation was G*Power v3.1.9.7 (8). 
4.3.2. Statistical design, method, and analytical procedures 
Design: Open, non-comparative, multicentre, prospective, interventional trial. 
The principle of intention-to-treat (ITT), as far as practically possible, will be the main strategy of the analysis 
adopted for the primary endpoint and all the secondary endpoints. These analyses will be conducted on all 
participants. 
No imputations will be made on missing data. 
The statistical plan details the following 3 analysis sets which will be evaluated in this study: 
• 
The ITT population, which includes each patient enrolled in the study that used at least one dose 
of the investigational product and had at least one efficacy assessment. 
• 
The Per-Protocol population, which excludes patients with major protocol deviations or violations 
(e.g., did not use the investigational product, did not attend all the visits, or had missing data 
regarding the primary endpoint) and includes those with valid observations on the primary 
endpoint. 
• 
Safety population, which includes each patient enrolled in the study that used at least one dose of 
the investigational product. 
The protocol outlines that a two-sided p-value of 0.05 or less will be used to declare statistical significance for 
all analyses. Similarly, all confidence intervals will be calculated at the 95% level. 
No adjustment for multiplicity will be made to adjust the type 1 error rate for secondary endpoints. If 
necessary, relevant results from other studies already reported in the literature will be considered in the 
interpretation of results. 
If a patient is missing information for one or more variables, the missing data will not be replaced. 

 
 
 
 
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All statistical analyses will be performed using the R statistical software v 4.2.2 (9), or the latest stable version 
at the time of statistical analysis. 
The final analysis will be completed after all patients have been exited from the study, all queries have been 
resolved, and the database has been locked. 
The overall type I error rate will be preserved at 5%. All tests will be two-sided. Data from unscheduled visits 
will not be included in the analysis. 
Statistical analyses will be conducted on all patients who have successfully completed the study without a 
protocol deviation that is regarded as impacting the assessment of the key variables (as per protocol). The 
quality and completeness of the collected data will be evaluated preliminarily compared to data analysis. If a 
patient is missing information for one or more variables, even after the resolution of its query, the missing 
data will not be replaced. If a patient has been involved in violation of inclusion/exclusion criteria, the 
respective data will be excluded from the analysis. Quantitative variables (i.e., demographic) if normally 
distributed will be described through media, and standard deviation (SD); non-normally distributed variables 
will be described using median and range of interquartile. The Student's t-test and the Mann-Whitney U will 
be employed to perform comparative analysis in accordance with the distribution of these variables. Factorial 
variance analysis can also be used to evaluate any interactions between quantitative variables and linear 
progression models to relate possible confounding bias with independent variables. 
Categorical variables will be finally described using frequencies and percentages and comparative analysis will 
use the χ2 test. 
The safety analysis will be done on the safety population. 
Minor deviations from the original statistical plan (SAP) will be considered acceptable (e.g., due to the non-
parametrical form of the data, statistical tests will be adjusted accordingly). Major deviations from the SAP will 
be reported by the statistician to the Clinical Project Manager and will result in clinical trial protocol 
amendments. 
Tables will include baseline characteristics of the participants, medical history and concomitant medications, 
and safety outcomes. A CONSORT diagram illustrating the flow of patients through the study is also planned. 
Additional details about statistical analysis will be documented in the Statistical Analysis Plan (SAP), enclosed 
in the Trial Master File.  
5. 
DEVIATIONS FROM THE PROTOCOL  
The investigator is not allowed to deviate from the Protocol, except if the deviation affects the patient's rights, 
safety and well-being, or the scientific integrity of the trial. 
Generally, any deviation from the protocol must be verified, reported and analysed by the Investigator and the 
Sponsor and, immediately after, communicated to the EC. The Investigator will not apply this statement under 
emergency circumstances (20,21). 
All spontaneous protocol deviations shall be recorded and reported to the Sponsor. Deviations shall be also 
reported to the regulatory authorities if required by national regulations. All deviations will be included, as 
required, in the study report (SR). 

 
 
 
 
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6 
TERMINATION OF THE STUDY 
6.1. 
END OF THE TRIAL AND ITS DURATION  
The end of trial will be estimated in 8 months from the site activation. 
6.2. 
PREMATURE TERMINATION/SUSPENSION OF THE TRIAL 
The Sponsor may stop this trial in a Centre for any of the following reasons: 
• 
the Centre cannot include an adequate number of patients. 
• 
Serious and/or persistent non-compliance with the protocol. 
• 
Careless or premeditated false documentation in the trial documentation. 
• 
Inadequate cooperation with the CRO and/or Centre. 
• 
Non-compliance with GCP or Competent Authority (CA) or EC requirements. 
• 
The Investigator asks to discontinue the trial. 
• 
Lack of confidentiality. 
If the trial is prematurely terminated or suspended for any reason: 
• 
the patients will be informed promptly by the Investigator, and the EC and Regulatory Authorities 
will be notified. 
• 
The Sponsor shall remain responsible for providing resources to fulfil the obligations from the 
protocol and existing agreements for following up with the patients enrolled in the clinical 
investigation. 
7. 
COMPLIANCE TO ETHICS AND REGULATORY 
7.1. 
GUIDELINE AND LEGISLATION 
The protocol of the present trial is developed in accordance with ICH Harmonized Tripartite guidelines for 
GCP requirements and Local Romanian legislation. 
 
7.2. 
ETHICS COMMITTEE APPROVAL 
Prior to the initiation of the trial, the Investigator must submit all the documents requested by each centre EC 
for review and approval. The Investigator, and any other member of the team, if also a member of the EC, 
must not participate in the decision-making. A signed and dated letter identifying the members of the EC 
reviewing this protocol will be requested. 
7.3. 
INFORMED CONSENT AND PATIENT INFORMATION 
The Investigator is responsible for and will obtain the signed consent form from each patient in the trial. As 
this is not a clinical trial only data protection consent will be used as requested by GDPR legislation. All patients 
invited to participate in the trial are entitled to make their decision based on all currently available information 
provided to them by the Investigator/designee. In addition, they will be given the Data Privacy Sheet (DPS) a 
document in Romanian language, written in clear and concise lay language for review and consideration. These 
documents must have been previously approved by the relevant EC and may further be updated as new 
important information becomes available that may affect the patient’s willingness to participate or continue 
in the trial.  
The patients must be made aware that they can refuse to join the trial or can withdraw their consent at any 
time without prejudicing further medical care. The contact details of the Investigator (telephone no, etc.) will 
be provided. The patients must also know that their personal records may be reviewed in confidence by the 

 
 
 
 
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Sponsor's staff or representatives and by the authorities and that personal information will be collected and 
retained in a confidential database. Conditions for ensuring the anonymity of data and the security and 
confidentiality of the database will be explained.  
Consent will always be given in writing after the patient had had adequate time to review the information and 
ask questions. The patient and the Investigator conducting the informed consent discussion will both 
personally write the name, sign and date these consent forms. Two copies of the data privacy consent form 
shall be signed. The Investigator shall provide one signed copy of the signed data privacy consent and one copy 
of the data privacy sheet to the patient and retain the second copies of the signed forms in the onsite study 
file. The forms will be reviewed by CRO personnel. 
 
7.4. 
VULNERABLE POPULATION 
No vulnerable population will be included in the present trial. 
7.5. 
PATIENT’S DATA PROTECTION 
The rights, safety and well-being of the participants are the most important considerations and should prevail 
over the interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training and experience to 
perform their respective tasks. 
This trial will not use the services of study personnel where sanctions have been invoked or where there has 
been scientific misconduct or fraud (e.g., loss of medical licensure, debarment). Systems with procedures will 
be implemented to assure the quality of every aspect of the trial. 
The Sponsor, its delegates and regulatory authorities have direct access to patient records and for the 
protection of the enrolled patients, this study will be conducted respecting the current GDPR regulation.  
According to local Legislation regarding the protection of personal data, the responsible for the data 
treatment/intervention of the patient in each clinical Centre is the medical doctor responsible for the Centre. 
Electronic data capture forms are HIPAA, BAA and GDPR compliant. Data storing services are verified (SSAE 18 
SOC 1 and 2 reports) with international and regional standards and terms. 
Services are under contractual commitment to meet US and EU customer data residency requirements. 
Privacy and security commitments:  
• 
levels access structure. 
• 
No mining of customer data for advertising. 
• 
No voluntary disclosure of customer data to law enforcement agencies. 
 
7.6. 
ETHICAL PRINCIPLES 
This study will be conducted in accordance with the ethical principles originated in the Declaration of Helsinki 
(Seventh revision, 2013), the Convention of Oviedo, April 4th, 1997, and the additional Protocol January 12th, 
1998, and will be consistent with GCP. In addition, the study will follow international laws and regulations and 
the national laws of Romania, the country in which the trial is performed, as well as any applicable guidelines. 
If there are conflicts between local laws and regulations, more stringent requirements will be adopted. 
 

 
 
 
 
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7.7.  
INSURANCE  
The Sponsor needs to purchase additional insurance for the patients enrolled, specifically designed to cover 
the medical device trial. The insurance certificate will be attached to the TCF and the TMF. The payment of the 
insurance will be performed by the CRO (as the contracting party) and BIOKOSMES will be the insured. 
7.8. 
DECLARATION OF INTERESTS  
No competing interests or conflict of interest should exist between the involved Investigators and the Sponsor 
of the study. 
8. 
QUALITY ASSURANCE 
8.1. 
QUALITY CONTROL PROCEDURES 
Quality control (QC) procedures will be implemented for the data entry system and data QC checks that will 
be run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
The Centres will provide direct access to all trial related source data/documents, and reports for the purpose 
of monitoring and auditing by the Sponsor, and inspection by local and regulatory authorities. 
8.2. 
AUDITS AND INSPECTIONS 
Authorized representatives of the Sponsor or CA or EC may visit the investigation site to perform 
audits/inspections during the trial or after. 
8.3. 
STAFF TRAINING  
Before the site activation, CRO personnel will conduct a site initiation visit. The purpose of the visit is to provide 
training to the involved site personnel including, but not limited to the following items:  
• 
protocol and execution thereof. 
• 
Filling out the questionnaire. 
• 
Maintenance of ISF. 
The staff present at the site initiation visit will sign a confirmation document that they were trained. The 
original of this document will be included in the ISF and the TMF. 
9. 
REFERENCES 
1. Lohsiriwat V. Hemorrhoids: from basic pathophysiology to clinical management. World J Gastroenterol. 
2012 May 7;18(17):2009–17.  
2. Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011 Mar;24(1):5–13.  
3. Thomson JPS, Goligher JC. Surgery of the anus, rectum and colon. J. C. Goligher. Fourth Edition. 264 × 
198 mm. Pp. 968 + vii, with 654 illustrations. 1980. London: Baillière Tindall. £35·00. BJS Br J Surg. 
1980;67(7):532–532.  
4. Kestřánek J. Hemorrhoid management in women: the role of tribenoside + lidocaine. Drugs Context. 
2019 Sep 13;8:212602.  

 
 
 
 
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5. Rørvik HD, Styr K, Ilum L, McKinstry GL, Dragesund T, Campos AH, et al. Hemorrhoidal Disease Symptom 
Score and Short Health ScaleHD: New Tools to Evaluate Symptoms and Health-Related Quality of Life in 
Hemorrhoidal Disease. Dis Colon Rectum. 2019 Mar;62(3):333–42.  
6. Khan MA, Chowdri NA, Parray FQ, Wani RA, Mehraj A, Baba A, et al. “PNR-Bleed” classification and 
Hemorrhoid Severity Score—a novel attempt at classifying the hemorrhoids. J Coloproctology. 2020 Oct 
1;40(4):398–403.  
7. Pietroletti R, Giuliani A, Buonanno A, Mattei A, Fiasca F, Gallo G. Efficacy and Tolerability of a New 
Formulation in Rectal Ointment Based on Zn-L-Carnosine (Proctilor®) in the Treatment of Haemorrhoidal 
Disease. Front Surg. 2022 Mar 24;9:818887.  
8. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the 
social, behavioral, and biomedical sciences. Behav Res Methods. 2007 May;39(2):175–91.  
9. R Core Team (2020). — European Environment Agency [Internet]. [cited 2022 Sep 12]. Available from: 
https://www.eea.europa.eu/data-and-maps/indicators/oxygen-consuming-substances-in-rivers/r-
development-core-team-2006 
10. 14:00-17:00. ISO 14155:2020 [Internet]. ISO. [cited 2022 Sep 13]. Available from: 
https://www.iso.org/cms/render/live/en/sites/isoorg/contents/data/standard/07/16/71690.html 
11. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical 
devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and 
Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC (Text with 
EEA relevance)Text with EEA relevance [Internet]. Apr 24, 2020. Available from: 
http://data.europa.eu/eli/reg/2017/745/2020-04-24/eng 
12. EMA. ICH E6 (R2) Good clinical practice [Internet]. European Medicines Agency. 2018 [cited 2022 Sep 
13]. Available from: https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice 
13. Sun Z, Migaly J. Review of Hemorrhoid Disease: Presentation and Management. Clin Colon Rectal Surg. 
2016 Mar;29(1):22–9.  
14. Tjandra JJ, Tan JJY, Lim JF, Murray-Green C, Kennedy ML, Lubowski DZ. Rectogesic (glyceryl trinitrate 
0.2%) ointment relieves symptoms of haemorrhoids associated with high resting anal canal pressures. 
Colorectal Dis Off J Assoc Coloproctology G B Irel. 2007 Jun;9(5):457–63.  
15. Safdar N, Abbo LM, Knobloch MJ, Seo SK. Research Methods in Healthcare Epidemiology: Survey and 
Qualitative Research. Infect Control Hosp Epidemiol. 2016 Nov;37(11):1272–7.  
16. Hjortswang H, Järnerot G, Curman B, Sandberg-Gertzén H, Tysk C, Blomberg B, et al. The Short Health 
Scale: a valid measure of subjective health in ulcerative colitis. Scand J Gastroenterol. 2006 
Oct;41(10):1196–203.  
17. Stjernman H, Grännö C, Järnerot G, Ockander L, Tysk C, Blomberg B, et al. Short health scale: a valid, 
reliable, and responsive instrument for subjective health assessment in Crohn’s disease. Inflamm Bowel 
Dis. 2008 Jan;14(1):47–52.  
18. Slappendel R, Simpson K, Dubois D, Keininger DL. Validation of the PAC-SYM questionnaire for opioid-
induced constipation in patients with chronic low back pain. Eur J Pain Lond Engl. 2006 Apr;10(3):209–
17.  

 
 
 
 
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19. Lee MJ, Morgan J, Watson AJM, Jones GL, Brown SR. A validated severity score for haemorrhoids as an 
essential prerequisite for future haemorrhoid trials. Tech Coloproctology. 2019 Jan;23(1):33–41.  
20. Bhatt A. Protocol deviation and violation. Perspect Clin Res. 2012 Jul;3(3):117.  
21. Ghooi RB, Bhosale N, Wadhwani R, Divate P, Divate U. Assessment and classification of protocol 
deviations. Perspect Clin Res. 2016 Sep;7(3):132–6.  
 
 

 
 
 
 
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10. 
ANNEX 1 Medical Device Composition   
Quantitative composition and functions of the ingredients  
INGREDIENTS 
 
RM NAME / INCI NAME 
QUANTITY % Ingredient FUNCTION  
 
ACQUA PURIFICATA Ph.Eur. 
60,60000 
 
Solvent 
AQUA 
60,600000 
Solvent 
 
CREMEOL PS 17 / CEGESOFT PS 17 
6,00000 
 
Emollient 
OLUS OIL 
6,000000 
Emollient 
 
CLAROWAX MS 4000 - ex SYNTEWAX 
MS4000 (ex GLYCMONOS A 4000) 
5,00000 
 
Emollient 
GLYCERYL STEARATE 
1,400000 
Emulsifying  
 
PEG-75 STEARATE 
1,400000 
Emulsifying 
 
ISODECYL LAURATE 
0,700000 
Emollient 
 
PEG-8 STEARATE 
0,700000 
Emulsifying  
 
CETEARYL ALCOHOL 
0,700000 
Emulsifying / Emulsion 
Stabilising 
 
PARAFFIN 
0,100000 
Emollient 
 
ISOCET 
5,00000 
 
Emulsion stabilising 
CETEARETH-20 
3,125000 
Emulsifying 
 
ISOSTEARYL ALCOHOL 
1,875000 
Emulsifying / Emulsion 
Stabilising 
 
OLIO VASELINA LEGGERA/OLIO DI 
VASELINA 102 
5,00000 
 
Useful for intended 
use 
PARAFFINUM LIQUIDUM 
5,000000 
Film forming agent 
 
VASELINA FILANTE PH.142 G 
4,00000 
 
Useful for intended 
use 
PETROLATUM 
4,000000 
Film forming agent 
 
SORBITOLO 70%/SORBITOL LGK 
3,00000 
 
Humectant 
HYDROGENATED STARCH HYDROLYSATE 
2,100000 
Humectant 
 
AQUA 
0,900000 
Solvent 
 
E/GLICO CENTELLA ASIATICA / 
PENNYWORT GLYCOLIC EXTRACT 002880 
2,00000 
 
Skin conditioning 
PROPYLENE GLYCOL 
1,302000 
Solvent - Humectant 
 
AQUA 
0,349000 
Solvent 
 
CENTELLA ASIATICA EXTRACT 
0,349000 
Skin conditioning 
 
OLIO MANDORLE DOLCI 001098 
2,00000 
 
Emollient 
PRUNUS AMYGDALUS DULCIS OIL 
2,000000 
Emollient 
 
SABONAL C1618 30/70 (ex ecorol 68/30) 
/ NAFOL 1618S 
2,00000 
 
Emulsion stabilising 

 
 
 
 
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CETEARYL ALCOHOL 
2,000000 
Emulsifying / Emulsion 
stabilising  
 
EUXYL K700 
1,50000 
 
Preservative 
PHENOXYETHANOL 
0,469500 
Preservative 
 
BENZYL ALCOHOL 
0,469500 
Preservative 
 
POTASSIUM SORBATE 
0,282000 
Preservative 
 
AQUA 
0,277500 
Solvent 
 
TOCOPHEROL 
0,001500 
Antioxidant 
 
IPPOCASTANO 20% ESTRATTO SECCO 
IDROALCOLICO COD.3518320 
1,00000 
 
Skin conditioning 
AESCULUS HIPPOCASTANUM SEED 
EXTRACT 
0,650000 
Skin conditioning 
 
AQUA 
0,200000 
Solvent 
 
MALTODEXTRIN 
0,150000 
Binding 
 
SOPSIL 350 G 
1,00000 
 
Useful for intended 
use 
DIMETHICONE 
1,000000 
Film forming agent 
 
DIPOTASSIUM GLYCYRRHIZINATE 
0,50000 
 
Humectant 
DIPOTASSIUM GLYCYRRHIZATE 
0,500000 
Humectant / Skin 
conditioning 
 
ZANTALENE (R) 
0,50000 
 
Skin conditioning 
OLEYL ALCOHOL 
0,400000 
Solvent 
 
ZANTHOXYLUM BUNGEANUM FRUIT 
EXTRACT 
0,100000 
Skin conditioning 
 
LECINOL S 10 
0,30000 
 
Emulsifying 
HYDROGENATED LECITHIN 
0,300000 
Emulsifying 
 
PANTROFINA Beta/STEARIL 
GLYCYRRHETINATE 
0,20000 
 
Skin conditioning 
STEARYL GLYCYRRHETINATE 
0,200000 
 Skin conditioning 
 
ACIDO LATTICO 80% 
0,10000 
 
pH regulator 
LACTIC ACID 
0,080000 
Buffering – pH regulator 
 
AQUA 
0,020000 
Solvent 
 
CALMOSENSINE SP 
0,10000 
 
Useful for intended 
use 
BUTYLENE GLYCOL 
0,067200 
Solvent 
 
AQUA 
0,025000 
Solvent 
 
LAURETH-3 
0,004500 
Emulsifying / Surfactant 
 
HYDROXYETHYLCELLULOSE 
0,002000 
Film forming agent 
 
ACETYL DIPEPTIDE-1 CETYL ESTER 
0,001000 
Skin conditioning 
 
POTASSIUM SORBATE 
0,000300 
Preservative 
 

 
 
 
 
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DERMAFEEL ALLANTOIN (EX PHYLCARE 
ALLANTOINA) 
0,10000 
 
Skin conditioning 
ALLANTOIN 
0,100000 
Skin conditioning 
 
EDTA SALE BISODICO NA2 / VERSENE 
Na2 
0,10000 
 
Chelating 
DISODIUM EDTA 
0,100000 
Chelating 
 
 
11. 
ANNEX 2 Goligher Classification   
 
 
 
Bibliographical references: (3,4) 
 
 

 
 
 
 
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12. 
ANNEX 3 Collected Variables   
Short Health Scale for Haemorrhoidal Disease (SHSHD)  
 
Bibliographical references (5,16,17) 
Haemorrhoidal Disease Symptom Score (HDSS)  
 
Bibliographical references: (5,19) 
 
 

 
 
 
 
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Haemorrhoid Severity Score (HSS) 
 
Bibliographical references: (6) 
 
 

 
 
 
 
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13. 
ANNEX 4 Adverse Event Classification   
From ISO 14155:2020 
 
Table 1: Categories of adverse events. 
ADVERSE EVENTS 
Non-device-related 
Device- or procedure-related 
 
Non-serious 
Adverse Event (AE)a 
(3.2) 
Adverse Device Effect 
(ADE) 
(3.1) 
 
 
 
Serious 
 
 
Serious Adverse Event 
(SAE)b 
(3.45) 
Serious Adverse Device Effect 
(SADE) 
(3.44) 
Anticipated 
Unanticipated 
Anticipated Serious Adverse 
Device Effect 
(ASADE)c 
(3.1, Note 1 to entry) 
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
(3.51) 
a 
b 
c 
Includes all categories. 
Includes all categories that are serious. 
Includes all categories that are related to the device or the 
investigational procedure 
 
 

 
 
 
 
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14. 
ANNEX 5 Declaration of Helsinki 
 
WMA Declaration of Helsinki 
Ethical Principles for Medical Research involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the:  
29th WMA General Assembly, Tokyo, Japan, October 1975  
35th WMA General Assembly, Venice, Italy, October 1983  
41st WMA General Assembly, Hong Kong, September 1989  
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General 
Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added)  
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 59th WMA General 
Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical 
principles for medical research involving human subjects, including research on identifiable human material 
and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied 
with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these 
principles.  
 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will 
be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act 
in the patient's best interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human subjects. 
6. The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 

 
 
 
 
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7. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, 
right to self-determination, privacy, and confidentiality of personal information of research subjects. The 
responsibility for the protection of research subjects must always rest with the physician or other health 
care professionals and never with the research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No national 
or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections 
for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers 
requires the supervision of a competent and appropriately qualified physician or other health care 
professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in research only 
to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research study will not adversely affect the 
health of the patients who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
 
Risks, Burdens and Benefits  
16. In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful assessment of predictable risks 
and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits 
to them and to other individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed 
and documented by the researcher.  
18. Physicians may not be involved in a research study involving human subjects unless they are confident that 
the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study.  
 
Vulnerable Groups and Individuals 

 
 
 
 
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19. Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive to the health needs 
or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, 
this group should stand to benefit from the knowledge, practices or interventions that result from the 
research. 
 
Scientific Requirements and Research Protocols  
21. Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and 
adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research 
must be respected. 
22. The design and performance of each research study involving human subjects must be clearly described 
and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding 
funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and 
information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must 
be duly qualified. It must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to 
the protocol may be made without consideration and approval by the committee. After the end of the 
study, the researchers must submit a final report to the committee containing a summary of the study’s 
findings and conclusions.  
 
Privacy and Confidentiality  
24. Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
 
Informed Consent  

 
 
 
 
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25. Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual 
capable of giving informed consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each potential subject 
must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential 
subject must be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific information needs 
of individual potential subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.  
All medical research subjects should be given the option of being informed about the general outcome and 
results of the study. 
27. When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under 
duress. In such situations the informed consent must be sought by an appropriately qualified individual 
who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is intended to promote the health of the 
group represented by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to the 
consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed 
consent is a necessary characteristic of the research group. In such circumstances the physician must seek 
informed consent from the legally authorised representative. If no such representative is available and if 
the research cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never 
adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
 
Use of Placebo 

 
 
 
 
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33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the 
best proven intervention(s), except in the following circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective 
than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or 
safety of an intervention  
and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving 
the best proven intervention.  
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, researchers and host country governments should make provisions 
for post-trial access for all participants who still need an intervention identified as beneficial in the trial. 
This information must also be disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly available 
the results of their research on human subjects and are accountable for the completeness and accuracy of 
their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted for publication. 
 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent from 
the patient or a legally authorised representative, may use an unproven intervention if in the physician's 
judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention 
should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all 
cases, new information must be recorded and, where appropriate, made publicly available. 
 
 

 
 
 
 
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5. PATIENT DIARY 
 
PATIENT CODE _ _.  _ _ _ 
 
 
 
Visit data _ _.  _ _.  _ _ _ _ 
 
DATE 
Application 
Other drugs 
Other diseses 
Note 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Compilation instruction 
Please from tomorrow for 14 days each day fill this diary. 
In the first column insert the data, in the column from two to six put a cross at any Proctinus cream 
application. 
If you take any drug note in the other drug column the name of each drug taken 
In the general health column insert information if you have any different disease than hemorroides. 
In the column note insert any other relevant information. 
For any doubt on the diary filling please contact the doctor of this study 
 
Dr._____________ contact number__________________ 
 
 
 

 
 
 
 
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6. CRF 
 
 
 

 
 
 
 
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7. LABELLING AND INSTRUCTIONS FOR USE 
 
 
 
 
LABELLING AND INSTRUCTION FOR USE 
0VNL2FI00121_artwork  Rev.01-2020 
ANNEX 9   
Code and trade names 
Technical documentation ID 
0BIO4A004CPR 
MDD:TF_ENG_34 
Rev. N. 
Date 
20 
17/05/2024 
 
 

 
 
 
 
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MASTER TEXT 0BIO4A004CPR 
Tube 
0BIO4A004CPR  
Provides symptomatic relief from hemorrhoids and anal irritation 
Helps to relieve pain, itching and burning 
Emulsion with applicator 
30mL 
1.06 fl.oz 
--------------------------------------------------------------------------------------------------------------- 
0BIO4A004CPR provides symptomatic relief from hemorrhoids and anal irritation.  
It has a protective, lubricating and refreshing action. 
For directions on how to use, please read carefully instructions for use 
 
Warnings 
Intended for individual use only and not to be shared. 
Keep out of reach of children. 
Do not use after the expiry date. 
Do not use if tube is damaged. 
 
With a reusable applicator 
 
 
Biokosmes s.r.l. – socio unico 
 
Via dei Livelli 1, 23842 Bosisio Parini (LC) ITALY 
Manufactured in Italy 
DISTRIBUTOR: name and address 
0477   
 
 
 
 
 
 

 
 
 
 
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Carton 
0BIO4A004CPR  
Provides symptomatic relief from hemorrhoids and anal irritation 
Helps to relieve pain, itching and burning 
Emulsion with applicator 
30mL 
1.06 fl.oz 
---------------------------------------------------------------------------------------------------------------- 
 
Biokosmes s.r.l. – socio unico 
 
Via dei Livelli 1, 23842 Bosisio Parini (LC) ITALY 
 
Manufactured in Italy 
DISTRIBUTOR: name and address 
 0477   
 
 
 
With a reusable applicator 
 
30mL 
1.06 fl.oz 
---------------------------------------------------------------------------------------------------------------- 
0BIO4A004CPR is a protective emulsion. 
It provides relief from hemorrhoids and anal irritation  
It has a protective, lubricating and refreshing action. 
 
For directions on how to use, please read carefully instructions for use 
 
----------------------------------------------------------------------------------------------------------------------------------- 
Composition: 
AQUA, OLUS OIL, PARAFFINUM LIQUIDUM, PETROLATUM, CETEARETH-20, CETEARYL ALCOHOL, 
HYDROGENATED STARCH HYDROLYSATE, PRUNUS AMYGDALUS DULCIS OIL, ISOSTEARYL ALCOHOL, PEG-75 
STEARATE, GLYCERYL STEARATE, PROPYLENE GLYCOL, DIMETHICONE, PEG-8 STEARATE, ISODECYL LAURATE, 
AESCULUS HIPPOCASTANUM SEED EXTRACT, DIPOTASSIUM GLYCYRRHIZATE, BENZYL ALCOHOL, 
PHENOXYETHANOL, OLEYL ALCOHOL, CENTELLA ASIATICA EXTRACT, HYDROGENATED LECITHIN, 
POTASSIUM SORBATE, STEARYL GLYCYRRHETINATE, MALTODEXTRIN, ALLANTOIN, PARAFFIN, DISODIUM 
EDTA, ZANTHOXYLUM BUNGEANUM FRUIT EXTRACT, LACTIC ACID, BUTYLENE GLYCOL, LAURETH-3, 
HYDROXYETHYLCELLULOSE, TOCOPHEROL, ACETYL DIPEPTIDE-1 CETYL ESTER 
 
Warnings 
Intended for individual use only and not to be shared. 
Keep out of reach of children. 
Do not use after the expiry date. 

 
 
 
 
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Do not use if tube is damaged. 
Store in a dry place and away from direct light 
 
----------------------------------------------------------------------------------------------------------------------------------- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
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Instructions for use 
0BIO4A004CPR  
Provides symptomatic relief of hemorrhoids and anal irritation 
Helps to relieve pain, itching and burning 
 
How it works 
0BIO4A004CPR is a soft and light hydrophilic emulsion that offers protection to the irritated areas. 
It is a specific adjuvant for the symptomatic relief of internal and external haemorrhoids and anal irritation. 
The product creates a physical barrier that protects the peri-anal tissue, minimizing the possibility of 
bacterial colonization and contact with environmental dirt, which may exacerbate haemorrhoid condition. 
 
Due to its formulation, it contributes to physiological restoration of the anal and perianal 0BIO4A004CPR 
has a protective, lubricating and refreshing action. 
 
0BIO4A004CPR has emollient properties, which help to prevent irritation and discomfort of the perianal 
area - this gives relief from pain, burning, itching and other related complaints. 
 
Its application leaves the treated area soft and moisturised, avoiding the onset of irritation and cracking of 
the skin. The lubricating action helps to facilitate bowel movement, thus minimising the trauma and pain 
sensation associated with defecation. 
It also supports the physiological repairing process. 
The product is not evaluated during pregnancy and breastfeeding. In case of pregnancy or breast feeding, 
consult with your medical professional or pharmacist. 
 
0BIO4A004CPR provides relief: 
✓ when you are suffering from haemorrhoids both internal and external 
✓ when you have discomfort of the anal and perianal areas, such as itching and burning 
✓ when you are sensitive to anal irritations 
 
How to use 
0BIO4A004CPR is applied into the anal cavity and to the surrounding perianal area to relieve symptoms 
associated to haemorrhoids and anal irritation. 
 
• 
EXTERNAL APPLICATION 
In the case of discomfort on the outer anal area, you can apply 0BIO4A004CPR with your finger and gently 
massage in. The product can also be used before bowel movement to facilitate defecation (always take 
care to thoroughly wash the affected area and your hands before and after using the product). 
 
• 
INTERNAL APPLICATION 
0BIO4A004CPR has a special applicator and this can be screwed onto the tube. This special applicator will 
allow you to apply the product into the anal cavity.  
 
Always take care to thoroughly wash the affected area and your hands before and after using the product. 
1. Take the cap off the tube and use the backside of the cap to pierce the sealed tube, prior to initial use. 

 
 
 
 
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2. Screw the applicator onto the opening of the tube and place gently inside the anal cavity (you can also 
apply a thin layer of the cream on the edge of the applicator to facilitate the insertion into the anal 
cavity). 
3. Squeeze the tube to allow a sufficient quantity of emulsion to come out. 
4. After use, carefully clean the applicator with a wet paper towel and leave to dry 
5. When finished, cover the applicator with the cap. 
 
Application 
Apply the product as and when required, up to three/four times per day. 
To prevent anal irritation and cracking of the skin, it is possible to apply 0BIO4A004CPR once a day. 
 
Ingredients 
AQUA, OLUS OIL, PARAFFINUM LIQUIDUM, PETROLATUM, CETEARETH-20, CETEARYL ALCOHOL, 
HYDROGENATED STARCH HYDROLYSATE, PRUNUS AMYGDALUS DULCIS OIL, ISOSTEARYL ALCOHOL, PEG-75 
STEARATE, GLYCERYL STEARATE, PROPYLENE GLYCOL, DIMETHICONE, PEG-8 STEARATE, ISODECYL LAURATE, 
AESCULUS HIPPOCASTANUM SEED EXTRACT, DIPOTASSIUM GLYCYRRHIZATE, BENZYL ALCOHOL, 
PHENOXYETHANOL, OLEYL ALCOHOL, CENTELLA ASIATICA EXTRACT, HYDROGENATED LECITHIN, 
POTASSIUM SORBATE, STEARYL GLYCYRRHETINATE, MALTODEXTRIN, ALLANTOIN, PARAFFIN, DISODIUM 
EDTA, ZANTHOXYLUM BUNGEANUM FRUIT EXTRACT, LACTIC ACID, BUTYLENE GLYCOL, LAURETH-3, 
HYDROXYETHYLCELLULOSE, TOCOPHEROL, ACETYL DIPEPTIDE-1 CETYL ESTER. 
 
Undesirable effects  
There are no known undesirable effects deriving from the use of 0BIO4A004CPR, however: 
* Do not use in the presence of hypersensitivity to any of the ingredients. 
* If you have doubts, apply a small amount of the emulsion on the inside of the forearm. If irritable red 
spots appear, we advise you not to use the product. 
* Inform your doctor or pharmacist of any undesirable effects or if symptoms persist.  
 
Warnings 
The product is intended for individual use only and not be shared. 
Keep out of reach of children. 
Store in a dry place, away from direct light at room temperature (between 5° and 30° C). 
Do not use if the pack is damaged. 
Do not use after the expiry date indicated on the packaging. 
Do not ingest. 
Avoid contact with eyes. In case of contact with eyes: flush thoroughly with water and eventually seek 
medical advice. 
After use, carefully clean the applicator, leave to dry and cover the applicator with the cap. 
If symptoms persist after initial 30 days, seek advice from a medical professional. 
The product is not evaluated during pregnancy and breastfeeding. If you are pregnant/breastfeeding 
consult your doctor before use. 
 
Please note 
In case of persistent or recurrent complaints, you should always contact your physician.  

 
 
 
 
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Also in the case of worsening or when symptoms of inflammation, allergic reaction or infection occur 
consult a doctor. 
 
Possible interactions: 
At present there are no known interactions between the product and drugs or other medical devices. 
However, in the case of concomitant, continuous and prolonged use of drugs, in particular anticoagulants, 
antiplatelets or sedative medications, it is advised to consult a physician before application of this product. 
 
Size: 30ml tube with reusable applicator 
 
 
0477 
 
 
Biokosmes s.r.l. – socio unico 
 
Via dei Livelli 1, 23842 Bosisio Parini (LC) ITALY 
Manufactured in Italy 
DISTRIBUTOR: name and address 
Revision 01-2020 
 
SYMBOL 
MEANING 
0477    
CE mark issued by Notified Body 0477 
 
Manufacturer 
 
See instructions for use before using the product 
 
Store between 5°C and 30°C  
 
 
 
Expiry date 
 
Batch number 
 

 
 
 
 
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8. INFORMED CONSENT FORM 
Informed Consent form for adult patients invited to take part in  
Post-Marketing Clinical Follow-Up trial to evaluate the performance and safety of the medical device 
PROCTOeze® PLUS in the relief of haemorrhoidal disease and anal irritation symptoms 
 
Principal Investigator: Dr. Sisu Lucia - Cristina 
Organization: C.M.I Dr. Sisu Lucia - Cristina 
Sponsor: BIOKOSMES Srl 
Protocol code: OpBio/0123/MD 
Protocol version: 1.0/20231201 
 
This Informed Consent Form has two parts: 
• 
Information Sheet (to share information about the research with you) 
• 
Certificate of Consent (for signatures if you agree to take part) 
• 
You will be given a copy of the full Informed Consent Form 
• 
 
PART I: Information Sheet 
Introduction 
The trial you are invited to join aims to conduct research on the haemorrhoidal disease and its impact on the 
patient’s quality of life. Your study doctor is going to give you information about the trial and associated 
procedures and invite you to be part of this research. You do not have to decide today whether or not you will 
participate in the trial. Before you decide, you can talk to anyone you feel comfortable with about the trial.  
There may be some words that you do not understand. If needed, please ask your study doctor to explain.  
Similarly, if you have any questions later, you can ask the study doctor or their staff. 
Purpose of the research 
The acute clinical manifestation of the haemorrhoidal disease is commonly known as haemorrhoidal crisis and 
it is characterized by rectal bleeding, itching, pain or swelling, all of which cause discomfort for the patient and 
have a negative effect on their quality of life. 
The Sponsor has developed PROCTOeze® PLUS, a soft and light hydrophilic emulsion to help relieve the 
symptoms, which is largely used in the clinical practice of thousands of medical doctors in Italy, Romania, 
Iceland, Bulgaria, Taiwan, and Israel. PROCTOeze® PLUS is commercialized in Romania with the brand name 
PROCTINUM® 
The reason the Sponsor is conducting this trial is to evaluate if the administration of PROCTOeze® PLUS will 
help improve the symptomatology in patients suffering from symptomatic haemorrhoids and anal irritation.  
Type of Research Intervention 
This trial involves 2 physical visits to the doctor’s office, the administration of PROCTOeze® PLUS emulsion for 
2 weeks and follow-up phone-call from the doctor. 

 
 
 
 
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Participant selection 
You have been invited to participate in this trial by your doctor because you suffer from symptomatic 
haemorrhoids. 
Voluntary Participation 
Your participation in this research is entirely voluntary. It is your choice whether to participate or not. Whether 
you choose to participate or not, all the services you receive at this clinic will continue and nothing will change. 
If you choose not to participate in this trial, you will be recommended alternative standard of care treatment 
that is routinely recommended in this clinic for haemorrhoidal disease. You may change your mind later and 
stop participating even if you agreed earlier. 
Information on the Trial Medical Device [PROCTOeze® PLUS] 
The medical device we are testing in this research is called PROCTOeze® PLUS. It has been tested before with 
people who suffer from haemorrhoidal disease and anal irritation. Romanian National Authority (ANMDM) has 
already granted marketing authorisation for this medical device, as it has proven to be efficient, safe and well-
tolerated by the patients. The present research is conducted to comply with the manufacturer’s requirement 
to routinely present results of post-marketing clinical follow-up trials to the Authorities. 
There are no known side-effects associated to the use of PROCTOeze® PLUS other than sensitivity to any of its 
components. 
Procedures and Protocol 
During the trial you make 2 visits to the clinic and will receive one follow-up phone-call. 
• 
At the first visit, the study doctor will ask you a few questions about your general health and medical 
history, perform a general physical examination and record your vital signs, including haemorrhoids 
evaluation and confirmation of diagnosis. You will be asked to fill in 2 questionnaires to self-evaluate 
your quality of life in relation to the Haemorrhoidal Disease and you will receive the Patient Diary, the 
IMD for administration and instructions on how to use both of them during the next 2 weeks. 
• 
At the next visit, which will take place 2 weeks later, you will again be asked some questions about 
your health, including haemorrhoids evaluation, your vital signs will be recorded and you will be asked 
to fill in again the 2 questionnaires to self-evaluate your quality of life in relation to the Haemorrhoidal 
Disease. At this visit, you will have to return the filled-in Patient Diary and IMD (unused IMD, empty 
tube/box) to the study doctor. 
• 
After 2 weeks, you will receive a follow-up call from the study doctor to evaluate your general health 
and the effects of the treatment. 
Duration  
The trial takes place over 30 days. During that time, it will be necessary for you to come to the doctor’s office 
on 2 days, for approximately 1 hour each day. We would like to call you 2 weeks after your last clinic visit for a 
final check-up.  
In total, you will be asked to come 2 times to the doctor’s office in 1 month. At the end that month, the trial 
will be finished. 
Side Effects 

 
 
 
 
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As already mentioned, there are no known side-effects associated to the use of PROCTOeze® PLUS other than 
sensitivity to any of its components. However, your study doctor will follow you closely and keep track of any 
unwanted effects or any problems. You are also encouraged to inform your study doctor immediately if you 
experience any side-effects while under treatment in this trial. 
Risks 
By participating in this research, you will be not be at any knowed risk than you would otherwise be. There is, 
for example, a very low risk that your haemorrhoids symptoms will not get better.  If this is the case, you can 
stop the administration of PROCTOeze® PLUS at any time and try other treatment option available on the 
market.  
Benefits  
If you participate in this research, you will benefit from a free-of-charge treatment for your Haemorrhoidal 
Disease and your participation will help us find the answer to the research question.  
Reimbursements 
You will not be given any money or gifts to take part in this research. The IMD under evaluation (PROCTOeze® 
PLUS) will be provided free of charge for the whole duration of the trial. 
Confidentiality 
Your study doctor will not be sharing the identity of those participating in the research and the information 
that is collected from this research project will be kept confidential. Information about you that will be 
collected during the research will be put away and no-one but the researchers will be able to see it. Any 
information about you will have a number on it instead of your name. Only the researchers will know what 
your number is. It will not be shared with or given to anyone. 
Who will have access to your personal data collected during the trial? 
Your data, in particular personal and health data, will be processed only to the extent that they are 
indispensable to the objective of the trial and for pharmacovigilance purposes, in compliance with EU 
Regulation 2016/679, known as GDPR (General Data Protection Regulation) and with Legislative Decree 10 
August 2018, no. 101. In practical terms, the documents relating to the participant will be kept in a safe place 
and will not report his/her name in clear text, only known to the researchers, but an identification code. 
The data, made anonymous, may be subject to control by regulatory bodies and used for scientific publications 
(journals, conferences). 
Your clinical data collected for the purposes of the trial, as well as the results of the tests carried out, will be 
stored for the time required by the regulations and subsequently destroyed. They will not be destroyed only if 
a) it is no longer possible to trace them back to your identity, because they have been anonymized during the 
trial itself; b) in the presence of your specific informed consent. 
If the personal data are transferred to a third country or to an international organization, all the guarantees 
will be adopted which are provided for by Article 46 of the GDPR 679/2016. 
Further information is included in the attached data processing authorization form. 

 
 
 
 
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Sharing the Results 
Once the trial is over and all the resulting data have been collected, they will be analyzed to draw conclusions. 
The investigators and the Sponsor undertake to make them available to the scientific community and Notified 
Body. 
Right to Refuse or Withdraw 
You do not have to take part in this research if you do not wish to do so and refusing to participate will not 
affect your treatment at this clinic in any way.  You will still have all the benefits that you would otherwise have 
at this clinic. You may stop participating in the research at any time that you wish without losing any of your 
rights as a patient here. Your treatment at this clinic will not be affected in any way. 
Early Termination 
Your study doctor may decide to terminate your participation in the trial if: 
• 
Your health conditions were to change and participation in the trial proved potentially harmful; 
• 
New information is available and the trial is no longer in your best interest; 
• 
You do not follow the agreed rules for participation in the trial; 
• 
For women: you get pregnant during the trial; 
• 
The trial is stopped by the competent authorities. 
 
Alternatives to Participating 
If you do not wish to take part in the research, your doctor will recommend alternative standard treatment 
available on the market for Haemorrhoidal Disease. 
Who to Contact if you join the trial 
For any doubt and unforeseeable or unscheduled event during the trial (doubts relating to the treatment in 
progress, side effects, decision to abandon the trial, etc.), you can contact:   
Dr. Lucia Cristina Sisu 
Phone: (+40) 0744960358 
Email: dr.cristinasisu@gmail.com 
Approvals 
This trial and the present document have been reviewed and approved by the Bioethics Committee for 
Medicines and Medical Devices, which is a national Romanian committee whose task it is to make sure that 
research participants are protected from harm.  Among other things, the Ethics Committee has verified the 
compliance of the trial with the standards of Good Clinical Practice and with the ethical principles expressed 
in the Declaration of Helsinki and that your safety, rights and well-being have been protected. 
More details about the Ethics Committee are available at https://www.adsm.ro/comisia-de-bioetica-a-
medicamentului-si-a-dispozitivelor-medicale/ . 
 

 
 
 
 
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PART II: Certificate of Consent 
I have read the foregoing information, or it has been read to me. I have had the opportunity to ask questions 
about it and any questions that I have asked have been answered to my satisfaction.  I consent voluntarily to 
participate as a participant in this trial. 
 
Print Name of Participant__________________  
 
 
 
 
 
Signature of Participant ___________________ 
 
Date ___________________________ 
 
Day/month/year 
 
  
 
 
 
 
 
Statement by the researcher/person taking consent 
I have accurately read out the information sheet to the potential participant, and to the best of my ability made 
sure that the participant understands the purpose of the trial, the procedures, the possible risks and benefits 
and the possible alternatives. 
I confirm that the participant was given an opportunity to ask questions about the study, and all the questions 
asked by the participant have been answered correctly and to the best of my ability. I confirm that the 
individual has not been coerced into giving consent, and the consent has been given freely and voluntarily.  
A copy of this ICF has been provided to the participant. 
 
Print Name of Researcher/person taking the consent________________________ 
 
 
 
 
Signature of Researcher /person taking the consent__________________________ 
 
Date ___________________________                                     Day/month/year 
 

 
 
 
 
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9. STATISTICAL ANALYSIS 
Statistical Methods 
Descriptive statistics (mean, standard deviation - SD- median, first and third quartile -Q1-Q3, min-max) have 
been calculated for quantitative variables.  
Absolute and percent frequencies have been calculated for qualitative variables. 
Comparison between gender on quantitative variables normally/symmetrically distributed have been carried 
out by means of the Student's t test. 
The change of the total of the SHSDH (primary objective of the study), on the total of the HSS and HDSS 
(secondary objectives of the study) between baseline and the end of the study has been assessed, according 
to the protocol, by means of the Wilcoxon signed-rank test. 
In addition, the change between Visit 1 and Visit 2 of SHSDH, HSS, and HDSS has been modeled between the 
two genders by means of the repeated measurement ANOVA with gender as a fixed factor between patients, 
time as a fixed factor within patients and their interaction. 
 
Demographic Dataset 
In this study have been enrolled 50 patients (34 - 68.0% - females and 16 - 32.0% males, Table 1). 
Table 1 
GENDER 
Frequency 
Percent 
Cumulative 
Frequency 
Cumulative 
Percent 
Females 
34 
68.00 
34 
68.00 
Males 
16 
32.00 
50 
100.00 
 
Their age was mean (±SD) equal to 49.9 years (13.9) (Table 2). Females had a mean age of 50.6 (±13.7) years; 
mean age of males was 48.6 (±14.7) years (Table 2.1).  
Table 2 
Analysis Variable : AGE 
Mean Std Dev Minimum 
Lower 
Quartile Median 
Upper 
Quartile Maximum 
Lower 95% 
CL for Mean 
Upper 95% 
CL for Mean 
49.98 
13.90 
29.0 
37.0 
47.50 
60.0 
87.0 
46.03 
53.93 
 
Table 2.1 
Analysis Variable : AGE 
GENDER 
N 
Obs 
Mean Std Dev Minimum 
Lower 
Quartile Median 
Upper 
Quartile Maximum 
Lower 95% 
CL for Mean 
Upper 95% 
CL for Mean 
Females 
34 
50.64 
13.69 
29.0 
39.0 
49.0 
62.0 
78.0 
45.87 
55.42 
Males 
16 
48.56 
14.69 
29.0 
37.0 
45.5 
57.5 
87.0 
40.73 
56.39 
 
The difference between the mean age of females and age was not statistically significant (Student's t test 
equal to -0.49, P = 0.6259; the test has been considered with the variances pooled owing to a statistically not 
significant difference between the variances of the age in the two groups) (Table 3). 

 
 
 
 
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Table 3 
Variable 
Method 
Variances 
T Value 
DF Prob t 
AGE 
Pooled 
Equal 
-0.49 
48 0.6259 
 
Figure 1 
 
 
The above figure shows the distribution of the variable age in males (above) and females (under). Obviously, 
owing also the low number of samples in the two classes, practically no conclusions about the distribution of 
the variable age can be made. Superimposed there is the density function of a normal distribution and of a 
“kernel density function”. The kernel density estimate (shown as a red dashed line) is a statistical method for 
smoothing the data distribution in comparison to the histogram  
 
 
 

 
 
 
 
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Diary dataset. 
During the 14 days of the study, patients used a mean total of cream doses of 34.44 (6.23, median equal to 
34, first and third quartile: 31-38, min-max: 14-56).  
Table 4. shows the descriptive statistics (mean (±SD), median with first (Q1) and third (Q3) quartile, and the 
minimum and the maximum (min-max) of the total number of cream applications in the 14 days and at each 
day. 
 
Table 4 
  Variable (N=50) 
Mean   Std Dev 
Median   (Q1- Q3) 
Min - Max 
Total n.    
34.44    (6.23) 
34.00  (31.00-38.00) 
14.00 - 56.00 
Day1     
1.88     (0.87) 
2.00  ( 1.00- 3.00) 
1.00 -  4.00 
Day2     
2.52     (0.65) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day3     
2.60     (0.76) 
3.00  ( 2.00- 3.00) 
0.00 -  4.00 
Day4     
2.60     (0.70) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day5     
2.44     (0.79) 
3.00  ( 2.00- 3.00) 
0.00 -  4.00 
Day6     
2.58     (0.67) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day7     
2.58     (0.64) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day8     
2.60     (0.67) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day9     
2.50     (0.61) 
2.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day10    
2.52     (0.68) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day11    
2.66     (0.69) 
3.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day12    
2.42     (0.70) 
2.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day13    
2.32     (0.65) 
2.00  ( 2.00- 3.00) 
1.00 -  4.00 
Day14    
2.22     (0.65) 
2.00  ( 2.00- 3.00) 
1.00 -  4.00 
 
It is possible to see that, apart from the first day, the mean values are similar for all the days. In addition, 
only for two days (day 3 and day 5) have 0 cream application as the minimum value. However, it has to stress 
that it is better to describe a discrete variable with the absolute and percent frequencies as the following 
Table 4.1. shows the absolute frequency and percent of the number of cream applications for each day 
 
 

 
 
 
 
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Table 4.1 
n. 
Number 
Frequency 
Percent % 
Day1 
1 
21 
42.00 
 
2 
15 
30.00 
 
3 
13 
26.00 
 
4 
1 
2.00 
Day2 
1 
2 
4.00 
 
2 
22 
44.00 
 
3 
24 
48.00 
 
4 
2 
4.00 
Day3 
0 
1 
2.00 
 
1 
1 
2.00 
 
2 
19 
38.00 
 
3 
25 
50.00 
 
4 
4 
8.00 
Day4 
1 
3 
6.00 
 
2 
17 
34.00 
 
3 
27 
54.00 
 
4 
3 
6.00 
Day5 
0 
1 
2.00 
 
1 
4 
8.00 
 
2 
19 
38.00 
 
3 
24 
48.00 
 
4 
2 
4.00 
Day6 
1 
1 
2.00 
 
2 
23 
46.00 
 
3 
22 
44.00 
 
4 
4 
8.00 
Day7 
1 
1 
2.00 
 
2 
22 
44.00 
 
3 
24 
48.00 
 
4 
3 
6.00 
Day8 
1 
3 
6.00 
 
2 
16 
32.00 
 
3 
29 
58.00 
 
4 
2 
4.00 
Day9 
1 
1 
2.00 
 
2 
25 
50.00 
 
3 
22 
44.00 
 
4 
2 
4.00 
Day10 
1 
3 
6.00 
 
2 
20 
40.00 
 
3 
25 
50.00 
 
4 
2 
4.00 
 
 

 
 
 
 
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Day11 
1 
2 
4.00 
 
2 
17 
34.00 
 
3 
27 
54.00 
 
4 
4 
8.00 
Day12 
1 
3 
6.00 
 
2 
26 
52.00 
 
3 
18 
36.00 
 
4 
3 
6.00 
Day13 
1 
4 
8.00 
 
2 
27 
54.00 
 
3 
18 
36.00 
 
4 
1 
2.00 
Day14 
1 
5 
10.00 
 
2 
30 
60.00 
 
3 
14 
28.00 
 
4 
1 
2.00 
 
From this Table 4.1, it seems possible to see that in the last days of the clinical trial less that 4 cream 
application a day was done. 
 
 

 
 
 
 
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Scales 
SHSHD 
The total of the four items of the SHSHD scale was 14.04 (±7.79) Visit 1 and 7.80 (±3.69) Visit 2 giving a 
difference of 6.24 (±5.51) from Visit 1 minus Visit 2. Table 5 shows  
The difference turned out to be statistically different (P < 0.0001) at the Wilcoxon signed-rank test. (Table 5.1, 
second row: Signed-Rank; then there is the value of the statistics equal to 540 and in the last column the p-
value)) 
Furthermore, the mixed factorial ANOVA with gender as a fixed factor showed a statistically nonsignificant 
interaction "gender by visit" (P = 0.2720) leading to conclude that the decrease pattern was similar for females 
and males.  
Indeed, the decrease is about of 43.7% for females and of 45.6 for males.  
Table 5.2 shows the terms of the Table ANOVA for repeated measurements: The first two rows refer to the 
“Between subjects” part of the analysis represented by the two groups of the Gender. The last three rows 
refer to the “Within Subject” part of the analysis represented by the Visit (Visit 1 – Baseline - and Visit 2 – 
end of treatment) and by the interaction “Visit by Gender”. Finally, the last row of the “Between Subjects” 
and of the “Within Subject” refers to the error. 
The table has to be read by starting from the interaction: if the interaction is not statistically significant it is 
possible to consider if the term “Visit” is statistically significant as the expression of a difference between the 
means value at Visit 1 and at visit 2, pooled on the two group of the fixed “Between Subjects” factor gender.  
So, it is possible to see that the interaction is not statistically significant (P=0.2720) and that the difference 
between the two visits is statistically significant (P<0.0001) as a further confirmation of the result obtained 
on the difference by the Wilcoxon signed-rank test.  
Finally, the gender term expresses the mean pattern of Females and Males on the two visits. A statistically 
significance means that there is a difference between the two genders starting from the baseline. In other 
terms Females (or Males) show a lower (greater) score of the total of the scale. A different behavior of the 
total score of the scale between the two genders under the treatment is given by the significance of the 
interaction term. The p-value of 0.1154 of the gender means that the means of the total score of the scale is 
similar both at baseline and at end of the trial-  
Table 5.3 shows the mean (DS) of the total score of the scale at the two visits for females and males. Actually, 
males show a mean value greater than females particularly at baseline, but this conclusion is not supported 
by the evidence of a statistically significant result. 
 
 

 
 
 
 
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Figure 2 
 
 
SHSHD: Panel A. Visit 1  
Panel B. Visit 2 
 
Figure 2 (panel A and Panel B) shows the box plot of the SHSHD total at baseline (visit 1) and at the end of the 
study (Visit 2). The upper and lower segment of the rectangle represent the third and first quartile, 
respectively. The line in the rectangle represents the median and the diamond in the rectangle represents the 
arithmetic mean. Finally, the two segments at the end of the two lines coming out the rectangle show the 
minimum and the maximum values. It is well known that if the arithmetic mean is too far the median, the data 
are skewed: positively if the median is greater then the median and negatively if the arithmetic mean if lower 
than the median. The asymmetry of the distribution is also demonstrated by the fact that the median is not at 
the middle of the rectangle fairly equidistant from the upper and lower sides of the rectangle. 
 
 

 
 
 
 
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HDSS 
The total of the five items of the HDSS scale was 10.12 (±3.60) Visit 1 and 7.20 (±2.47) Visit 2 giving a difference 
of 2.92 (±2.51) from Visit 1 minus Visit 2. Table 6 shows in addition also the minimum-maximum values 
together with the median and the first and the third quartile. 
The difference turned out to be statistically different (p < 0.0001) at the Wilcoxon signed-rank test (Table 6.1). 
Furthermore, the mixed factorial ANOVA with gender as a fixed factor showed a statistically nonsignificant 
interaction "gender by visit" (P = 0.8792) leading to conclude that the decrease pattern was similar for females 
and males. (Table 6.2)  
Indeed, the decrease is about of 29.6% for females and of 27.5 for males. 
In addition. the difference between the two visits turned out to be statistically significant (P<0.0001). Finally. 
the two genders showed similar mean values of the total score of the scale both at baseline and at the end of 
the trial as Table 6.3 shows. 
Figure 3 
 
     
 
HDSS: Panel A. Visit 1 
         Panel B. Visit 2 
 
 

 
 
 
 
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HSS 
The total of the four items of the HSS scale was 8.50 (±2.11) Visit 1 and 6.48 (±2.17) Visit 2 giving a difference 
of 2.02 (±1.71) from Visit 1 minus Visit 2. (Table 7) 
The difference turned out to be statistically different (p < 0.0001) at the Wilcoxon signed-rank test. (Table 7.1) 
Furthermore, the mixed factorial ANOVA with gender as a fixed factor showed a statistically significant 
interaction gender by visit (P = 0.0272) leading to conclude that the decrease pattern was not similar for 
females and males. Table 7.2.  
Indeed, the decrease is about of the 27.4% for females and of 15.5% for males (Table 7.3).  In this case, the 
difference between the two visits has to be assessed separately within each gender by means of a multiple 
comparison procedure such as can be done by the Bonferroni’s correction; the decrease is statistically 
significant for both genders.   
Figure 4 
 
 
HSS: Panel A. Visit 1 
Panel B. Visit 2 
 
 
 
 

 
 
 
 
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Table 5 
SHSHD 
Means (SD) of total SHSHD at Visit1 Visit2 by Gender 
 
Label 
Total SHSHD V1 
Total SHSHD V2 
DIFF Total SHSHD V_1 - V_2 
Mean 
Std 
Dev Minimum 
Lower 
Quartile Median 
Upper 
Quartile Maximum 
Lower 
95% 
CL for 
Mean 
Upper 
95% 
CL for 
Mean 
14.04 
7.80 
6.24 
7.79 
3.69 
5.51 
4.00 
4.00 
0.00 
7.00 
5.00 
2.00 
12.00 
8.00 
4.00 
21.00 
9.00 
9.00 
28.00 
19.00 
18.00 
11.83 
6.75 
4.67 
16.25 
8.85 
7.81 
 
Table 5.1 
SHSHD: Tests For Location 
Wilcoxon signed-rank on the difference V1-V2 
 
Test 
Stat pType 
pValue 
Student's t 
8.003921 Pr > |t| 
<.0001 
Signed Rank 
540.5 Pr >= |S| <.0001 
 
Table 5.2 
SHSHD 
Table of ANOVA for repeated measurements 
 
Dependent 
Source 
DF 
SS 
MS FValue ProbF 
Between Subjects 
GENDER 
1 147.01 147.01 
2.57 0.1154 
Between Subjects 
Error 
48 2744.35 57.17 
_ 
_ 
Within Subject 
VISIT 
1 940.28 940.28 
62.18 <.0001 
Within Subject 
VISIT*GENDER 
1 
18.68 18.68 
1.24 0.2720 
Within Subject 
Error(VISIT) 
48 725.88 15.12 
_ 
_ 
 
Table 5.3 
SHSHD 
Means (SD) of total SHSHD at Visit1 Visit2 by Gender 
 
GENDER N 
Mean Visit 1 
SD Visit 1 
Mean Visit 2 
SD Visit 2 
Females 34 
12.91 
7.67 
7.26 
2.99 
Males 
16 
16.44 
7.72 
8.94 
4.77 
 
 
 

 
 
 
 
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Table 6  
HDSS: Table 6 - Descriptive statistics 
Total of HDSS - V1, V2 and difference V1-V2 
 
Label 
Total HDSS V1 
Total HDSS V2 
DIFF Total HDSS V_1 - V_2 
Mean 
Std 
Dev Minimum 
Lower 
Quartile Median 
Upper 
Quartile Maximum 
Lower 
95% 
CL for 
Mean 
Upper 
95% 
CL for 
Mean 
10.12 
7.20 
2.92 
3.60 
2.47 
2.51 
5.00 
5.00 
-2.00 
8.00 
5.00 
1.00 
9.00 
7.00 
2.00 
13.00 
8.00 
5.00 
19.00 
16.00 
9.00 
9.10 
6.50 
2.21 
11.14 
7.90 
3.63 
 
Table 6.1  
HDSS: Tests For Location 
Wilcoxon signed-rank tests on the difference V1-V2 
 
Test 
Stat pType 
pValue 
Student's t 
8.213142 Pr > |t| 
<.0001 
Signed Rank 
479 Pr >= |S| <.0001 
 
Table 6.2  
HDSS 
Table of ANOVA for repeated measurements 
 
Dependent 
Source 
DF 
SS 
MS FValue ProbF 
Between Subjects 
GENDER 
1 28.45 28.45 
1.82 0.1836 
Between Subjects 
Error 
48 749.99 15.62 
_ 
_ 
Within Subject 
VISIT 
1 188.24 188.24 
58.38 <.0001 
Within Subject 
VISIT*GENDER 
1 
0.08 
0.08 
0.02 0.8792 
Within Subject 
Error(VISIT) 
48 154.76 
3.22 
_ 
_ 
 
Table 6.3 
HDSS 
Means (SD) of total HDSS at Visit1 Visit2 by Gender 
 
GENDER N 
Mean Visit 1 
SD Visit 1 
Mean Visit 2 
SD Visit 2 
Females 34 
9.74 
3.48 
6.85 
2.27 
Males 
16 
10.94 
3.80 
7.94 
2.79 
 
 
 

 
 
 
 
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Table 7 
HSS: Table 7 - Descriptive statistics 
Total HSS - V1, V2 and difference V1-V2 
 
Label 
Total HSS V1 
Total HSS V2 
DIFF TOT_HSS1 - TOT_HSS2 
Mean 
Std 
Dev Minimum 
Lower 
Quartile Median 
Upper 
Quartile Maximum 
Lower 
95% 
CL for 
Mean 
Upper 
95% 
CL for 
Mean 
8.50 
6.48 
2.02 
2.11 
2.17 
1.71 
6.00 
4.00 
0.00 
7.00 
5.00 
1.00 
8.00 
6.00 
1.00 
10.00 
7.00 
3.00 
14.00 
13.00 
7.00 
7.90 
5.86 
1.53 
9.10 
7.10 
2.51 
 
Table 7.1 
Table 7.1 - HSS: Tests For Location 
Wilcoxon signed-rank tests on the difference V1-V2 
 
 
Test 
Stat pType 
pValue 
Student's t 
8.361742 Pr > |t| 
<.0001 
Signed Rank 
517.5 Pr >= |S| <.0001 
Table 7.2 
Table 7.2 - HSS 
Table of ANOVA for repeated measurements 
 
Dependent 
Source 
DF 
SS 
MS FValue ProbF 
Between Subjects GENDER 
1 
0.13 0.13 
0.02 0.8983 
Between Subjects Error 
48 377.36 7.86 
_ 
_ 
Within Subject 
VISIT 
1 71.78 71.78 
53.40 <.0001 
Within Subject 
VISIT*GENDER 
1 
6.98 6.98 
5.19 0.0272 
Within Subject 
Error(VISIT) 
48 64.51 1.34 
_ 
_ 
 
Table 7.3 
Table 7.3 - HSS 
Means (SD) of total HSS at Visit1 Visit2 by Gender 
 
GENDER N 
Mean Visit 1 
SD Visit 1 
Mean Visit 2 
SD Visit 2 
Females 34 
8.71 
2.15 
6.32 
2.33 
Males 
16 
8.06 
2.02 
6.81 
1.80