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Bacterial vaginosis (BV) is the most common cause of vaginal discharge. It is caused by an imbalance in the normal vaginal microbiota. Symptoms include an offensive odour. Standard oral or vaginal antimicrobial treatments have high immediate cure rates but almost as high recurrence rates. pHyph, a vaginal pessary, contains glucono-delta-lactone (GDL) and sodium gluconate (NaG) which restore normal pH and disrupt the associated biofilm.
Aim
To investigate the clinical performance of pHyph, for both treatment and recurrence prevention. Design An open-label, single arm, multi-centre first in women study.
Setting
Two private gynaecology clinics in Skåne County, Southern Sweden.
Methods
Twenty four adult women with confirmed bacterial vaginosis received the investigational product for self-administration on days 0, 2, 4, and 6 and were assessed on day 7. Clinical cure was defined as absence of three of four Amsel’s criteria (pH excluded) on day 7. Safety and tolerability were also recorded. Those not cured by day 7 received a prolonged treatment protocol. Results There were three withdrawals, two before the day 7 assessment. 18/22 (82 %) were clinically cured at day 7. The pessary was well tolerated. Recurrence rates at 14 days in patients cured at day 7 after receiving standard study treatment (n = 18) were 1/18 (5.6 %) with no additional recurrences reported at 35 days. Three of four patients not cured at 7 days received continued treatment (day 7, 9, 11, and 13), but none were cured at 14 days.
Conclusion
pHyph has the potential for both high cure rates and a reduction in recurrence.
Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women, characterised by a dysbiosis or microbial imbalance of the vaginal microbiota [
2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge.
]. Signs and symptoms include an often profuse thin, white, “fishy” smelling vaginal discharge, in the absence of itching, although up to 50 % of women may be asymptomatic [
2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge.
BV has been associated with pelvic inflammatory disease and adverse pregnancy outcomes such as late miscarriage and preterm birth, premature rupture of membranes, chorioamnionitis and post-partum endometritis [
Standard treatment consists of oral or topical vaginal antimicrobials, with cure rates of 80–90 % at 1 week, but recurrence rates of 15–30 % within 3 months. [
]. This results in women requiring repeated treatments, with a risk of developing antimicrobial resistance, and of disturbing the normal vaginal microbiota further [
]. Some women resort to self-management strategies such as lactic acid agents, douching, oral or vaginal probiotics, yoghurt or antiseptic washes and creams, with little proven efficacy [
Overgrowth of predominantly anaerobic vaginal organisms (e.g. Gardnerella vaginalis, Prevotella spp., Atopobium vaginae, Mycoplasma hominis, Mobiluncus spp.I results in a shift from the normal lactobacilli to a polymicrobial state and a pathological biofilm formation which is associated with an increase in vaginal pH above 4.5 [
2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge.
A biofilm is defined as an assembly of microbial cells in a dense, structured, polymicrobial community that is associated and strongly adherent to a surface and enclosed in a polymeric matrix of primarily polysaccharide material [
]. This reduces antimicrobial penetration and serves as a medium for extrachromosomal DNA transfer, which may facilitate acquisition of antimicrobial resistance. In combination these mechanisms can dramatically decrease susceptibility to antimicrobial treatment [
]. With increasing antimicrobial resistance, the focus of research into treatment of many infections is shifting from targeting bacterial growth/division resulting in bactericide or bacteriostasis, towards innovative approaches such as triggering the biofilm dispersal or preventing its formation [
Antimicrobial resistance is one of the World Health Organisation’s top ten threats to global health in 2019 and research into novel non-antimicrobial based treatments is timely [
]. GDL and NaG are both accepted as safe food additives, and suitable for use in clinical testing and have been formulated as the “pHyph” slow-release vaginal pessary (Fig. 2) [
]. In contact with the vaginal fluid they are hydrolysed to gluconic acid, which is weakly acidic, thereby restoring the vaginal pH to normal. This inhibits the growth of Gardnerella vaginalis. GDL disrupts the biofilm both via provision of alternative carbohydrate sources, which diminish biofilm formation, and by a direct disruptive effect via reduced vaginal pH [
It has been proposed that BV-associated Gardnerella vaginalis instigates the colonisation of the vaginal epithelium and functions as a scaffold to which other species subsequently attach [
]. Agents disrupting the formation and maintenance of the biofilm, such as the pHyph pessary, thus present a possible avenue for non-antimicrobial treatment of BV and may also reduce recurrence rates.
The aim of this study was to investigate the clinical performance of pHyph in an open label study for BV treatment and prevention of its recurrence.
Material and methods
Participants were adult women seen at two private gynaecological clinics in Sweden, one in Helsingborg and one in Lund with confirmed BV according to fulfilment of at least three of the four Amsel’s criteria (detailed in the inclusion criteria, Box 1). Ethics approval for the study was granted (DNR2018/817).
Adult, post-menarchal, pre-menopausal women aged 18 years or older
•
Diagnosis of BV according to Amsel’s criteria, defined as having at least 3 of the 4 following criteria:
1
Thin, white, yellow, homogenous discharge
2
Clue cells on microscopy (more than 20 percent of epithelial cells)
3
pH of vaginal fluid above 4.5
4
Release of fishy odour “i.e. a positive whiff test” when alkali (10 % potassium hydroxide [KOH] solution) is added
•
Having decisional capacity and providing written informed consent
•
Negative urine pregnancy test at screening
•
Refrain from using any intravaginal products
•
(i.e., contraceptive creams, gels, foams, sponges, lubricants, or tampons, etc.) during the study period
•
Refrain from sexual intercourse or use a condom until Day 7
•
Signed informed consent and willing and able to comply with all study requirements
Exclusion Criteria:
•
Patients with known or apparent signs of other vaginal infections (vulvovaginal candidiasis, Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, Herpes simplex, or human papillomavirus) at screening
•
Anticipated menstruation during the treatment period (Day 0 till Day 7)
•
Patients who are pregnant or breastfeeding
•
Patients who were treated for BV within the past 14 days
•
Patients who are currently receiving antibiotic therapy unrelated to BV or have received antibiotic therapy within the past 14 days
•
Patients who have used pH-modifying vaginal products within the last 14 days
•
Patients who have received an investigational drug in a clinical investigation within 30 days prior to screening
•
Known/previous allergy or hypersensitivity to any product constituent
•
Any medical condition that in the Investigator’s judgments would make the patient unsuitable for inclusion
Inclusion and exclusion criteria are detailed in Box 1.
Intervention
On Day 0, participants had a gynaecological examination, vaginal samples taken, and received the investigational product to be self-administered on days 0, 2, 4, and 6 (Fig. 1). Participants were examined after 7 days with respect to BV signs and symptoms.
Fig. 1Study flow chart. BV = Bacterial vaginosis. Treatment was given on days marked with an arrow.
The investigational product, pHyph, is shown in Fig. 2. pHyph is a white, convex, bullet-shaped vaginal pessary, approximately 17 mm in length, to be administered vaginally with a CE-marked vaginal pessary applicator (Schägner GmbH, Steinmauern, Germany).
Cure; defined as absence of the three, non-pH related Amsel criteria, namely, discharge, clue cells and fishy odour. The absence of the fourth Amsel criterion; pH above 4.5, was not included in the definition of cure.
If the patient was not cured at day 7, she received a further treatment course, identical to the first on days 7, 9, 11, and 13 and had a gynaecological examination with respect to BV signs and symptoms again day 14.
Patients were followed-up by telephone up to 29 days after the last treatment.
Secondary endpoints
Patient questionnaires were used for assessing BV symptoms, usability (ease of use, product drip, comfort, and odour of the pessary), and adverse events (AEs).
Vaginal samples were used for confirming diagnosis and for future microbiome analyses, although not reported in this article.
Theory and calculation
Statistical analysis
Sample size (n = 24) selection was based on achieving 90 % power to show that the one-sided 95 % confidence interval for the observed cure rate was above 40 %, assuming the true clinical cure rate, as defined in this study, to be equal to 70 %.
Results
28 patients were screened and 24 enrolled (aged 18–49; mean age 33) and treated between 21 st January 2019 and 20th November 2019 (Fig. 3). There were three withdrawals, two before data were collected for the day 7 clinical cure rate, leaving 22 women (n = 22/24, 92 %) who completed 7 days of treatment. 21 women completed the study in its entirety. The reasons for withdrawal were “withdrawal of informed consent” in two cases and investigator decision, based on an adverse event, in one case (pain and itching in the vagina). 18/22 (82 %) women were clinically cured at day 7.
16 patients had experienced at least one episode of BV previously in the past 12 months; 7 had recurrent BV, defined as three or more other episodes of BV in the past year. Women with recurrent BV had a higher cure rate of 86 % (6/7) than women with less than three episodes of BV in the past year. Results including the subgroup analysis are shown in Table 1.
Table 1Results including subgroup analysis (BV, bacterial vaginosis).
Subgroup analysis
n/number assessed (%)
Cure at 7 days, women reporting ≥ 3 previous BV infections
6/7 (86 %)
(last 12 months) (n = 7)
Cure at 7 days, women reporting < 3 previous BV infections
9/12 (75 %)
(last 12 months) (n = 12)
Cure at 7 days, women abstained from reporting no. of previous BV infections (n = 3)
Recurrence rates at 14 days in cured patients were low at 5.6 % (1/18) with no additional recurrences reported at 35 days.
Three of the four uncured patients at 7 days received prolonged treatment (on day 7, 9, 11, and 13). The fourth woman withdrew. None of the women were cured even at 14 days, and all instead received rescue treatment of metronidazole (400–500 mg, twice daily, oral treatment) for 7 days.
Secondary endpoints
The majority of participants found the pessary easy to use (n = 23/24; 96 %), gentle (n = 20/24; 83 %) and odour free (n = 20/24; 83 %), whilst more than half found the pessary dripless (n = 16/24; 67 %).
Discussion
Main finding
This study has shown this novel BV treatment gives high short-term cures rates of 82 % (n = 18/22) at day 7, and low rates of recurrence at 14 days of 5.6 % (n = 1/18), with no additional recurrences reported at 35 days. However, none of the uncured patients at 7 days were cured with prolonged treatment (n = 3, 1 withdrawal of consent from trial) and received rescue treatment with standard of care.
The early cure rate is comparable with standard treatment cure rates of 80–90 % at 7 days.
Recurrence appears to be lower than standard of care at 5.6 % at one month compared to 15–30 % with standard of care at 3 months [
This is the first clinical study of this new treatment, but the sample size is small and there was no control group. Established antimicrobial treatments have been assessed in much larger comparative studies. For example the Cochrane review of metronidazole and clindamycin included 24 trials and 4422 participants [
The follow up interval for recurrence was shorter than typically quoted for standard of care (35 days vs 90 days), which make comparison for recurrence less reliable. [
Comparisons of recurrence rates with traditional antimicrobials are challenging due to recurrence rates being reported over varying timeframes. Nevertheless our observed recurrence rate of 1/18 at day 14 and no additional recurrences reported at day 35, compares favourably with reports of recurrence rates after antibiotics high as 80 % [
This evidence is insufficient to recommend this experimental treatment in clinical practice as yet.
Implications for research
Randomised controlled comparisons with placebos and with older established treatments are a priority. Plans for a large EU funded double-blind randomised placebo-controlled trial in the UK and Sweden are underway.
Looking further ahead there may also be applications in the treatment of pregnant women, where BV and vaginal dysbiosis can have consequences far beyond the symptoms of an odorous discharge, increasing the risks for late miscarriage; low birth weight [
]; chorioamnionitis [20]; and post-partum endometritis.
Controlled studies in pregnancy are essential before this treatment is used in the setting but should be a priority.
Conclusion
This proof of concept trial has shown promising results for both treatment and recurrence prevention sufficient to justify further controlled trials.
Ethical approval
Ethics approval for the study was granted (DNR2018/817) on 25/10/2020 by Regionala Etikprövningsnämnden EPN Lund, Regional ethics committee Lund. Study participants gave their consent at the first visit.
Funding
Gedea Biotech AB. Grants from SWELIFE (a Swedish government strategic innovation programme) and Medtech4Health – Project for better health 2017-2018, Dnr 2018-00275 and H2020-SMEInst-2018-2020-1, proposal no 835509.
Declaration of Competing Interest
The authors report no declarations of interest.
Appendix A. Supplementary data
The following is Supplementary data to this article:
2018 European (IUSTI/WHO) International Union against sexually transmitted infections (IUSTI) World Health Organisation (WHO) guideline on the management of vaginal discharge.
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