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Trial registered on ANZCTR


Registration number
ACTRN12624001180505
Ethics application status
Approved
Date submitted
12/09/2024
Date registered
26/09/2024
Date last updated
20/12/2024
Date data sharing statement initially provided
26/09/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of tREating aSymptomatic infEctions To resTore fERtility: The RESETTER Study
Scientific title
A prospective, single-centre, multi-site clinical trial of the effect of a combined partner treatment program for clearance of asymptomatic genital Mycoplasmas on unexplained fertility and clinical pregnancy rates
Secondary ID [1] 312958 0
Nil known.
Universal Trial Number (UTN)
Trial acronym
RESETTER
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infertility 335130 0
Condition category
Condition code
Reproductive Health and Childbirth 331630 331630 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Couples will submit semen, penile and vaginal swab samples for analysis; A portion of semen samples will undergo routine analysis as per World Health Organisation (WHO) guidelines, and the remaining semen will be utilised for DNA extraction alongside penile and vaginal swab samples. Semen, penile and vaginal swabs will undergo qPCR analysis for the presence of Genital Mycoplasmas, and where one or more are identified in at least one partner, couples will be treated with either doxycycline (M. hominis and U. urealyticum) and/or azithromycin or moxifloxacin (M. genitalium) as per standard treatment guidelines. Moxifloxacin will only be used in participants where antibiotic resistance markers are identified in M. genitalium based on the four 23S rRNA mutation targets (A2058T, A2058C, A2058G, A2059G) included in the SpeeDx MG ResistancePlus assay. Lactobacillus and Bifidobacterium spp. will be quantified in vaginal swabs. Women will receive a vaginal Lactobacillus sp. probiotic for five weeks post-treatment and then both partners will provide follow-up semen, penile and vaginal swab samples for repeat analysis.

1) Azithromycin dihdyrate, 250mg tablets (Azithromycin, Sandoz) - AUST R 58797. This is a broad-spectrum antibiotic of the macrolide class. In this trial it will be used to treat Mycoplasma genitalium colonisation without macrolide resistance mutations. Azithromycin is the current gold standard for treatment of uncomplicated macrolide sensitive M. genitalium infections, with the 2021 European guidelines reporting a cure rate of 85-95%. Azithromycin is sold in a 500mg tablet form, but in this trial pharmacies will dispense it as 500mg tablets with defined break-points (already present from the manufacturer) and instruct participants on how to break the tablets in half to obtain 250mg doses. An initial dose of 500mg, followed by 250mg daily for a further four days is the recommended dosing regimen.

2) Doxycycline, 100mg tablets (Doxycycline, Sandoz) - AUST R 66302. Doxycycline is a broad-spectrum antibiotic of the tetracycline class that is effective against Gram positive and negative pathogens, as well as Genital Mycoplasmas, Spirochaetes and some parasites. In this trial it will be used to treat colonisation by Ureaplasma urealyticum and Mycoplasma hominis; it is well-recognised as being effective against both of these organisms, with low-levels of resistance documented. The dosing strategy to be used in this trial will mirror that used in a similar trial by Ahmadi et al. 2017, consisting of 100mg twice daily for seven days.

3) Moxifloxacin, 400mg tablets (Moxifloxacin APO) – AUST R 309824. Moxifloxacin is a broad-spectrum antibiotic of the quinolone class that is effective against Gram positive and negative pathogens, as well as Genital Mycoplasmas. In this trial it will be used to treat colonisation by macrolide-resistant M. genitalium. The dosing strategy to be used is as per the European Guidelines, consisting of 400mg daily for seven days.

4) Lactobacillus crispatus (2 billion CFU), Lactobacillus gasseri (2 billion CFU), Lactobacillus rhamnosus (1.25 billion CFU), Lactobacillus reuteri (1.25 billion CFU) (V-Spot, CGS Pharma/Amelia Bio). V-spot is a commercial vaginal probiotic preparation that is TGA-approved. It contains a mixture of Lactobacillus sp., including L. crispatus, L. gasseri, L. rhamnosus and L. reuteri. In the current trial it is being administered post-antibiotic treatment via vaginal application (insertion of a vaginal pessary) to help restore the vaginal microbiota to an optimal state. Dosing strategy is once daily for six days, followed by weekly administration for four weeks (five weeks treatment in total).

Treatment compliance will be recorded using a medicine accountability log that is included with the treatment pack and will be returned at the same time follow-up samples are collected.
Intervention code [1] 329490 0
Treatment: Drugs
Intervention code [2] 329491 0
Early detection / Screening
Comparator / control treatment
Couples seeking assessment for unexplained infertility who test negative to genital mycoplasmas. The couples will not receive any treatment as part of their participation in the trial. They will continue to receive standard clinical care for unexplained infertility assessment, which may include other fertility treatments, however, such treatments are unlikely to occur within three months of being recruited to the study (based on the normal timeframe required for initial diagnostic testing undertaken as part of clinical investigation for unexplained infertility). It should be noted that all couples receiving treatment will also continue to undergo the same standard diagnostic testing as these couples.
Control group
Active

Outcomes
Primary outcome [1] 339363 0
Change in the rate of clinical pregnancy at three months post-treatment in couples treated for Genital Mycoplasma colonisation.
Timepoint [1] 339363 0
Baseline (pre-treatment) and three months post-completion of treatment.
Secondary outcome [1] 439664 0
Semen pH
Timepoint [1] 439664 0
Baseline and six weeks post-completion of treatment.
Secondary outcome [2] 439927 0
Sperm concentration
Timepoint [2] 439927 0
Baseline and six weeks post-completion of treatment
Secondary outcome [3] 439928 0
Semen viscosity
Timepoint [3] 439928 0
Baseline and six weeks post-completion of treatment
Secondary outcome [4] 439931 0
Total sperm count
Timepoint [4] 439931 0
Baseline and six weeks post-completion of treatment
Secondary outcome [5] 439932 0
Motile sperm/mL semen
Timepoint [5] 439932 0
Baseline and six weeks post-completion of treatment
Secondary outcome [6] 439933 0
Total sperm motility (%)
Timepoint [6] 439933 0
Baseline and six weeks post-completion of treatment
Secondary outcome [7] 439934 0
Progressive sperm motility (%)
Timepoint [7] 439934 0
Baseline and six weeks post-completion of treatment
Secondary outcome [8] 439935 0
Non-progressive sperm motility (%)
Timepoint [8] 439935 0
Baseline and six weeks post-completion of treatment
Secondary outcome [9] 439936 0
Immotile sperm (%)
Timepoint [9] 439936 0
Baseline and six weeks post-completion of treatment
Secondary outcome [10] 439937 0
Normal sperm morphology (%)
Timepoint [10] 439937 0
Baseline and six weeks post-completion of treatment
Secondary outcome [11] 439938 0
Sperm DNA fragmentation index (%)
Timepoint [11] 439938 0
Baseline and six weeks post-completion of treatment
Secondary outcome [12] 439939 0
Semen liquefaction
Timepoint [12] 439939 0
Baseline and six weeks post-completion of treatment
Secondary outcome [13] 439940 0
Semen appearance
Timepoint [13] 439940 0
Baseline and six weeks post-completion of treatment
Secondary outcome [14] 439941 0
Semen volume
Timepoint [14] 439941 0
Baseline and six weeks post-completion of treatment

Eligibility
Key inclusion criteria
Aged 18 years + and attending either Concept Fertility or City Fertility clinics for investigation of unexplained infertility (unable to achieve clinical pregnancy after 12 months of regular unprotected sexual intercourse, where no other physiological or pathological diagnoses can explain this).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Currently pregnant, symptomatic genital tract infections, antimicrobial therapy within the past 14 days, known allergy to tetracycline or macrolide antibiotics.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
Descriptive data summaries will use means and standard deviations or medians and interquartile ranges for continuous variables, and frequencies and proportions for categorical variables.

Initial summary analyses will use Fisher’s exact tests or Chi-square tests to estimate the difference in proportion of conception between the treated couples and untreated couples (primary endpoint). Multivariable logistic regression will be used to compare the outcome (conception vs. non-conception) between the two groups whilst simultaneously adjusting for other factors such as recruitment site, demographics (e.g. age) and number/combination of Genital Mycoplasma variants present. Analyses will be based on an intention to treat principle, with a secondary assessment as a per protocol analysis, taking into account whether couples completed treatment fully or partially.

Sub-analyses will also be conducted on the primary endpoint stratified by whether one or both partners test positive to the target bacteria, what bacteria they test positive to, and the associated individual treatment success rates.

Fisher's exact and Chi-square tests will be used to estimate the difference in proportions of males with sperm/semen parameters that meet the WHO criteria and those that don't, between the group of men who test positive for Genital Mycoplasmas and the group who test negative.

Multivariable linear regression will be used to compare each semen and sperm parameter (secondary endpoints) between males in whom Genital Mycoplasmas are present or absent, adjusting for factors such as age.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/01/2025
Actual
Date of last participant enrolment
Anticipated
13/01/2027
Actual
Date of last data collection
Anticipated
13/04/2027
Actual
Sample size
Target
440
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 317390 0
University
Name [1] 317390 0
University of Western Australia
Country [1] 317390 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
Country
Australia
Secondary sponsor category [1] 319681 0
None
Name [1] 319681 0
Address [1] 319681 0
Country [1] 319681 0
Other collaborator category [1] 283333 0
Commercial sector/Industry
Name [1] 283333 0
Amelia Bio
Address [1] 283333 0
Country [1] 283333 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316117 0
The University of Western Australia Human Research Ethics Committee
Ethics committee address [1] 316117 0
Ethics committee country [1] 316117 0
Australia
Date submitted for ethics approval [1] 316117 0
01/11/2023
Approval date [1] 316117 0
31/01/2024
Ethics approval number [1] 316117 0
2023/ET000878

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136846 0
A/Prof Matthew Payne
Address 136846 0
UWA Division of Obstetrics and Gynaecology, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008
Country 136846 0
Australia
Phone 136846 0
+61 08 6458 1331
Fax 136846 0
Email 136846 0
matthew.payne@uwa.edu.au
Contact person for public queries
Name 136847 0
Matthew Payne
Address 136847 0
UWA Division of Obstetrics and Gynaecology, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008
Country 136847 0
Australia
Phone 136847 0
+61 08 6458 1331
Fax 136847 0
Email 136847 0
matthew.payne@uwa.edu.au
Contact person for scientific queries
Name 136848 0
Matthew Payne
Address 136848 0
UWA Division of Obstetrics and Gynaecology, King Edward Memorial Hospital, 374 Bagot Road, Subiaco, WA 6008
Country 136848 0
Australia
Phone 136848 0
+61 08 6458 1331
Fax 136848 0
Email 136848 0
matthew.payne@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.