bacterial vaginosis ( bv ; nonspecific vaginitis ) is the most common outpatient vaginal disease in women of childbearing age .
bv is judged as an inflammatory process associated with the disruption of the normal vaginal lactate producing bacteria ( mainly species of lactobacillus genus ) followed by an overgrowth of gardnella and other anaerobic species .
strong sexual activity , use of tight clothes , vaginal douching , and prolonged exposure to local irritants ( i.e. , scented soap ) are considered as risk factors for bv [ 4 , 5 ] .
symptoms of bv include a change in the amount , colour , or smell of normal vaginal discharge and vulvovaginal discomfort ( irritation , itching , and burning ) .
an increased local ph ( > 4.5 ) and a positive whiff - test of the vaginal fluid support the diagnosis of bv . a vaginal swab test
importantly , bv can be associated with serious sequelae such as abortion , preterm delivery , and increased susceptibility to hiv infection and other sexually transmitted infections .
the watery extract of triticum vulgare , the active ingredient of fitostimoline ( farmaceutici damor s.p.a . , naples - italy ) , increases the healing processes both in cutaneous and noncutaneous tissues [ 6 , 7 ] ; gynaecological formulations of fitostimoline ( vaginal cream , ovule , and vaginal washing ) are currently approved and marketed for the topical treatment of different inflammatory and dystrophic processes of the female reproductive system .
this study was performed to evaluate the efficacy and safety of fitostimoline 20% vaginal cream , 600  mg ovules , and 40% vaginal washing in comparison with benzydamine hydrochloride 0.5% vaginal cream and 0.1% vaginal washing ( tantum rosa , angelini s.p.a . ,
benzydamine hydrochloride is a local anti - inflammatory and analgesic agent   marketed worldwide for the symptomatic treatment of gynaecological conditions and widely used in the topical treatment of bacterial vaginosis .
women aged between 16 and 70 years with evidence of bv were enrolled ; patients entered the study if they had at least two subjective symptoms and two objective signs ( at least of moderate degree ) of vaginal inflammation .
other gynaecological diseases ( in addition to bv ) , immunosuppressive diseases ( i.e. , hiv infection ) , or treatments with antibiotics , anti - inflammatory agents , analgesics , antineoplastic , or immunosuppressive drugs in the previous 10 days were considered as exclusion criteria .
the study was performed according to an open - label , controlled , randomized , multicentre , 3-arm ( fitostimoline cream , fitostimoline ovules , and tantum rosa cream ) parallel design .
the selection of an open - label design was due to the use of different pharmaceutical forms during the study . at the baseline visit ,
eligible patients were randomly assigned to receive one of the following treatments for 7 consecutive days : fitostimoline vaginal cream + fitostimoline vaginal washing , fitostimoline ovules + fitostimoline vaginal washing or tantum rosa vaginal cream + tantum rosa vaginal washing .
vaginal creams and ovules were applied in the evening , vaginal washings in the morning .
concomitant treatments with systemic or topical antibiotics , anti - inflammatory agents , or analgesics were not allowed .
a vaginal swab test was performed at the baseline visit ; in case of specific pathogen organisms growth , patients were treated after the 7-day control visit with antibiotics or antimycotics according to the result of the antibiogram . for ethical reasons , experimental treatments were started before the results of vaginal swab were available ( some days required ) .
signs and symptoms of vaginitis were evaluated during the baseline visit and then after 7 days of treatment . a third follow - up visit 7 days after the end of treatment was performed only in those patients with negative vaginal swab and an incomplete symptoms improvement ( 60% ) .   six subjective symptoms ( burning , pain , itching , vaginal dryness , dyspareunia , and dysuria ) and 4 objective signs ( leucorrhoea , vulvar erythema , vulvar oedema , and presence of abrasion / erosion ) of vaginitis were evaluated by a semiquantitative scale ( 0 = absence ; 1 = mild ; 2 = moderate ; 3 = severe ) .
the primary efficacy endpoint was the percentage of patients with therapeutic success , defined as resolution of signs and symptoms of vaginitis ( total symptoms score < 2 ) at the end of treatment .
for the overall assessment of clinical outcome ( resolution , improvement , and failure : see the following ) , the results at the end of treatment were taken into account , except for those patients requiring a further follow - up visit .
the secondary efficacy variables were ( 1 ) the evolution of signs and symptoms of vaginitis , defined as the percentage of patients with resolution ( overall score  2 ) , improvement ( decrease of the overall score versus baseline  50% ) , or failure ( decrease of the overall score < 50% ) and ( 2 ) the change from the baseline of the semiquantitative score , expressed for both single signs and symptoms and their sum ( total symptoms score , tss ) .
adverse events occurrence and vital signs ( blood pressure , heart rate , body temperature ) were evaluated as safety parameters .
the sample size was calculated on the hypothesis of a therapeutic success rate of 95% in all groups , with a hierarchical order of comparison fitostimoline cream versus fitostimoline ovules and then pooled fitostimoline versus tantum rosa .
the two fitostimoline forms were considered therapeutically equivalent if the 95% ci of their difference was between 10% and + 10% .
once that the therapeutic equivalence between fitostimoline cream and ovules was demonstrated , the main efficacy comparison was performed between the pooled fitostimoline group and tantum rosa .
a sample size of approximately 100 patients per group was calculated to have a power of 90% of rejecting a hypothesis of nonequivalence or inferiority , respectively , at a level of significance of 0.025 in a one - sided test .
the following populations were considered for data analysis : intention to treat ( itt ) , that is , all randomized patients ; restricted intention to treat ( ittr ) , which included all randomized patients with at least one postbaseline control ; per protocol ( pp ) , that is , all itt population who do not have any major protocol violation ; safety population which included all randomized patients who received at least one application of the study medication .
the evaluation of primary efficacy endpoint was performed in both the ittr and in the pp population , while the analysis of the secondary efficacy endpoints was performed in the ittr population only ; safety variables were analyzed in the safety population .
the comparison between groups of categorical variables was performed by using the chi - square or the fisher exact test , while comparisons between groups of the tss were performed by using an ancova model on final values , with treatment as factor and the baseline value as covariate . for continuous or continuous - like variables , changes between groups
were analyzed by calculating the mean change from baseline and the corresponding 95% confidence interval ( ci ) .
the baseline demographic and clinical characteristics of the 291 women enrolled in the study ( itt population ) are reported in table 1 . no significant differences between groups
a total of 37 patients were excluded from the ittr population being efficacy data unavailable .
one hundred and 25 patients completed the study without any major protocol violation ( pp ) , while 122 were prematurely discontinued , mainly due to the growth of specific pathogen organisms in the vaginal swab ( figure 1 ) .
most patients ( 91.1% itt ) completed the study at the 7-day final visit , while a third follow - up visit was required by 3.4% of patients only . in 10 patients ( 3.4% ) , the final visit was anticipated , while 7 patients ( 2.4% ) did not perform any further evaluation after the baseline visit . the therapeutic success ( pp population )
was obtained in 41/41 ( 100% ) and 41/42 ( 97.6% ) of patients treated with fitostimoline cream and ovules , respectively , with a difference between groups of 2.38% ( 2.33% to 6.99% 95% ci ) .
therefore , the two fitostimoline groups were considered therapeutically equivalent , and all fitostimoline - treated patients were pooled and compared with tantum rosa group .
comparative results for the pooled fitostimoline and the tantum rosa group for the primary efficacy endpoint ( percentage of patients with therapeutic success ) are reported in table 2 for both the ittr and the pp populations .
the percentage of therapeutic success was 98.8% in the fitostimoline group and 92.8 in the tantum rosa group ( pp population ) , 82.8% and 78.6% , respectively , in the ittr population .
the lower confidence limit of the difference was above the predefined value of 10% in both the pp ( 2.20 ) and the ittr population ( 6.26 ) : therefore the treatment with fitostimoline ( vaginal cream and ovules ) was not inferior to tantum rosa vaginal cream . in the patients with positive vaginal swab , the percentage of therapeutic success was substantially similar with fitostimoline ( 66.3% ) and tantum rosa ( 67.5% ) , with a nonsignificant difference ( 1.25% ) between groups ( 95% ci 19.08 to 16.58 ) .
the outcome of vaginitis in term of resolution , improvement , or failure was slightly better , but not statistically different , in the fitostimoline group ( table 3 . )
a significant decrease of the tss versus baseline was observed in both groups ; the comparison between fitostimoline and tantum rosa did not reveal a significant difference in the ancova test ( p = 0.35 ) .
similar results were obtained for the scores of each individual signs and symptoms that decreased from the baseline with both treatments without significant differences between groups .
no serious adverse events were reported ; nonserious mild adverse events ( vaginal burning , vaginal discharge , and vaginal bleeding ) were observed at application site in 4 patients ( 1.4% ) in the whole , 2 ( 1.1% ) treated with fitostimoline , and 2 ( 2.0% ) treated with tantum rosa , without significant difference between groups ( p = 0.610 ) .
as the microbiological etiology of bv has not been completely defined , the role of nonantibiotic treatments should be continuously and carefully evaluated in randomized , controlled clinical trials .
the evening application of fitostimoline ovules or vaginal cream , both associated with a morning fitostimoline vaginal washing , induced a high percentage of clinical success ( 97.6% and 100% , resp . ) and the two pharmaceutical forms were considered therapeutically equivalent .
the pooled fitostimoline and the benzydamine hydrochloride ( tantum rosa vaginal cream + vaginal washing ) treatments were effective in reducing the subjective symptoms and the objective signs of bv , without significant differences between group .
the analysis of the primary efficacy endpoint ( percentage of patients with therapeutic success ) demonstrated the noninferiority of topical treatment of fitostimoline in comparison with benzydamine hydrochloride . even in the patients with 
vaginitis , a positive effect of both fitostimoline and benzydamine hydrochloride was demonstrated , with a percentage of therapeutic success of 66.3% and 67.5% , respectively , before the initiation of the specific antibiotic or antimycotic treatment .
minor local adverse events were infrequently observed in both groups ( 1.1% and 2.0% of patients with fitostimoline and benzydamine hydrochloride , resp . ) .
no serious adverse events were observed during the study . a limitation of the study can be the absence of a placebo group ; moreover this kind of study design has been judged as unethical .
additionally , the bacteriological test has not been repeated in the bv patients at the end of treatments , being the regression of clinical symptoms itself suggestive for the normalization of the vaginal flora . in conclusion ,
fitostimoline ( vaginal cream , ovules , vaginal washing ) was demonstrated to be an effective and well - tolerated treatment suitable for the topical management of bacterial vaginosis .
since bv is still characterized by a high recurrence rate , the long - term therapeutic effect of topical triticum vulgare extract ( fitostimoline ) should be the subject of future clinical evaluation .
 two hundred and 91 patients showing signs and symptoms of bacterial vaginosis ( bv ) were randomized to receive topical treatment with fitostimoline ( vaginal cream and vaginal ovules + vaginal washing ) or benzydamine hydrochloride ( vaginal cream + vaginal washing ) for 7 days . 
 signs ( leucorrhoea , erythema , oedema , and erosion ) and symptoms ( burning , pain , itching , vaginal dryness , dyspareunia , and dysuria ) ( scored 03 ) were evaluated at baseline and at the end of treatment ; the total symptoms score ( tss ) was also calculated . in 125 patients , 
 a bacterial vaginosis was confirmed by vaginal swab test . 
 the primary efficacy variable analysis , that is , the percentage of patients with therapeutic success ( almost complete disappearance of signs and symptoms ) , demonstrated that fitostimoline ovules and vaginal cream were therapeutically equivalent and that pooled fitostimoline treatment was not inferior to benzydamine hydrochloride . 
 all the treatments were well tolerated , with only minor local adverse events infrequently reported . 
 the results of this study confirmed that gynaecological fitostimoline is a safe and effective topical treatment for bv . 
1. Introduction
2. Patients and Methods
3. Results
4. Conclusions