Multicenter Pilot Study to Compare the Efficacy of a Combination of Vaginal Capsules With Acid Boric, L.Gasseri and L.Rhamnosus Versus the Reference Medication in Patients With Vaginal Candidiasis or Bacterial Vaginosis
Phase: PHASE4
Conditions: Candidiasis, Vaginosis, Bacterial
Sponsor: Laboratorios Ordesa

MULTICENTRIC PILOT STUDY TO COMPARE THE 
EFFECTIVENESS OF VAGINAL CAPSULES WITH BORIC ACID 
AND L. GASSERI AND L. RHAMNOSUS VERSUS ANOTHER 
DRUG WITH THE SAME ROUTE OF ADMINISTRATION IN 
PATIENTS WITH VULVOVAGINITIS DUE TO BACTERIAL OR 
CANDIDAL AETIOLOGY 
 
Protocol code: DOBO-01-16 
 
CLINICAL TRIAL PROTOCOL 
(Version 1.5) 
 
 
Principal Investigator and Coordinator: 
 
 
Collaborating Investigators:  
 
Type of Document:  Clinical Trial Protocol 
Development Phase: Postmarketing 
Final Protocol Date: 17 February 2016 
 
 
CONFIDENTIAL 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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PROTOCOL SIGNATURE PAGE 
DOBO-01-16 PILOT STUDY PROTOCOL 
I have read this protocol and agree to conduct this clinical trial in accordance 
with all the protocol’s stipulations, current legislation and the Helsinki 
Declaration. 
 
 
Investigator: 
______________________ 
_______________  
_______________ 
Name  
 
 
Signature 
 
 
Date 
 
Co-investigator: 
______________________ 
_______________  
_______________ 
Name  
 
 
Signature 
 
 
 
Date 
 
 
 
 
 
 
 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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EMERGENCY TELEPHONE NUMBERS 
In the event of an emergency, quickly call the doctor responsible and/or the 
person responsible for monitoring the trial. 
INVESTIGATOR RESPONSIBLE 
 
 
 
TRIAL MONITORING 
Person responsible 
for monitoring the 
trial 
Telephone number 
during office hours 
Telephone number 
after office hours 
Fax number 
 
 
 
 
 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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1 SUMMARY 
1.1 Title 
Multicentric pilot study to compare the effectiveness of vaginal capsules with 
boric acid and L. gasseri and L. rhamnosus versus another drug with the same 
route of administration in patients with vulvovaginitis due to bacterial or candidal 
aetiology. 
1.2 Protocol code 
EUDRACT Code: 2016-000371-24 
Sponsor Code: DOBO-01-16 
1.3 Sponsor 
Laboratorios Ordesa, S.L. 
Carretera del Prat, 9-11; 
08830, Sant Boi de Llobregat, Barcelona. 
Medical Management: 
Dr Mireia Morera Inglés 
Gastroenterology specialist doctor 
Medical Management Technician: 
Marta Guarro Riba 
Dietician-nutritionist 
1.4 Principal investigator and study coordinator 
Dr  
Gynaecology Department 
 
Seville 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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1.5 Collaborating investigators 
Dr Pilar Sanjuán Cárdenas 
Gynaecology Department 
Seville. 
Dr Néstor Herráiz Esteban 
Gynaecology Department 
 Zaragoza. 
Dr Marta Lamarca Ballestero 
Gynaecology Department 
Zaragoza. 
1.6 Centres where the study is scheduled to be performed 
National gynaecology and emergency clinics: 
1. Seville 
 
 
2. Zaragoza 
 
 
1.7 Ethical Review Committees (ERC) 
All the study materials have been reviewed and approved by: 
- 
ERC of the Virgen Macarena-Virgen del Rocío University Hospitals 
(Seville) (rERC) 
- 
Aragon ERC (CEICA) 
The Biomedical Research Ethics Coordinator Committee of Andalucía 
(CCEIBA) will be the trial coordinator in Andalusia. 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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1.8 Study healthcare product and control treatment 
o Study healthcare product: boric acid 150 mg, Lactobacillus gasseri, 
Lactobacillus rhamnosus and prebiotics. 
o Pharmaceutical form: Capsule 
o Route of administration: Vaginal 
o Therapeutic group: D08AD. Antiseptics and disinfectants - Products 
with boric acid. 
• Control treatment (I): Clotrimazole 100 mg (Gine-Canesten®). 
o Pharmaceutical form: Tablet 
o Route of administration: Vaginal 
o Therapeutic 
group: 
D01AC. 
Antifungal 
agents 
for 
topical 
dermatological use - Imidazole and triazole derivatives. 
• Control treatment (II): Clindamycin 100 mg (Dalacin®) 
o Pharmaceutical Form: Suppository 
o Route of administration: Vaginal 
o Therapeutic 
Group: 
J01FF. 
Lincosamide 
macrolides 
and 
Streptogramins - Lincosamides. 
1.9 Clinical trial phase 
Postmarketing. 
1.10 Objectives 
Main: 
To assess the effectiveness of a vaginal application formula with boric acid and 
probiotics for the treatment of symptomatic episodes of vulvovaginitis (VV) 
against a control pharmacological treatment (according to the VV aetiology). 
Secondary: 
• To determine the incidence of recurrence/relapse at 3 months. 
• To assess the level of post-treatment vaginal flora restoration. 
• To characterise the different symptomatic and microbiological profiles of 
vulvovaginitis. 
• To assess the tolerance and safety of the product. 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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1.11 Study design 
Multicentric, Open, Prospective, Drug-controlled Randomised Clinical Trial. 
1.12 Disease under study 
Infectious vulvovaginitis (including vulvovaginal candidiasis and bacterial 
vaginosis). 
1.13 Type of study 
Clinical trial with healthcare products and pharmaceutical specialities. Pilot 
study. 
1.14 Study population 
Women over 18 years of age who consult the gynaecologist due to suspicion of 
infectious vulvovaginitis. 
1.15 Monitoring 
Clever Instruments S.L. will be responsible for the logistics and monitoring of 
the study. 
1.16 Treatment duration 
Healthcare product subject to study:  7 days 
Control drug (I):   
 
 
6 days 
Control drug (II):   
 
 
3 days 
1.17 Expected clinical trial duration 
The planned duration for the recruitment of patients will be 4 months with a 
follow-up period of 3 months. 
 
 
 
 
 
 
 
 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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INDEX 
 
1 
SUMMARY.............................................................................................................. 4 
1.1 
Title .................................................................................................................... 4 
1.2 
Protocol code ..................................................................................................... 4 
1.3 
Sponsor .............................................................................................................. 4 
1.4 
Principal investigator and study coordinator ..................................................... 4 
1.5 
Collaborating investigators ................................................................................ 5 
1.6 
Centres where the study is scheduled to be performed ...................................... 5 
1.7 
Ethical Review Committees (ERC) ................................................................... 5 
1.8 
Study healthcare product and control treatment ................................................ 6 
1.9 
Clinical trial phase ............................................................................................. 6 
1.10 Objectives .......................................................................................................... 6 
1.11 Study design ....................................................................................................... 7 
1.12 Disease under study ........................................................................................... 7 
1.13 Type of study ..................................................................................................... 7 
1.14 Study population ................................................................................................ 7 
1.15 Monitoring ......................................................................................................... 7 
1.16 Treatment duration ............................................................................................. 7 
1.17 Expected clinical trial duration .......................................................................... 7 
2 
INTRODUCTION AND JUSTIFICATION OF THE STUDY ........................ 12 
3 
OBJECTIVES OF THE STUDY ......................................................................... 14 
3.1 
Main objective ................................................................................................. 14 
3.2 
Secondary objectives ....................................................................................... 14 
4 
SOURCE OF INFORMATION ........................................................................... 14 
5 
SCOPE OF THE STUDY ..................................................................................... 14 
6 
STUDY DESIGN ................................................................................................... 14 
6.1 
Type of study ................................................................................................... 14 
6.2 
Study population .............................................................................................. 15 
6.2.1 
Inclusion criteria ....................................................................................... 15 
6.2.2 
Exclusion criteria ...................................................................................... 15 
6.2.3 
Rescue criteria .......................................................................................... 15 
6.2.4 
Discontinuation criteria ............................................................................ 16 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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6.3 
Observation period ........................................................................................... 16 
6.3.1 
Inclusion period ........................................................................................ 16 
6.3.2 
Follow-up period ...................................................................................... 17 
6.3.3 
Baseline Visit – V0 (inclusion) ................................................................. 17 
6.3.4 
Control telephone contact a week after starting the treatment: ................ 18 
6.3.5 
1st Control Visit (V1) ................................................................................ 19 
6.3.6 
Telephone interview (TI) 8 weeks after the inclusion .............................. 20 
6.3.7 
2nd Control Visit (V2) ................................................................................ 20 
6.4 
Description of the intervention ........................................................................ 20 
6.5 
Randomisation ................................................................................................. 21 
6.6 
Concomitant treatments ................................................................................... 21 
6.7 
Compliance with the intervention .................................................................... 21 
6.8 
Pre-determination of sample size ..................................................................... 21 
7 
VARIABLES AND MEASURING INSTRUMENTS ........................................ 22 
7.1 
Main assessment variables ............................................................................... 22 
7.2 
Secondary assessment variables ...................................................................... 22 
7.3 
End points ........................................................................................................ 22 
8 
STATISTICAL ANALYSIS ................................................................................. 23 
8.1 
Descriptive statistics ........................................................................................ 23 
8.2 
Objectives of the study .................................................................................... 23 
9 
ETHICAL CONSIDERATIONS ......................................................................... 24 
9.1 
General considerations ..................................................................................... 24 
9.2 
Assessment of the risk-benefit for the research patients .................................. 25 
9.3 
Information sheet and informed consent (Annexes 1 and 2) ........................... 25 
9.4 
Review of the Ethics Committee ..................................................................... 26 
9.5 
Data confidentiality .......................................................................................... 26 
9.6 
CRF records and reports .................................................................................. 27 
9.6.1 
Monitoring Reports ................................................................................ 27 
9.6.2 
Safety Reports ......................................................................................... 28 
9.6.3 
Protocol Premature Termination or Suspension ................................. 28 
9.6.4 
Final Investigator Report ....................................................................... 28 
9.7 
Monitoring ....................................................................................................... 29 
9.8 
Study budget .................................................................................................... 29 
9.9 
Insurance .......................................................................................................... 29 
10 PRODUCT PREPARATION AND CONSERVATION ................................... 29 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
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10.1 Conditioning .................................................................................................... 29 
10.2 CT sample, product or treatment labelling ...................................................... 30 
10.3 Conservation, distribution and return .............................................................. 30 
11 ADVERSE EVENTS ............................................................................................. 30 
11.1 Types ................................................................................................................ 31 
11.2 Clinical signs secondary to the use of the study drug ...................................... 31 
11.3 Serious Adverse Events ................................................................................... 31 
11.4 Action taken and resolution of AE .................................................................. 32 
11.5 Follow-up of patients with AE ......................................................................... 33 
12 REFERENCES ...................................................................................................... 33 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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GLOSSARY OF ABBREVIATIONS 
AE 
Adverse Event 
BMI 
Body Mass Index 
BV 
Bacterial vaginosis 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CT 
Clinical Trial 
ERC 
Ethical Review Committee 
GCP 
Good Clinical Practice 
IC 
Informed Consent 
ICH 
International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IS 
Information Sheet 
rERC 
Reference Ethical Review Committee 
SAE 
Serious Adverse Event 
STD 
Sexually Transmitted Diseases 
VAS 
Visual Analogue Scale 
VV 
Vulvovaginitis 
VVC 
Vulvovaginal Candidiasis 
 
 
 
 
 
 
 
 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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2 INTRODUCTION AND JUSTIFICATION OF THE STUDY 
Female lower genital tract infections are classified according to the primary 
location of signs and symptoms, theoretically distinguishing between vulvitis, 
vaginitis and endocervicitis. However, in practice, the inflammatory process is 
not usually limited to a single location, so in most patients it is manifested as 
vulvovaginitis (VV)1. 
VV, which can affect both the vaginal mucosa and vulvar skin, is typically 
associated to symptoms and discomfort such as leukorrhea, itching, stinging, 
dysuria and, in some cases, dyspareunia2. Most of these symptoms have an 
infectious origin, which is why their standardised approach involves the use of 
antifungal and/or antibiotic treatments3. 
According to different sources, VV represents more than one third of 
gynaecological consultations. Although most symptomatic episodes are 
effectively controlled with the different therapeutic alternatives available, the 
identification of pathogens resistant to the typically-used treatments4 raises the 
need to look for new alternatives. 
It is estimated that 20-25% of VV are caused by different yeast species 
belonging to the Candida sp family, with the most frequent genus being C. 
albicans (more than 80% of cases). Furthermore, bacterial vaginosis (BV), 
which causes 40-50% of VV, is associated with different microorganisms such 
as 
Gardnerella 
vaginalis, 
Mycoplasma, 
Bacteroides, 
Mobiluncus, 
Peptostreptococcus, among others5. 
Most of these microorganisms are part of the vaginal flora without clinically 
manifesting themselves. Evidence suggests that a change in the flora’s 
balance, particularly in the population of acidifying bacteria in the vaginal 
environment such as Lactobacillus, influences the growth of another type of 
microorganisms that finally cause the patient to become symptomatic6. 
Recurring forms, more typical in the case of candidiasis (≥4 episodes/year) 7,8, 
usually occur during the 3 months after treatment9. The most accepted theory to 
explain this phenomenon is related to the persistence of the pathogen in the 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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vagina, corroborated by the isolation of forms with the same karyotype in 
recurrences10-12. 
Among the different treatment alternatives for infectious VV, the use of boric 
acid has been described as an effective, well-tolerated and particularly useful 
therapeutic option in the case of recurrent VV and candidiasis associated with 
non-albicans Candida13,14. Most studies with vaginal boric acid have studied its 
administration at doses of 600 mg13,14. 
Boric acid is considered a topical action agent that, by combining its 
bacteriostatic, fungistatic and fungicidal properties15, has shown effective results 
in the control of infectious VV symptoms16. Although its mechanism of action is 
not clearly defined, a potential inhibitor effect of fungal oxidative metabolism 
that favours the properties previously described has been proposed17. 
In addition, many studies have been carried out in recent years that show 
positive results regarding the use of probiotics in patients with VV of infectious 
origin18. The use of these products in the treatment of infectious VV is based on 
the role of Lactobacillus as bacterial flora, maintaining a vaginal pH that 
promotes balance in the vaginal microenvironment, controlling the growth of 
potential pathogens that cause VV and reducing the possibility of 
overcolonisation by Candida18. There is little evidence available regarding the 
simultaneous use of antiseptics such as boric acid with probiotics to treat this 
type of patients. 
De Seta and col. carried out a comparative study of conventional therapies for 
BV (Clindamycin) and VC (clotrimazole) and a combination of boric acid with 
probiotics (Lactobacillus sp.) in which a better concentration of lactobacilli was 
observed in the group treated with boric acid + probiotics 3 weeks after 
completing the treatment. These patients also registered a significant 
improvement in symptoms such as stinging, itching, the presence of leukorrhea 
and fetid vaginal discharge19. 
For all these reasons, the combination of boric acid with probiotics is postulated 
as a potential therapeutic alternative for the treatment of infectious VV, which 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
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may end up being incorporated into the usual therapeutic arsenal against VV, 
and should therefore be compared to other current reference treatments in daily 
clinical practice. 
3 OBJECTIVES OF THE STUDY 
3.1 Main objective 
To assess the effectiveness of the vaginal capsule with boric acid and L. 
gasseri and L. rhamnosus for the treatment of symptomatic episodes of 
vulvovaginitis (VV) against a control pharmacological treatment (according to 
the VV aetiology). 
3.2 Secondary objectives 
• To determine the incidence of recurrence/relapse at 3 months. 
• To assess the level of post-treatment vaginal flora restoration. 
• To characterise the different symptomatic and microbiological profiles of VV. 
• To assess the tolerance and safety of the product. 
4 SOURCE OF INFORMATION 
The information will be obtained from the data collected during the patient’s 
clinical visit, as well as from the data recorded by the patients and the self-
administered scales of the Patient Questionnaires and Notebooks that will be 
handed to them by the investigators. 
5 SCOPE OF THE STUDY 
Outpatient gynaecology and national emergency clinics. 
6 STUDY DESIGN 
6.1 Type of study 
Multicentric, open, prospective, drug-controlled, randomised pilot clinical trial in 
patients with vulvovaginitis of bacterial and candidal aetiology. Patients will be 
randomly assigned to two groups (healthcare product subject of study (boric 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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acid + L. gasseri and L. rhamnosus) or control treatment). The ratio will be 1:1 
between the study product and the control treatment. 
6.2 Study population 
6.2.1 Inclusion criteria 
• Women ≥ 18 years of age. 
• Women with clinical manifestations of infectious VV. 
• Women who agree to participate by signing the informed consent form. 
6.2.2 Exclusion criteria 
• Symptoms (high suspicion) compatible with infection due to Chlamydia 
trachomatis, Trichomona vaginalis, Neisseria gonorrhoeae or Herpes 
simplex. 
• Use of antifungal or probiotic agents during the last 2 weeks prior to the 
study. 
• Patients who are receiving any other treatment with probiotics, vitamin 
complexes that may significantly interfere with the study assessments. 
• Pregnant patients. 
• Patients who may become pregnant (if there is a reasonable doubt about the 
possibility of pregnancy at the time of inclusion or during the study a blood 
pregnancy test will be performed to rule out this possibility). 
• Patients who are menstruating at the time of inclusion. 
• Breast-feeding patients. 
• Immunocompromised patients. 
• Patients who, based on the investigator’s criteria, are not expected to 
complete the follow-up. 
6.2.3 Rescue criteria 
In cases where the patient requires “rescue treatment”, the treatments will be 
crossed. In the event of changing treatment group (crossover), the patient will 
be considered to be back at V0 and the tests/examinations corresponding to the 
baseline visit will be repeated. 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
Protocol DOBO-01-16 version 1.5 of 17 February 2016    
 
 
      
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The patient will change group to receive alternative treatment in the following 
cases: 
• Patient with hypersensitivity to the first assigned treatment. 
• Worsening of symptoms within 3-4 days of starting the assigned treatment. 
• Evidence or indications of lack of effectiveness after the first assigned 
treatment. 
• Patient who demonstrates a willingness to change treatment. 
• In cases where the perceived lack of effectiveness is associated with a 
suspected mixed aetiology infection (candidal and bacterial): 
 If they are in the control group, they will be changed to the treatment 
under study (boric acid + L. gasseri and L. rhamnosus). 
 If they are in the study group, they will be changed to the antifungal 
treatment (Gine-Canesten®; Clotrimazole 100 mg). If this treatment 
fails, BV will be treated with antibiotic treatment (Dalacin®; 
Clindamycin 100 mg). 
6.2.4 Discontinuation criteria 
• Patients who, during the study period, receive/use some type of treatment 
and/or intervention (probiotics, vitamin complexes or vaginal showers) that 
may significantly interfere with the study assessments. 
• Patients who, even while receiving the rescue treatment, show a lack of 
effectiveness*. Patients who, after the baseline visit, are suspected to have 
an infection due to Chlamydia trachomatis, Trichomona vaginalis, Neisseria 
gonorrhoeae or Herpes simplex. 
 
*These patients will also be subject to follow-ups during the 3 months of study. 
6.3 Observation period 
6.3.1 Inclusion period 
The gynaecologist will choose the patients as they go to the clinic and meet the 
inclusion and exclusion criteria, according to the consecutive sampling 
technique. The assignment of the study treatment will be randomised, 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
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depending on the previously-established code that will be assigned to each 
patient as they are included in the study. A recruitment period of 4 months and 
a follow-up period of 3 months are planned. Recruitment of participating centres 
will be competitive. 
6.3.2 Follow-up period 
Follow-up will be 3 months from the inclusion visit (V0). Patients should attend 
two control visits in person and answer two telephone interviews. 
6.3.3 Baseline Visit – V0 (inclusion) 
After the case history and initial examination, which will serve to substantiate 
the suspicion of VV due to infection, patients will be recommended to participate 
in the trial provided they meet the inclusion/exclusion criteria. Once the patient 
Information Sheet (PIS) has been handed over, the patient has signed the 
Informed Consent (IC) form and the investigator has verified that the patient 
meets the inclusion and exclusion criteria, they will proceed to fill in the CRF 
baseline visit sections. 
During this first visit, socio-demographic data, relevant clinical history and 
gynaecological history will be recorded. The investigator will assess the 
patient’s symptoms by recording the presence of clinical signs and symptoms of 
infectious VV (stinging, itching, erythema, oedema, abnormal vaginal discharge, 
etc.) and the Sobel score20,21 (see section 7.0).The vaginal pH determination 
test will then be carried out and the samples for the different laboratory tests will 
be collected, which will consist of: spreading the vaginal discharge sample on a 
slide to subsequently count the Lactobacillus spp. and collecting the discharge 
sample with a swab that will also be used for the diagnostic confirmation culture 
and for the fresh vaginal smear. The samples will be stored properly according 
to the instructions specified in the manual of use of the sampling kit until the 
samples are collected. 
The patient will be given the treatment corresponding to the code assigned to 
her, reminding her that she has the possibility of changing treatment group, at 
the time that she deems appropriate. If the assigned treatment is ineffective or 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
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is not tolerable, the patient may contact the hospital to bring the first control visit 
forward and request a change of treatment. 
During the baseline visit, the patient will be given a CRF which she must fill in 
and return at the end of the visit and a card with a link to the online home CRF 
(Patient diary) that must be filled in over the course of the study. The home CRF 
will be used to monitor the patient during the follow-up weeks. The home CRF 
may also be delivered on paper and the patient must deliver it later. 
The investigator will give the patient product for one treatment cycle (which may 
range from 3 days (Clindamycin) to 7 days (boric acid 150 mg, L. gasseri, L. 
rhamnosus)). 
The patient must return the empty blisters and/or surplus product during the first 
control visit. One week after the baseline visit, the patient will be contacted by 
telephone to find out her condition and if she is responding to the treatment, to 
assess the need for a rescue treatment or to arrange the first control visit. The 
first in-person control visit (V1) will be carried out at least 2 weeks after the 
treatment has been completed. 
6.3.4 Control telephone contact a week after starting the treatment: 
The investigator will contact the patient and will proceed with a brief 
questionnaire to decide whether the patient responds correctly to therapy 
depending on the symptoms the patient will describe and their severity. The 
different options in this scenario are: 
Patient condition 
Investigator’s action 
Disappearance of 
symptoms 
In-person appointment (V1) within two weeks of the 
telephone contact and the end of the treatment (21 days 
from V0). 
Improvement of symptoms, 
but the patient still has mild 
clinical signs and symptoms 
In-person appointment (V1) within two weeks of the 
telephone contact and the end of the treatment (21 days 
from V0); we recommend that she request an 
appointment if there is no improvement in the following 
days. If there is a suspicion that there is still an 

Multicentric pilot study to compare the effectiveness of vaginal capsules with boric acid and L. Gasseri and L. 
Rhamnosus versus another drug with the same route of administration in patients with vulvovaginitis due to bacterial or 
candidal aetiology. 
 
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infection, rescue treatment will be recommended. 
Deterioration/Lack of 
effectiveness 
The patient must arrange an appointment as soon as 
possible to proceed with the alternative rescue 
treatment. 
Depending on the investigator’s criteria, an appointment will be made with the 
patient for an in-person visit. When making an in-person appointment, the 
investigator will take into account the date of the patient’s last menstruation to 
prevent it from coinciding with the patient’s 1st control visit. To this end, the 
investigator may slightly extend the 2-week margin previously established 
between the call and the control visit. 
6.3.5 1st Control Visit (V1) 
The second in-person visit of the study will be carried out approximately two 
weeks after completing the treatment. 
As with V0, the investigator and the patient will have a CRF that they must fill in. 
The investigator will record the data regarding the clinical examination and 
repeat the tests and collect the samples corresponding to V1. The results of the 
analytical tests carried out during V0 will also be recorded. 
The patient will fill in the corresponding CRF and return it at the end of the visit. 
An approximate time and date will be specified for the follow-up telephone 
interview around 2 months after the inclusion and an appointment will be made 
for the final follow-up visit (3 months from the patient’s inclusion in the study). 
If the investigator suspects a potential lack of effectiveness of the assigned 
treatment, rescue with the other therapeutic alternative of the study may be 
suggested according to the aetiology of the VV. In the event of crossing 
treatments, this visit will be considered the new baseline visit (V0), for the 
purpose of collecting data and samples. The same procedure will be followed if 
the second visit is brought forward at the patient’s request. 

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6.3.6 Telephone interview (TI) 8 weeks after the inclusion 
Approximately 8 weeks after the baseline visit, the investigator will telephone 
the patient to interview her, with the main objective of knowing if there are signs 
of recurrence of VV. 
The patient will confirm whether she is regularly filling in the online CRF and 
that she is not taking/using any products that may interfere with the assessment 
of the study objectives (see section 6.2.4: Discontinuation criteria). 
The investigator will fill in a short form as a summary of the interview and 
confirm the appointment for the third and last in-person visit (V2). The patient 
will be reminded that, if the home CRF is completed on paper, she must deliver 
it during the last visit. 
6.3.7 2nd Control Visit (V2) 
Three months after the baseline visit, the patient will go to the last control visit, 
to assess the incidence of VV recurrences during the follow-up period. The 
investigator will perform, as in all visits, the corresponding case history and 
examination and will record data on clinical manifestations. This visit does not 
include taking samples for laboratory tests. If the patient has filled in the home 
CRF on paper, she must deliver it during this last visit. 
6.4 Description of the intervention 
The intervention will be assigned to each patient according to the code 
assigned by order of inclusion in the study and will be used for randomisation. 
In the case of the control group, the specific treatment will be indicated after 
randomisation depending on the aetiology of the VV: 
1) Candidal VV: 
a. Vaginal capsule with 150 mg of Boric Acid and Probiotics (L. gasseri 
and L. rhamnosus) plus prebiotics (1 capsule/24h for 1 week) 
b. Clotrimazole vaginal tablet 100 mg/24h, 6 days (Gine-Canesten®) 
2) Bacterial VV: 

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a. Vaginal capsule with 150 mg of Boric Acid and Probiotics (L. gasseri 
and L. rhamnosus) plus prebiotics (1 capsule/24h for 1 week) 
b. Clindamycin vaginal suppository 100 mg/24h, 3 days (Dalacin®) 
6.5 Randomisation 
Patients will be randomly assigned to two groups according to the product 
under study or control product (two interventions considered as standard clinical 
practice based on the suspicion of aetiology associated to the VV). Random 
assignment of patients will be implicit in the code that will be assigned to them 
consecutively in each centre at the time of inclusion. The proportion of patients 
will be 1:1 between the study group and control group. Random lists will be 
generated with a software using blocks with up to three repetitions of the same 
treatment. 
6.6 Concomitant treatments 
The existence of concomitant treatments will be recorded. Only treatments that 
can influence the trial results will be reason for withdrawal of the product 
(section 6.2.4). 
6.7 Compliance with the intervention 
Compliance with the indicated intervention will be checked with the data 
recorded by the patient in the home CRF, with direct questions during the 
second visit (first control visit) and empty blisters returned by the patient. 
6.8 Pre-determination of sample size 
A minimum of 50 patients are expected to be distributed between the study 
group (boric acid 150 mg, L. gasseri, L. rhamnosus) and control group 
(Clotrimazole 100 mg or Clindamycin 100 mg). 

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7 VARIABLES AND MEASURING INSTRUMENTS 
7.1 Main assessment variables 
• Presence and severity of clinical signs/symptoms associated to VV that the 
patient presents. 
• Sobel score: Semi-quantitative scale where itching, erythema, oedema and 
stinging are indicated from 0 to 3: Absent (0), mild (1), moderate (2), severe 
(3)20,21. 
• Vaginal pH (to be determined by placing a vaginal discharge sample in 
contact with reactive pH indicator strips). 
• Fresh vaginal smear (presence of “clue cells” or hyphas). 
• Vaginal discharge sample culture. 
• Lactobacillus spp. count in vaginal discharge. 
• Relevant gynaecological history (including previous VV episodes). 
• Compliance with the treatment and the gynaecologist’s recommendations. 
• Adverse Events. 
7.2 Secondary assessment variables 
• Socio-demographic data (age, marital status, etc.). 
• Anthropometric data (height, weight, BMI). 
• Relevant clinical history. 
• Gynaecological history (surgery, STD, etc.). 
• Current gynaecological situation (menopause, parity, stable partner, use of 
contraceptive methods). 
7.3 End points 
• Number of patients with VV recurrence during the follow-up period in each 
treatment group (incidence of recurrences after 3 months). 
• Number of patients with resolved symptoms in each group 2 weeks after 
finishing the treatment. 
• Changes in vaginal pH level in each group. 
• Number of patients with “clue cells” or hyphas in the fresh smear. 

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• Profile and proportion of pathogen isolation in culture. 
• Increase in the population of Lactobacillus spp. post-treatment. 
• Rescue success rate in different scenarios. 
• Relationship between compliance and treatment effectiveness. 
• Relationship between compliance and recurrence after 3 months. 
• Percentage of cases with good treatment tolerability. 
• Rate of adverse events. 
• Treatment tolerability. 
• Proportion of patients with mixed infections (VC + BV). 
8 STATISTICAL ANALYSIS 
All data will be analysed using the SPSS-Windows statistical package. 
8.1 Descriptive statistics 
Descriptive statistics will be made of all the variables included in the CRF. 
Categorical variables will be presented in the form of lists of frequencies and 
proportions. For quantitative variables (continuous or ordinal), central tendency 
(mean, medium, mode) and dispersion indices (standard deviation and 
maximum and minimum values) will also be presented. 
8.2 Objectives of the study 
The analysis of the main objective will focus on the comparison of the 
effectiveness of the product under study (boric acid + L. gasseri and L. 
rhamnosus) and that of the control treatment with solid vaginal forms, according 
to the usual clinical practice (clotrimazole or clindamycin) and assessed 
according to the patient’s clinical symptom scores (VAS, Sobel score) 
approximately 2 weeks after the end of the treatment. To do this, T tests for 
independent samples or non-parametric Mann–Whitney U tests will be used. 
For the secondary objectives, the level of restoration of vaginal flora will be 
assessed by comparing the Lactobacillus count in baseline discharges and 2 
weeks after treatment through T tests for related samples or non-parametric 

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Wilcoxon or McNemar tests. The incidence of recurrences/relapses at 3 months 
will be studied by means of proportion comparison tests (Pearson’s chi-squared 
test). The characterisation of the different symptomatic and microbiological 
profiles of VV, as well as the tolerability, compliance and adverse events, will be 
analysed through descriptive statistics. 
The possibility of carrying out additional analyses, depending on the results, 
with the relevant statistical tests in each case is not ruled out. 
9 ETHICAL CONSIDERATIONS 
9.1 General considerations 
This study must be carried out in accordance with the provisions of this protocol 
and the standards of Good Clinical Practice (GCP), as described in: 
• ICH Harmonised Tripartite Guideline for Good Clinical Practice, 1996. 
Directive 91/507/EEC: Good Clinical Practice Guidelines for trials on 
medicinal products in the European Community. 
• Helsinki Declaration in its latest revised version (Fortaleza, 2013) (Annex-
1). 
The study will only begin after obtaining written authorisation from the Ethical 
Review Committee of the Macarena-Virgen del Rocío University Hospitals in 
Seville, which act as a reference centre (rERC). 
Except for emergency situations, changes or deviations from the protocol will 
not be permitted without documented approval. 
The rERC shall be informed of any changes and shall approve in writing any 
changes or deviations that may increase the risks of the subject and/or may 
adversely affect the rights of the patient or the validity of the research. This 
stipulation does not apply to changes made to reduce inconveniences or 
prevent risks to subjects or to changes affecting the administrative aspects of 
the study (e.g. change of monitor). 

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9.2 Assessment of the risk-benefit for the research patients 
In any case, the patient will receive a specific therapeutic alternative, in 
accordance with the diagnosis established by the investigator, so the suitability 
of the study treatments will not result in an increase in risk for the patient. 
If the investigator or patient perceive a lack of effectiveness of the treatment, 
the patient may be rescued with the therapeutic alternative considered within 
the study. 
9.3 Information sheet and informed consent (Annexes 1 and 2) 
The investigator is responsible for ensuring that the patient (and/or legally 
authorised representative) understands the risks and benefits of her 
participation in the study, answering any questions that may be raised during 
the study, and sharing any new information that could influence her decision to 
continue to participate in the study in a timely manner. 
The patient (or her legal representative) shall be informed of the characteristics 
of the CT, orally and in writing, by means of the PATIENT INFORMATION 
SHEET. 
Finally, after being fully informed of the implications and restrictions of the 
protocol, having answered her questions and before starting the study, the 
patient will be asked to provide written INFORMED CONSENT. The patient 
information sheet model and the informed consent form are attached as an 
annex to this protocol. By signing and dating the informed consent form, the 
subject declares her voluntary participation and intention to comply with the 
Study Protocol and the Investigator Instructions and to respond to the questions 
raised during the Study. 
The subject will keep the information sheet throughout the study, with all 
relevant study information, including the investigator’s contact information. The 
investigator must keep the informed consent in the study file. 

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9.4 Review of the Ethics Committee 
This protocol will be approved by the Ethical Review Committee of the Virgen 
Macarena-Virgen del Rocío University Hospitals in Seville, which will act as a 
reference committee for the other participating centres. 
Any member of the Ethics Committee who has direct contact with this study as 
an investigator or as a member of staff of the centre will abstain from voting to 
approve the protocol. 
All changes to the protocol will be specified as an amendment. The method for 
performing amendments will follow the standardised procedures according to 
RD223/2004. 
9.5 Data confidentiality 
By signing the protocol, the investigator agrees to keep all the information 
provided by the Sponsor in strict confidence and to insist on his team and the 
rERC keeping this confidence. The study documents provided by the Sponsor 
(protocols, investigator manual, CRFs and other materials) must be 
conveniently stored in the investigator’s file, to ensure their confidentiality. The 
investigator will in turn ensure that the investigator’s file is kept in accordance 
with the conditions specified in Directive 2001/20/EC. 
The investigator will ensure the anonymity of the participants. Both in CRFs and 
other CT documents, subjects cannot be identified by their names but by an 
identification code. The investigator will keep a record of the inclusion of 
subjects showing the codes, names and contact information. 
The information provided to the investigator by the Sponsor may not be 
disclosed to third parties without the direct written authorisation of the sponsor, 
except to the extent necessary to obtain the informed consent of the patients 
who wish to participate in this CT. 
The information obtained will be considered strictly confidential on the basis of 
Organic Law 15/1999, of 13 December, on Personal Data Protection. (Official 
State Gazette No. 298, of 14-12-1999, p. 43088-43099) and its development 

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regulations. Medical data will be collected in accordance with Recommendation 
No. R (97) 5, of 13 February 1997, by the Committee of Ministers of the Council 
of Europe to the Member States on Medical Data Protection. 
9.6 CRF records and reports 
The investigator must ensure the accuracy, completion and relevance of the 
data communicated to the sponsor in the CRF and in all the reports requested. 
The data will be recorded in an online CRF to which only the investigator will 
have access through a user and password, both of which will be personal and 
non-transferable. All data obtained will be stored in an electronic file restricted 
to the staff of each centre and for which the principal investigator will be 
responsible. 
Any change or correction to a CRF must be requested to the CRO responsible 
for monitoring, Clever Instruments S.L., by contacting the person responsible for 
the data management designated by the study sponsor. Changes must be 
documented and the investigator must keep records of changes and 
corrections. 
The investigators or the institution must keep the CT documents, as required by 
applicable regulations. The investigator or institution must take measures to 
prevent the accidental or premature destruction of these documents. 
At the request of the monitor, auditor, ERC or regulatory authority, the 
investigator/institution must have all records related to the CT available. 
9.6.1 Monitoring Reports 
The sponsor or CRO must send written summaries of the trial status to the 
rERC annually, or more frequently, if required by the rERC. 
The sponsor or CRO must provide timely written reports to the rERC and, 
where relevant, to the institution on changes that significantly affect the 
development of the trial and/or increase the risk to the subjects. The 
investigator must supervise and sign these reports. 

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9.6.2 Safety Reports 
The sponsor must be immediately informed of all serious adverse events, 
except those specified in the protocol or other document. These will be promptly 
reported in writing in detail and within the periods specified by the sponsor in 
the protocol. These follow-up reports must identify the subjects using the codes 
assigned in the CT and not by name, personal identification numbers and/or 
addresses. 
9.6.3 Protocol Premature Termination or Suspension 
If the study ends prematurely or is suspended for any reason, the 
investigator/institution must promptly inform the subjects of the study, providing 
them with appropriate therapy and follow-up. In addition: 
• If the investigator terminates or suspends the study without prior agreement 
with the sponsor, the investigator must inform the institution where relevant, 
and the investigator/institution must promptly inform the sponsor and the 
ERC, as well as send a detailed written explanation of the termination or 
suspension to the sponsor and the ERC. 
• If the sponsor terminates or suspends the study, the investigator must 
promptly inform the institution where relevant and the investigator/institution 
must promptly inform the ERC, sending a detailed written explanation of the 
termination or suspension. 
• If the ERC withdraws the approval of the study, the investigator must inform 
the institution where relevant and the investigator/institution must promptly 
notify the sponsor and provide a detailed written explanation. 
9.6.4 Final Investigator Report 
When the study is completed, the investigator, where relevant, must inform the 
institution. The investigator/institution must provide the ERC with a summary of 
the study’s results. 

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9.7 Monitoring 
It is established that the study will be carried out at regular intervals. Monitoring 
will be carried out by the monitor(s) designated by the Sponsor. Regular 
contacts will be established between the Monitor(s) and the Investigator. 
The Monitor will be responsible for verifying compliance with the protocol and 
the integrity, consistency and reliability of the data entered in the CRFs. To do 
this, the monitor must be able to access the participant’s medical history and 
other documents. The investigator or his collaborators agree to cooperate with 
the monitor to ensure that the detection of any problem during the monitoring is 
resolved. 
Extraordinary audits can be carried out to guarantee the validity of the study 
data and compliance with the regulations in force. 
9.8 Study budget 
The economic aspects of the study are detailed in the corresponding annex in a 
separate document. 
9.9 Insurance 
The sponsor of the study (Laboratorios Ordesa S.L.) will subscribe to an 
insurance policy that covers any damages that may be caused to the 
participants as a result of the study. 
This insurance will also cover the responsibilities of the sponsor, the 
investigator and his collaborators and the head of the centre where the clinical 
study is carried out. 
10 PRODUCT PREPARATION AND CONSERVATION 
10.1 Conditioning 
The product under study (vaginal capsule with 150 mg of boric acid, 
Lactobacillus gasseri, Lactobacillus rhamnosus.) must be received by the 
hospital pharmacy, which will be responsible for the control, distribution and 

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return of the product under research. Enough product for 70 patients will be 
assigned, taking into account that the study group must receive product for one 
treatment week (1 box) during the baseline visit. 
10.2 CT sample, product or treatment labelling 
As this is an open study, products administered to patients will not have any 
special labelling and will be labelled in the same way as they are usually on the 
market. 
10.3 Conservation, distribution and return 
Products provided for the CT must be stored at room temperature in a restricted 
area free from extreme environmental conditions. This should be an area that 
can be closed, with access limited to the investigator. 
When received, an inventory of the shipment must be made. The document 
must be signed by the investigator or authorised person and a copy will be sent 
to the Monitor and another to the Investigator’s Archive. 
The investigator will be responsible for the return of the products, and will 
document any discrepancies in the formula stock records. 
11 ADVERSE EVENTS 
The Adverse Events (AE) that appear during the study will be assessed. An AE 
is any harmful event in a patient after randomisation and during a study, even if 
it is considered not related to the treatment of the study. In this CT, AEs will be 
collected and recorded in the CRF, provided that they are serious (if they 
cause clinical signs or symptoms and are considered clinically 
significant) and/or are related to the treatments under study. 
Diseases or medical conditions that were present before starting the medication 
under study will only be considered AEs if there is a worsening after the start of 
the study treatment (any procedure specified in the protocol). 
As far as possible, AEs will be described according to: 
• Duration (start and end dates). 
• Degree of severity (mild, moderate, severe). 
• Relationship with medication under study (suspected/not suspected). 

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• Action(s) taken to correct it. 
11.1 Types 
Any adverse and unintentional sign (abnormal and clinically significant 
analytical result) associated or not to the use of the drugs will be considered an 
adverse event. 
11.2 Clinical signs secondary to the use of the study drug 
i. 
Vaginal itching sensation13 
ii. 
Water discharge during treatment13 
iii. 
Vaginal erythema13 
iv. 
“Sandy” sensation during sexual intercourse14 
v. 
Acute systemic toxicity due to boric acid14 
vi. 
Chronic toxicity due to the use of boric acid14 
vii. 
Bacteraemia caused by Lactobacillus spp.17 
 
11.3 Serious Adverse Events 
 
Information on Serious Adverse Events (SAE) and Unexpected Serious 
Adverse Reactions (USAR) with suspicion of causal relationship with the 
treatments under study will be collected and recorded in the Serious Adverse 
Events notification form (RD223/2004). These serious adverse events must also 
be notified to the Spanish Agency of Medicines and Medical Products (AEMPS). 
The AEMPS will be notified by the ESIC, for which reason the investigator must 
notify them within 24 hours of knowing. Only serious, unexpected AEs related to 
treatments under study will be reported to the AEMPS. 
Any adverse event or adverse reaction is considered to be a SAE or USAR 
when, at any dose, it: 
• Leads to the death of the patient, 
• Threatens the life of the subject, 
• Forces the subject to be hospitalized or to extend their stay, 
• Leads to permanent or significant disability, or 
• Results in a congenital anomaly or malformation. 

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The intensity of the AE will be classified as mild, moderate or severe. The 
investigator will record the relationship of the study product with the AE 
according to the following causality terms: 
- 
Related: The AE follows a reasonable time sequence from the moment of 
exposure to the product. It cannot be explained by the subject’s clinical 
condition or by the study procedures/conditions. The AE decreases after the 
discontinuation of the study product and reappears once the study product is 
re-administered. 
- 
Potentially related: The AE follows a reasonable time sequence from the 
time of exposure to the product, but may have been caused by the subject’s 
clinical condition or by the study procedures/conditions. 
- 
Unlikely related: The temporary association between the AE and the study 
product is such that it is unlikely that there is any reasonable relationship 
between them. The relationship is not likely due to other possible 
explanations. 
- 
Not related: The AE has undoubtedly been caused by the subject’s clinical 
condition or by the procedures/conditions of the CT. A reasonable 
explanation must be given, for example, that the product has not been 
consumed under research or an incompatible temporary relationship. 
- 
Not assessable: The report indicating an adverse reaction cannot be judged 
because the information available is insufficient or contradictory, and no 
extra data can be added or verified. 
11.4 Action taken and resolution of AE 
The investigator will record the action(s) taken with the product and the effects 
of the event for each of the AEs, according to the following: 
- 
Action taken in relation to the product 
- 
Resolution 
 

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11.5 Follow-up of patients with AE 
Patients can be withdrawn from the CT at any time. Patients who have been 
withdrawn from the study due to an AE must be monitored by the investigator 
until the clinical result of the AE is determined. 
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3. Cancelo Hidalgo MJ, Beltrán-Vaquero D, Calaf Alsina J, Campillo Arias-
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17. De Seta F, Schmidt M, Vu B, Essmann M, Larsen B. Antifungal mechanisms 
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18. Falagas ME, Betsi GI, Athanasiou S. Probiotics for prevention of recurrent 
vulvovaginal candidiasis: a review. J Antimicrob Chemother. 2006; 58: 266-72. 
19. De Seta F, Rizzante E, Luksa V, De Leo R. Approcci alternativi alle 
infezioni del basso tratto genitale: il ruolo di un nuovo simbiótico a base 
di inulina, acido borico e una miscela L gasserii e L rhamnosus. Estratti 
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