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Trial registered on ANZCTR


Registration number
ACTRN12619000196145
Ethics application status
Approved
Date submitted
7/02/2019
Date registered
12/02/2019
Date last updated
28/01/2020
Date data sharing statement initially provided
12/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Treating male partners of women being treated for bacterial vaginosis (BV): randomised controlled trial
Scientific title
Treating male partners of women with bacterial vaginosis (BV) to reduce recurrence: randomised controlled trial
Secondary ID [1] 297285 0
StepUp RCT
Universal Trial Number (UTN)
U1111-1228-0106
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
bacterial vaginosis 311362 0
Condition category
Condition code
Infection 309999 309999 0 0
Other infectious diseases
Renal and Urogenital 310121 310121 0 0
Other renal and urogenital disorders
Reproductive Health and Childbirth 310122 310122 0 0
Other reproductive health and childbirth disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All female participants will receive first line recommended treatment, which is oral metronidazole (MTZ) 400mg tablets twice daily for 7 days, or if contraindicated, either alternate first line therapy: 7-day regimen of topical vaginal 2% clindamycin cream (intravaginally once daily at night) or 5 days of vaginal metronidazole gel (0.75% intravaginally once daily at night). Her male partner is then randomised to either the Intervention or Control group.

Male partners randomised to the Intervention Group will receive oral MTZ 400mg tablets twice daily and topical 2% clindamycin cream to be applied to the glans penis and upper shaft (under the foreskin if uncircumcised) twice daily for 7 days.

For all participants, adherence and adverse effects will be captured in post-antibiotic questionnaires (to be completed the day after treatment has been completed).
Intervention code [1] 313535 0
Treatment: Drugs
Comparator / control treatment
As topical placebos are highly likely to affect the penile microbiota and therefore influence the efficacy estimates, males randomised to the Control Group will not receive a placebo. The control for this trial is therefore current standard of care: treatment of the female with first line antibiotic therapy (no male treatment). This trial will be an open label randomised controlled trial.
Control group
Active

Outcomes
Primary outcome [1] 318910 0
BV recurrence defined as 3 or 4 Amsel’s criteria and a Nugent score (NS) of 4–10 within 12 weeks*

*The combination of at least 3 Amsel’s criteria (Amsel-BV) and a Nugent Score (NS) between 4 and 10 (Nugent-BV) will be used to diagnose BV in this trial.
The Amsel’s criteria include:
i) presence of a characteristic homogenous vaginal discharge;
ii) elevated vaginal pH >4.5;
iii) positive amine test (noticeable fishy odour on examination for non-laboratory sites);
iv) >=20% Clue cells on microscopy.
The Nugent method scores bacterial morphotypes on vaginal Gram stain:
i) a NS of 0–3 represents a lactobacillus dominant “optimal” vaginal microbiota,
ii) a NS of 4–6 an intermediate state with few lactobacilli and increased anaerobes,
iii) a NS of 7–10 is classified as Nugent-BV.
Combining a NS of 4–10 with at least 3 Amsel’s criteria optimises diagnosis of symptomatic BV.
Timepoint [1] 318910 0
12 weeks post randomisation
Secondary outcome [1] 366384 0
BV recurrence defined as NS of 7-10 by vaginal Gram stain, within 12 weeks
Timepoint [1] 366384 0
12 weeks post randomisation
Secondary outcome [2] 366385 0
BV recurrence defined as 3 or 4 Amsel’s criteria (presence of a vaginal discharge; elevated vaginal pH >4.5, positive amine test, >=20% Clue cells on microscopy of vaginal Gram stain), within 4 weeks
Timepoint [2] 366385 0
4 weeks post randomisation
Secondary outcome [3] 366386 0
BV recurrence defined as NS of 7-10 by vaginal Gram stain, within 4 weeks
Timepoint [3] 366386 0
4 weeks post randomisation
Secondary outcome [4] 366387 0
Recurrence of a microbiota characterised by BV-associated bacteria using high throughput sequencing and/or quantitative PCR, within 12 weeks
Timepoint [4] 366387 0
12 weeks post randomisation
Secondary outcome [5] 366388 0
Recurrence of a microbiota characterised by BV-associated bacteria using high throughput sequencing and/or quantitative PCR, within 4 weeks
Timepoint [5] 366388 0
4 weeks post randomisation

Eligibility
Key inclusion criteria
Females will be included if they fulfil the following criteria:
i) Are aged 18 years to pre-menopausal (defined as still menstruating within the last 12 months); and
ii) have symptomatic BV defined as 3 or 4 Amsel’s criteria and a Nugent score (NS) of 4–10; and
iii) have a regular male partner for the prior 8 weeks who is willing and eligible to participate; and
iv) are being treated with a first line recommended antimicrobial therapy for BV (including the following 3 options: 7 days of oral metronidazole 400mg bd is the preferred option but if not tolerated or is contraindicated 7 days of topical vaginal clindamycin cream or 5 days of intravaginal metro gel are acceptable; and
v) have sufficient English language proficiency to understand the study requirements; and
vi) provide written informed consent; and
vii) are willing and able to comply with protocol requirements including clinic visits at 4 and 12 weeks ; and
viii) do not have any of the exclusion criteria listed below.

Males nominated as the regular partner of a woman fulfilling inclusion criteria will be eligible if they:
i) Are aged 18 years or above; and
ii) enrol within a week of their partner with confirmed BV; and
iii) have sufficient English language proficiency to understand the study requirements; and
iv) provide written informed consent; and
v) are able to comply with protocol requirements; and
vi) do not have any of the exclusion criteria or contraindications listed for metronidazole.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
Participants will be deemed ineligible for the study if they meet any of the following exclusion criteria:
i) are a current sex worker; or
ii) have concurrent sexual partners; or
iii) are known to be HIV positive

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocations will be concealed with central randomisation via the internet/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A 1:1 randomisation ratio, in blocks of size four, will be used with stratification by intrauterine device (IUD)-use, circumcision status and recruitment site
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Primary Analysis
Modified-Intention-to-treat
The Primary Analysis is a modified intention-to-treat (miTT) analysis. Women will be analysed as randomised and will be eligible to be included in the mITT if they:
• returned for one or more clinical visit
• took one or more doses of antimicrobial therapy
• are part of the evaluable population

Secondary analyses
Per-protocol-analysis
1. The population of participants who qualify for the mITT population and;
2. They adhered to 10 or more doses of 14 (>70%) dose regimens (oral metronidazole or topical clindamycin cream in males), 5 or more doses of a 7 (>70%) dose regimen (intravaginal clindamycin cream) or all 5 doses of a 5 dose regimen (intravaginal metronidazole gel).

Stratified analyses
3. Analyses will be performed for the primary outcome comparing the pre-defined strata – i.e. 1) IUD vs no IUD and the primary outcome; and 2) circumcision and no circumcision for the primary outcome. Differences between the intervention groups will be assessed using tests for interactions. If there is consistent evidence of an interaction between the intervention and strata then will do efficacy analysis within each strata.

Safety evaluation
4. Serious adverse events, adverse events leading to cessation of treatment, and all reported clinical adverse events will be summarised. This will include every male who took one or more dose(s) of at least one of the investigational drugs.

Factors associated with recurrence
5. Factors associated with recurrence (Cox Regression analyses) including demographics, sexual behaviours, contraception use, smoking and other factors previously shown to be associated with BV recurrence.

Interim analysis
An interim analysis will be undertaken when the first 150 couples (75 in each arm) have reached the 12 week study endpoint and will include the stated primary and secondary measures of interest.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC

Funding & Sponsors
Funding source category [1] 301843 0
Government body
Name [1] 301843 0
National Health and Medical Research Council Australia
Address [1] 301843 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 301843 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Level 1, Chancellery Building D
26 Sports walk, Clayton Campus, Wellington Rd, Clayton VIC
3800 Australia
Country
Australia
Secondary sponsor category [1] 301589 0
None
Name [1] 301589 0
Address [1] 301589 0
Country [1] 301589 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302544 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 302544 0
Office of Ethics and Research Governance
Level 5, 553 St Kilda Rd
Melbourne
VIC 3004
Ethics committee country [1] 302544 0
Australia
Date submitted for ethics approval [1] 302544 0
25/10/2018
Approval date [1] 302544 0
05/11/2018
Ethics approval number [1] 302544 0
HREC 43565 (local reference 506/18)

Summary
Brief summary
Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge in women of reproductive age affecting between 12-30% of women, suggesting it may currently affect at least 1 million Australian women. We have shown that 1 in 2 women will get BV back again after recommended treatment. BV-associated bacteria are present in male partners of women with BV on the male genitals. We believe that these bacteria may be exchanged during sex and that this may be contributing to the high rates of women getting their BV back again. Currently only women are treated for BV and their male partners are not.

Our research study “StepUp RCT” aims to determine whether the combined antibiotic treatment of male partners of women receiving therapy for BV significantly reduces the risk of BV recurrence compared to no male treatment, in the 12 weeks after randomisation. We aim to recruit 342 couples in Melbourne and Sydney and we are using a randomised study design: half of men will receive antibiotic treatment (dual couple treatment) and the other half will not (female treatment only). We will collect genital specimens from all participants before and after treatment and then at weeks 4,8 and 12 to see if the female gets her BV back again or not.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90590 0
A/Prof Catriona Bradshaw
Address 90590 0
Melbourne Sexual Health Centre
580 Swanston St
Carlton Vic 3053
Country 90590 0
Australia
Phone 90590 0
+61 3 93416200
Fax 90590 0
Email 90590 0
catriona.bradshaw@monash.edu
Contact person for public queries
Name 90591 0
Dr Lenka Vodstrcil
Address 90591 0
Melbourne Sexual Health Centre
580 Swanston St
Carlton Vic 3053
Country 90591 0
Australia
Phone 90591 0
+61 3 93416244
Fax 90591 0
Email 90591 0
stopbv@mshc.org.au
Contact person for scientific queries
Name 90592 0
Dr Lenka Vodstrcil
Address 90592 0
Melbourne Sexual Health Centre
580 Swanston St
Carlton Vic 3053
Country 90592 0
Australia
Phone 90592 0
+61 3 93416244
Fax 90592 0
Email 90592 0
stopbv@mshc.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
If publishers require meta-data to be uploaded to accompany any related publications, only de-identified data that is not able to be linked to any individual would be considered for data sharing in alignment with the NHMRC Statement. New ID codes would be assigned to any data to be shared. Only information contained within the publication would be considered able to be shared.
When will data be available (start and end dates)?
From the conclusion of the trial and for 5 years after publication
Available to whom?
Microbiota sequencing data would be publically available
Other meta-data would only be considered by request.
Available for what types of analyses?
We would not share our whole database to limit the ability for an individual to identify themselves. Any laboratory/microbiota sequencing data will be made publicly available on a repository such as Short Read Archive (SRA) as is standard practice. Sequencing data only contains information related to bacterial sequences and only limited meta-data would be included.
How or where can data be obtained?
Sequencing data would be uploaded on a repository such as Short Read Archive (SRA).
Other meta-data may be uploaded with a manuscript as required by the publisher
What supporting documents are/will be available?
Study protocol
Statistical analysis plan
How or where can supporting documents be obtained?
Type [1] 6630 0
Study protocol
Citation [1] 6630 0
Link [1] 6630 0
Email [1] 6630 0
stopbv@mshc.org.au
Other [1] 6630 0
Attachment [1] 6630 0
Type [2] 6631 0
Statistical analysis plan
Citation [2] 6631 0
Link [2] 6631 0
Email [2] 6631 0
stopbv@mshc.org.au
Other [2] 6631 0
Attachment [2] 6631 0
Summary results
No Results