The Effect of Clindamycin and a Live Biotherapeutic on the Reproductive Outcomes of IVF Patients With Abnormal Vaginal Microbiota

Study Overview
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Brief Summary
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Study question: Does antibiotic alone or in combination with live biotherapeutic treatment of an abnormal vaginal microbiota improve the reproductive outcomes of IVF couples? Study hypothesis: The investigator hypothesize that treatment of the reproductive tract pathogens and restoration of vaginal Lactobacillus will improve the reproductive outcomes of IVF patients. What is known already? Ultra-deep sequencing methods enable the refinement of reproductive tract microbiology in infertile patients. A recent meta-analysis reported that 19% of infertile patients had abnormal vaginal microbiota Moreover, someone have detected the presence of a Gardnerella (G.) vaginalis dominated endometrial biofilm in 50% of non-infertile patients with abnormal vaginal microbiota undergoing curettage; thus the treatment of such an endometrial biofilm might play an important role for the endometrial receptivity and subsequently the clinical pregnancy rate. Pilot study: In a recent pilot study it was observed that an abnormal vaginal microbiota negatively affects the clinical pregnancy rate in IVF patients. In this study the prevalence of abnormal vaginal microbiota was 28% (36/130) and only 9% of patients with qPCR defined abnormal vaginal microbiota obtained a clinical pregnancy (p=0.004). This association remained significant in an adjusted analysis. Furthermore, the invetigators have preliminary results demonstrating that vaginal bacteria such as G. vaginalis can be found in the endometrium of IVF patients, which is also supported by recent publications What is the novelty of this study? To the investigators knowledge, no previous treatment study of abnormal reproductive tract microbiota has been performed in IVF patients; this relatively small intervention holds the potential to increase the baby-take-home rate after IVF treatment.

Official Title
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A Double-blind, Placebo-controlled Multicenter Trial on the Effect of Clindamycin and a Live Biotherapeutic on the Reproductive Outcomes of IVF Patients With Abnormal Vaginal Microbiota

Conditions
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Bacterial Vaginoses, Infertility, Female

Intervention / Treatment
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* Drug: Clindamycin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Abnormal vaginal microbiota. The screening swab should be repeated if more than 3 months old. HIV, Hepatitis B or C positivity. First, second or third IVF stimulation cycle or embryo transfer therefrom. BMI<35 Written informed consent. Exclusion Criteria: Known or suspected hypersensitivity to clindamycin. HPV CIN 2 or higher. Former or current inflammatory bowel disease Severe concomitant disease, including diabetes. MAX 2 embryos may be transferred Artificial heart valve Intrauterine malformations with operation indication as determined by treating physician (Polyps, Septum, fibroma)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clindamycin + LACTIN-V (L.crispatus)<br>Oral Clindamycin 300 mg 2 times per day for 7 days followed by LACTIN-V (Osel, Inc.) until completion of the clinical pregnancy scan at week 7-9. | Drug: Clindamycin<br>* Oral clindamycin 300mg/2xdaily in 7 days. LACTIN-V applicators 1x at night in 7 days, then 2xper week at night for 7 weeks.<br>* Other names: LACTIN-V;|
| Active Comparator: Clindamycin + placebo LACTIN-V<br>Oral Clindamycin 300 mg 2 times per day for 7 days followed by LACTIN-V placebo (Osel, Inc.) until completion of the clinical pregnancy scan at week 7-9. | Drug: Clindamycin<br>* Oral clindamycin 300mg/2xdaily in 7 days. LACTIN-V applicators 1x at night in 7 days, then 2xper week at night for 7 weeks.<br>* Other names: LACTIN-V;|
| Placebo Comparator: Placebo clindamycin + placebo LACTIN-V<br>Matching clindamycin placebo 2 times per day for 7 days followed by LACTIN-V placebo (Osel Inc.) until completion of the clinical pregnancy scan at week 7-9. | Other: Placebo<br>* The Clindamycin placebo appear identical to active clindamycin by filling capsules with Mannitolium. The LACTIN-V placebo product has no intrinsic effect and is used to study the effect of the therapeutically active product. It is supplied as a pre-filled vaginal applicator packaged under nitrogen gas with one desiccant packet (0.25 g) in a sealed foil pouch. Each applicator contains 200 mg of LACTIN-V placebo powder containing the inactive ingredients of the LACTIN-V drug product, but not Lactobacillus crispatus CTV-05 (CTV-05), the active ingedient. The excipients used in the manufacture of LACTIN-V placebo are identical to those in the LACTIN-V drug product. Each placebo applicator contains the following constituents: maltodextrin, trehalose, xylitol, colloidal silicon dioxide, and sodium ascorbate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical pregnancy per embryo transfer | Ultrasound scan detection of intrauterine fetal heartbeat in gestational week 7-9 | 7-9 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure of abnormal vaginal microbiota | A vaginal swab and qPCR-validated diagnostics for abnormal vaginal microbiota | 1-2 months | 
| Live birth rate | The birth of a live born child after 25 gestational weeks. | 25-42 weeks depending on pregnancy. | 
| Biochemical pregnancy | positive hCG blood test | 14 days gestation | 
| Implantation rate | The number of embryos implanting | pregnancy scan at 7-9 weeks | 
| early miscarriage | The loss of an hCG positive pregnancy | 14 days - 12 weeks gestation | 
| Number of late miscarriage | The of pregnancy in late pregnancy | 12 weeks gestation - to labour (i.e. not including still birth) | 
| Number of preterm birth | birth of a liveborn | prior to 37 gestational weeks | 
| Birth weight | weight at birth | 25-42 weeks gestation depending on pregnancy |