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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Infertility, Female; Bacterial Vaginoses
• Intervention / Treatment: Drug: Clindamycin; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 333
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Thor Haahr, MD; Phone Number: +4527885402; Email: thohaa@rm.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Copenhagen University Hospital, Rigshospitalet
    • Contact: Henriette Svarre, MD; Email: Henriette.Svarre.Nielsen@regionh.dk
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Stork Fertility Clinic VivaNeo
    • Contact: Vibeke Hartvig, MD; Email: vibeke.hartvig@storkklinik.dk
  • Hvidovre, Denmark, 2650
    • Recruiting
    • Hvidovre Hospital, The Fertility Clinic
    • Contact: Nina La Cour Freiesleben, MD; Email: nina.la.cour.freiesleben@regionh.dk
  • Skive, Denmark, 7800
    • Recruiting
    • Fertility Clinic Skive, Skive Regional Hospital
    • Contact: Thor Haahr, MD; Email: thorhaahr@hotmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Clindamycin + LACTIN-V (L.crispatus); 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; Oral clindamycin 300mg/2xdaily in 7 days. LACTIN-V applicators 1x at night in 7 days, then 2xper week at night for 7 weeks.; Other Names: LACTIN-V
Active Comparator: Clindamycin + placebo LACTIN-V; 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; Oral clindamycin 300mg/2xdaily in 7 days. LACTIN-V applicators 1x at night in 7 days, then 2xper week at night for 7 weeks.; Other Names: LACTIN-V
Placebo Comparator: Placebo clindamycin + placebo LACTIN-V; 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; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Peter Humaidan

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2017
• Primary Completion (Estimated): October 1, 2023
• Study Completion (Estimated): October 1, 2023

Study Registration Dates

• First Submitted: August 24, 2021
• First Submitted That Met QC Criteria: December 21, 2021
• First Posted (Actual): December 22, 2021

Study Record Updates

• Last Update Posted (Actual): July 6, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Vaginal Diseases; Vaginitis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Infertility; Vaginosis, Bacterial; Infertility, Female; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Clindamycin; Clindamycin palmitate; Clindamycin phosphate
• Other Study ID Numbers: AVM_Lacto_2015/582

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: To this date, the Danish Data Protection agency does not allow IPD to be shared. But if possible we will do so.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes