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Trial registered on ANZCTR


Registration number
ACTRN12612000065897
Ethics application status
Approved
Date submitted
29/12/2011
Date registered
12/01/2012
Date last updated
13/11/2012
Type of registration
Prospectively registered

Titles & IDs
Public title
The use of a probiotic to treat bacterial vaginosis and augment IVF pregnancy rates.
Scientific title
A randomised placebo controlled study comparing the use of a one month course of an oral probiotic therapy post tinidazole antibiotic treatment on the medium term (1 month) cure rate of bacterial vaginosis in a cohort of infertile women undergoing a frozen-thawed embryo transfer with documented evidence of bacterial vaginosis at trial entry.
Secondary ID [1] 279646 0
Nil
Universal Trial Number (UTN)
Trial acronym
The "ProViva" study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
bacterial vaginosis 285445 0
infertility 285446 0
In Vitro Fertilisation (IVF) 285447 0
Condition category
Condition code
Reproductive Health and Childbirth 285631 285631 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Women identified to have bacterial vaginosis will be administered a single 2 gm oral dose of the antibiotic Tinidazole, followed by a 4 week course of oral probiotic (2 capsules daily- total dose 4.6 Billion organisms Lactobacillus per day).
Intervention code [1] 283930 0
Treatment: Drugs
Comparator / control treatment
A single 2 gm dose of the antibiotic Tinidazole, followed by 2 placebo capsules daily for 4 weeks. The placebo capsules are identical in size, appearance and taste and contain glucose plus potato starch (141 mg and 18 mg respectively per capsule).
Control group
Placebo

Outcomes
Primary outcome [1] 286191 0
Cure of bacterial vaginosis as assessed by established clinical (Amsel) and laboratory (Nugent score) criteria.
Timepoint [1] 286191 0
Examination at the time of the embryo transfer, approximately 4 weeks after administration of the Tinidazole antibiotic and commencement of probiotic or placebo capsules.
Secondary outcome [1] 295333 0
Biochemical pregnancy rate (proportion of embryo transferes resulting in a positive serum bHCG result)
Timepoint [1] 295333 0
2 weeks after embryo transfer
Secondary outcome [2] 295334 0
Viable clinical pregnancy rate (proportion of transfered embryos that result in a viable fetal heart pulsation on ultrasound scan).
Timepoint [2] 295334 0
7-8 weeks gestation
Secondary outcome [3] 295335 0
miscarriage rate
Timepoint [3] 295335 0
assessed at time of first trimeter ultrasound (7-8 weeks gestation)
Secondary outcome [4] 296908 0
Concentration of bacterial vaginosis related endotoxins washed off the surface of the embryo transfer catheter after completion of the embryo transfer. Endotoxin will be quantified by the Endosafe-PTS assay system (Charles River, USA).
Timepoint [4] 296908 0
At the time of the embryo transfer

Eligibility
Key inclusion criteria
1. Presence of bacterial vaginosis infection on clinical examination and Nugent score assessment.
2. Undergoing a frozen embryo (vitrification) transfer cycle of IVF treatment
Minimum age
18 Years
Maximum age
40 Years
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Women receiving concurrent vaginal medication (progesterone, antifungal, antibiotic).
2. Allergy to Tindazole or metronidazole
3. Concurrent Candida vaginal infection
4. Women undergoing a frozen embryo transfer using "slow freeze" stored embryos.
5. Antibiotic use in the last 2 weeks
6. Prior enrolment in the ProViva Study

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)
Women who have just had an unsuccessful fresh embryo transfer and who have at least one vitrified frozen embryo in storage will be invited to “self test” themselves for the presence of BV using a vaginal pH glove. This glove has a pH meter on the index finger which when inserted into the vagina by the patient herself enables accurate measurement of vaginal acidity. A pH of 4.5 or less indicates normal vaginal environment and no BV is likely present. A pH of 4.7 and above is abnormal and highly suggestive of the presence of BV. Alternatively, if the woman does not wish to “self-test”, she can present to the clinic for a formal gynaecological examination and assessment. Those women screening positive by the glove pH test will then be invited to attend the clinic where they will undergo a gynaecological examination to confirm the presence of BV. This examination will include a clinical diagnosis of BV using the Amsel criteria and Nugent score testing. Only those women positive for BV on both Amsel and Nugent score tests, and who have no evidence of Candida on microscopy examination, will be enrolled in the next phase of the study. All patients entering the study will be administered a single 2gm oral dose of the antibiotic Tinidazole as soon as the diagnosis of BV is made (i.e. at the screening gynaecological examination). Participants will then be randomly allocated in equal numbers to commence either daily oral probiotic (two capsules orally daily) or an identical appearing placebo. This treatment will commence 2 weeks before the anticipated menstrual period date when the patient will book on for her frozen embryo IVF cycle. Treatment with either oral probiotic or placebo will continue until the embryo transfer day, which in general occurs approximately 2-3 weeks after the commencement of menses (i.e. total 4-5 weeks of probiotic / placebo treatment). At the time of the embryo transfer examination a repeat “proof of cure” BV gynaecological exam will be conducted using the Amsel criteria and Nugent score assessment. The oral study medication (active probiotic or placebo) will be taken on the day of embryo transfer but ceased at that point in time. The experimetal therapy (probiotic / placebo) capsules will be provided by the manufacturer (Hansen, Denmark) and will be identical in appearance and taste. Both study participants and research/ clinical personelle will be blinded to treatment allocation. Treatment packs will be sequentially numbered and prepared by a third party contractor, using a computer generated randomisation sequence. Research personelle will simply allocate study participants the next treatment pack in the numerical sequence.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A third party will use an on line random sequence generator program to construct the ransomised treatment schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
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)

Funding & Sponsors
Funding source category [1] 284429 0
Commercial sector/Industry
Name [1] 284429 0
Chr. Hansen
Address [1] 284429 0
Boge Alle 10-12, Horsholm
Denmark
Country [1] 284429 0
Denmark
Funding source category [2] 284430 0
Commercial sector/Industry
Name [2] 284430 0
Blackmores
Address [2] 284430 0
20 Jubilee Avenue
Warriewood
NSW 2102
Country [2] 284430 0
Australia
Primary sponsor type
University
Name
University of South Australia
Address
North Terrace
Adelaide
South Australia 5000
Country
Australia
Secondary sponsor category [1] 283353 0
Commercial sector/Industry
Name [1] 283353 0
Repromed
Address [1] 283353 0
180 Fullarton road
Dulwich
South Australia 5065
Country [1] 283353 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286402 0
University of South Australia Human Research Ethics
Ethics committee address [1] 286402 0
Mawson lakes Campus
Mawson Lakes boulevard
Mawson Lakes
South Australia 5095
Ethics committee country [1] 286402 0
Australia
Date submitted for ethics approval [1] 286402 0
12/12/2011
Approval date [1] 286402 0
11/01/2012
Ethics approval number [1] 286402 0
26633

Summary
Brief summary
Bacterial Vaginosis (BV) is very common clinical condition with prevalence rates between 10 and 30 % of women in the reproductive age group. While in some cases BV is asymptomatic, in many women BV produces annoying symptoms (vaginal discharge, offensive smell). BV may also interfer with successful implantation of an embryo during IVF treatment, as these bacteria may be introduced from the vagina into the uterus at the time of the embryo transfer, causing inflammation of the uterine lining (endometrium). BV has been linked with a reduction in implantation rates in IVF and an increase risk of miscarriage. Therefore effective long term treatment/ prevention of BV in an IVF setting is important. The aim of this study is to determine if the oral administration of a probiotic can result in vaginal colonization and a subsequent reduction in reoccurance of BV infection after antibiotic (tinidazole) treatment.
Trial website
None
Trial related presentations / publications
None
Public notes

Contacts
Principal investigator
Name 33565 0
Address 33565 0
Country 33565 0
Phone 33565 0
Fax 33565 0
Email 33565 0
Contact person for public queries
Name 16812 0
Dr Kelton Tremellen
Address 16812 0
180 Fullarton Road
Dulwich
South Australia 5065
Country 16812 0
Australia
Phone 16812 0
+61 8 83338111
Fax 16812 0
+61 883338188
Email 16812 0
ktremellen@repromed.com.au
Contact person for scientific queries
Name 7740 0
Dr Kelton Tremellen
Address 7740 0
180 Fullarton Road
Dulwich
South Australia 5065
Country 7740 0
Australia
Phone 7740 0
+61 883338111
Fax 7740 0
+61 8 83338188
Email 7740 0
ktremellen@repromed.com.au

No information has been provided regarding IPD availability
Summary results
No Results