One of the most anticipated clinical trials in the history of preterm birth prevention will soon begin in London, and it’s being run out of the March of Dimes Prematurity Research Center at Imperial College London.
The randomized controlled trial (RCT), known as the ”gold standard” of scientific study, will enroll women at high risk of preterm birth to take a live biotherapeutic, or a vaginal capsule containing ”good” Lactobacillus crispatus bacteria, for the duration of their pregnancies to see if it prevents the occurrence of preterm birth. The trial is the first RCT of a live biotherapeutic in pregnancy.
All those enrolled will be at high risk, meaning they gave birth preterm in a previous pregnancy. Women will then be randomized into two groups: ones who will receive the L. crispatus bacteria associated with a healthy reproductive system, and ones who will receive a placebo. It’s a double-blind trial, meaning neither the patients nor the scientists and doctors involved will know who gets the treatment and who gets the placebo.
If successful at significantly reducing preterm birth — preliminary findings are anticipated sometime in 2029 — the trial could enter a third phase in the U.S., and, if findings there are also positive, could result in the live biotherapeutic being available in OB-GYN offices globally, dramatically altering the prognosis for women at risk of preterm birth.
Called FLIP2, a reference to “flipping” the flora in a woman’s vagina from bad to good, the trial has been a decade in the making, and represents one of the most exciting developments in the field of preterm birth research and the race to find therapeutics that could prevent early labor.
“There’s been a lot of work to get here," said Dr. Lynne Sykes, an Imperial PRC co-director and one of two principal investigators of the FLIP2 trial. “We’re incredibly excited."
Though Imperial PRC scientists have been planning this trial for the better part of a decade, its roots can be traced back to the early 1980s, when Dr. Phil Bennett, the trial’s other principal investigator, was an early career scientist working at London’s Hammersmith Hospital. He was part of the research group that first discovered something special about a family of bacteria called lactobacillus that resided in the human body: it had anti-inflammatory properties. Since then, the lactobacillus family has stayed in the good graces of human health, with research finding tremendous benefit in the gut microbiome, a development that has led to a spike in the consumption of probiotic-rich foods like yogurt, kefir, kombucha, and sauerkraut.
But intestinal health wasn’t the apex for lactobacillus; at the same time, the family was also emerging as an incredibly powerful mediator of women’s reproductive health. In the last 15 years, with dramatic technological and scientific advances in the study of the vaginal microbiome (the collection of fungi, bacteria, and viruses in a woman’s vaginal canal), researchers began to uncover the benefits of a microbiome populated by members of the lactobacillus family — and one member in particular.
Scientific research, much of it led by Dr. Bennett, Dr. Sykes, and Dr. David MacIntyre at the Imperial PRC, showed L. crispatus to be the premier ”good guy” in the microbiome; its presence was linked with term birth, protection against HPV, HIV, cervical dysplasia, miscarriage, bacterial vaginosis, and more. Conversely, other bacteria not part of the lactobacillus family were associated with adverse reproductive outcomes. Colloquially among researchers, the other bacteria came to be known as the ”bad” and ”ugly” guys (although the Lactobacillus family does have a black sheep, L. iners, known to act badly from time to time and cause inflammation).
And while several different lactobacillus species contribute to good reproductive outcomes, L. crispatus emerged as the clear protagonist, partly because the species is coated in a protective shield that prevents it from interacting with pro-inflammatory receptors and causing inflammation in the vaginal canal. Though researchers have identified hundreds of L. crispatus strains, one called CTV-05 has been made into a vaginal suppository called LACTIN-V. This is the specific bacteria at the center of the FLIP2 trial.
But FLIP2 is not exactly LACTIN-V’s big debut. Several years ago, the team at Imperial conducted FLIP1, a feasibility study that saw high-risk pregnant women take LACTIN-V for the first time. But that study was not powered to look at pregnancy outcomes; instead, the purpose was to ensure the bacteria were safe and tolerable to patients, and that it was able to gain a foothold in the vagina. FLIP1 found both to be true: LACTIN-V was safe and could colonize microbiomes that were not already crispatus-dominant. And there was icing on the cake: the preterm birth rate for the group of women who took the live biotherapeutic plummeted from the expected 25%-28% to 12% — a whopping 50% reduction that sent a wave of excitement through the Imperial team.
So, after years of nonstop preparation, FLIP 2, the test of whether the crispatus live biotherapeutic can prevent preterm birth, is about to begin. For Dr. Bennett, who was among the first scientists to report the benefits of lactobacillus in the 1980s, the trial is personal.
“This is particularly exciting to me because I began my research career back in the early 1980s, discovering that lactobacilli are anti-inflammatory and the other organisms are inflammatory,” Dr. Bennett said last year. “So here I am, 40 years later, on the cusp of finding a way to reverse that situation using a therapy. So, for me, there’s sort of a coming full circle in my career.”
FLIP2 will enroll 360 pregnant women to take one LACTIN-V suppository daily starting at 12-14 weeks gestation to 34 weeks. The hypothesis goes that since bad and ugly vaginal bacteria are estimated to be responsible for upwards of 40% of all preterm births, a large chunk of women at risk of preterm birth has microbiomes populated with these players. Giving these women the good bacteria should "flip their flora” and lead to a reduction in preterm birth.
While the big question of the trial is whether women in the treatment group will have lower rates of preterm birth than those taking the placebo, Dr. Sykes and Dr. Bennett are not stopping there, collecting as much biological data as possible to ensure they make the most of the historic opportunity.
The team will take vaginal swabs from participants throughout the trial to see what kind of bacteria the women start the pregnancy with and what kind they end with, and whether those bacteria are causing inflammation. Inflammatory status of bacteria, no matter from which family or strain it comes, is the key arbiter of vaginal bacteria-related preterm birth risk. In fact, sometimes women with crispatus-dominant microbiomes will go on to have preterm birth, and those with bad or ugly compositions will not. Imperial researchers attribute to this to each woman’s unique immune system, with traditionally inflammatory bacteria leading to a low inflammatory response in some women, and traditionally anti-inflammatory bacteria leading to a higher than anticipated response in others. With FLIP2, the team wants to see if the live biotherapeutic can change the vaginal microbiome’s bacterial makeup, inflammatory profile, or both. But until now, identifying bacteria and inflammatory load in the vagina quickly and accurately was not easy.
That all changed with the work of Imperial’s Dr. MacIntyre, who several years ago led a team to create the DESI-MS, a device that identifies vaginal bacteria from a swab in under two minutes, and shows whether the bacteria are contributing to inflammation inside the microbiome. By allowing the comparison of the treatment group’s birth outcomes with their bacterial compositions and inflammatory status before and after the live biotherapeutic, FLIP2 will answer lingering questions about vaginal bacteria, inflammation, and preterm birth risk.
Critically, it will also shed light on whether the DESI device works as it should, validating the instrument used in the trial itself.
Additionally, the team will use those same swabs to check for blood type antigens in the cervicovaginal fluid of all study participants to see whether women with one blood type antigen have a higher risk of preterm birth than women with others. Thanks to recent research by Dr. Sykes, the team knows that secretion of blood type antigens adorned with the right sugars is associated with L. crispatus dominant vaginal microbiomes. The team will look at study participants’ antigen secretions to check whether antigens are being secreted at all (20% of women are non-secreters), and what their antigen sugar structure looks like. They’ll then compare that data to birth outcomes to see what new links they may make between blood type antigens and preterm birth risk.
“We are going to have a lot of answers at the end of this trial,” said Dr. Sykes. “We’ll be able to say whether LACTIN-V reduced preterm birth rates; whether it flipped the flora from bad to good; whether it tempered inflammation enough to prevent preterm birth; whether it worked best for one blood type over another; whether antigen non-secreters have a higher risk of preterm birth; whether our DESI system works as intended; and more.”
“This is really big.”
Plus, Dr. Bennett said the trial will also show whether all pregnant women would benefit from L. crispatus prenatally regardless of whether their vaginal microbiome is populated by good or bad bacteria to start.
“There is a lot to learn,” he said, “we'll be watching these women and this trial very closely.”