Phase 2 Placebo-controlled Randomized Trial of LACTIN-V (Lactobacillus Crispatus CTV-05) Among Women at High Risk of HIV Acquisition in Durban, South Africa

The purpose of this study is to assess the impact of LACTIN-V, a vaginally administered live biotherapeutic product (LBP) that contains the human L. crispatus CTV-05 strain, on the vaginal microbiome of Lactobacillus-deficient young women in the South African FRESH study who are at high risk for HIV acquisition.

Start Date10 May 2021

Sponsor / Collaborator

The University of California, San Francisco

[+6]

NCT03992534 / Unknown statusPhase 1IIT

Feasibility, Safety, Tolerance and Assessment of LACTIN-V Use in a Cohort of Pregnant Women at Risk of Preterm Birth

Preterm birth (PTB) is the primary cause of infant death worldwide. It has been shown that a vaginal microbiota deplete in Lactobacillus species is a risk factor for preterm labour. Conversely a vaginal microbiota dominated by Lactobacillus crispatus appears to be protective for these adverse outcomes. A wide range of 'over the counter' Lactobacillus spp. containing products targeted at 'vaginal health' and formulated for vaginal administration are available, but most of them do not contain vaginal species of Lactobacillus. The primary aim of this study is to determine whether vaginal supplementation with L. crispatus CTV-05 is associated with colonisation.

Start Date16 Sep 2019

Sponsor / Collaborator

Imperial College London

[+1]

NCT02766023 / CompletedPhase 2IIT

Phase II-b Randomized Double-Blind Placebo-Controlled Trial of Lactobacillus Crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis

This Phase 2b trial is designed to provide a screening evaluation for the hypothesis that, following a 5-day treatment with MetroGel® to treat BV, L. crispatus CTV-05 (LACTIN-V, Osel, Inc.) administered at 2 x 10^9 cfu/dose using a vaginal applicator reduces the 12-week incidence of BV recurrence when compared to placebo. The primary objectives of this study are: 1) To estimate the efficacy of repeated doses of LACTIN-V (2 x 10^9 cfu/dose) as compared to placebo in preventing BV recurrence by 12 weeks following treatment of BV with MetroGel vaginal gel (MetroGel). 2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of AEs between individuals randomized to LACTIN-V or placebo.

Start Date03 Jun 2016

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

100 Clinical Results associated with CTV-05

100 Translational Medicine associated with CTV-05

100 Patents (Medical) associated with CTV-05

Literatures (Medical) associated with CTV-05

14 Apr 2023·Beneficial microbes

Impact of Lactobacillus crispatus-containing oral and vaginal probiotics on vaginal health: a randomised double-blind placebo controlled clinical trial

Article

Author: Tamm, H ; Smidt, I ; Kõljalg, S ; Mändar, R ; Sõerunurk, G ; Piiskop, S ; Saare, M ; Ausmees, K ; Rööp, T ; Štšepetova, J ; Le, D D ; Salumets, A ; Jaagura, M

Health of reproductive tract is tightly associated with balance of microbial communities in this area. Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) represent common disturbances of vaginal communities. Vaginal discharge due to BV or VVC is a very frequent reason for visiting gynaecologist. We aimed to evaluate the impact of the novel evidence-based probiotics on BV and VVC patients. The study group included 89 BV and 93 VVC patients (aged 18-50 years) who were recruited into randomised double-blind placebo-controlled two-arm parallel trial. The patients of each diagnosis group received oral or vaginal probiotic capsules, or placebo capsules during 3 months. A probiotic capsule contained two (DSM32717 and DSM32720, in case of BV) or three (DSM32720, DSM32718 and DSM32716, in case of VVC) Lactobacillus crispatus strains. Vaginal, intestinal and general health was monitored weekly by questionnaire. Blood analyses were done in the beginning and at the end of trial. Vaginal samples were collected monthly, microscopic and molecular analyses were performed. The study revealed that both oral and vaginal capsules reduced the signs and symptoms in BV patients. Remarkable improvement was noted in Nugent score, amount and smell of discharge, but also in itching/irritation. Consumption of vaginal probiotics significantly increased the lactobacilli counts in their vagina while mean proportion of some BV-related bacteria decreased. In VVC patients, both oral and vaginal capsules lowered the combined score of two most important symptoms, amount of discharge and itching/irritation. In conclusion, the novel formulations of evidence-based well-focused probiotic L. crispatus strains are effective against BV and VVC being suitable for both vaginal and oral administration.Clinical trial registration: ISRCTN34840624, BioMed Central

23 Feb 2023·Beneficial microbes

Safety, tolerability, and acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) in pregnant women at high-risk of preterm birth

Article

Author: Bayar, E. ; Parks, T.P. ; Lee, P.P. ; Mountain, K. ; MacIntyre, D.A. ; Sykes, L. ; Bennett, P.R.

The vaginal microbiota is a determinant for the risk of preterm birth (PTB). Dominance of the vaginal niche by Lactobacillus crispatus associates with term delivery. This is the first observational clinical study of live vaginal biotherapeutics (Lactobacillus crispatus CTV-05 (LACTIN-V)) in pregnant women at high-risk of PTB. The primary aim was to explore safety, tolerability and acceptability of LACTIN-V in pregnancy. Women were offered a course of LACTIN-V at 14 weeks gestation for five consecutive days followed by weekly administration for six weeks. Participants were followed up at 15, 18-, 20-, 28- and 36-weeks’ gestation and at delivery for assessment of adverse events, compliance and tolerability. Participants completed a questionnaire to gauge experience and acceptability. In total, 73 women were recruited, of whom eight withdrew, leaving a final cohort size of 61. Self-reported compliance to the course was high (56/60, 93%). Solicited adverse events were reported in 13 women (19%) including changes in vaginal discharge, odour, colour or consistency of urine, itching and vaginal bleeding. One unsolicited adverse event was reported as haematuria at 38 weeks gestation, but was judged to be unrelated to LACTIN-V. No serious adverse events occurred. One mild adverse event led to study withdrawal. Thirty-one women completed an experience and acceptability questionnaire. Women found LACTIN-V easy and comfortable to use and the majority (30/31, 97%) would use LACTIN-V in future pregnancies. Eight women (8/31, 26%) found the schedule of use difficult to remember. The rate of PTB <34 weeks in this cohort was 3.3% compared to 7% in a historical cohort of 2,190 women at similar background PTB risk. With satisfactory uptake and good compliance, we demonstrate that LACTIN-V is safe and accepted in pregnancy, with high tolerability. Further studies are needed to assess colonisation of Lactobacillus crispatus CTV-05 and clinical efficacy.

16 Aug 2022·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

Lactobacillus crispatus Limits Bladder Uropathogenic E. coli Infection by Triggering a Host Type I Interferon Response

Q1 · CROSS-FIELD

Article

Author: Cho, Kyu Sang ; Choi, Hae Woong ; Kim, Young Ho ; Shin, Minhye ; Song, Chang Hyun ; Hayes, Byron W. ; Lee, Eun-Jin ; Abraham, Soman N. ; Suk, Gyeongseo ; Kim, Min Jung ; Noh, Joo Hwan ; Naskar, Manisha ; Abraham, Mathew A.

Many urinary tract infections (UTIs) are recurrent because uropathogens persist within the bladder epithelial cells (BECs) for extended periods between bouts of infection. Because persistent uropathogens are intracellular, they are often refractive to antibiotic treatment. The recent discovery of endogenous Lactobacillus spp. in the bladders of healthy humans raised the question of whether these endogenous bacteria directly or indirectly impact intracellular bacterial burden in the bladder. Here, we report that in contrast to healthy women, female patients experiencing recurrent UTIs have a bladder population of Lactobacilli that is markedly reduced. Exposing infected human BECs to L. crispatus in vitro markedly reduced the intracellular uropathogenic Escherichia coli (UPEC) load. The adherence of Lactobacilli to BECs was found to result in increased type I interferon (IFN) production, which in turn enhanced the expression of cathepsin D within lysosomes harboring UPECs. This lysosomal cathepsin D–mediated UPEC killing was diminished in germ-free mice and type I IFN receptor–deficient mice. Secreted metabolites of L. crispatus seemed to be responsible for the increased expression of type I IFN in human BECs. Intravesicular administration of Lactobacilli into UPEC-infected murine bladders markedly reduced their intracellular bacterial load suggesting that components of the endogenous microflora can have therapeutic effects against UTIs.

News (Medical) associated with CTV-05

12 Dec 2023

·www.biospace.com

Suzhou OSAI Biopharma Announces Positive Phase III Clinical Trial Results for Lactobacillus Crispatus Live Bacteria Capsule, Significantly Reducing Recurrence of Gynecological Infections

SUZHOU, China--(BUSINESS WIRE)-- Suzhou OSAI Biopharma, Inc., a biopharmaceutical company focused on developing live biotherapeutic products (LBPs), today announced that its Phase III clinical trial of vaginal L. crispatus live bacteria capsule (Lc262-1) has successfully met its primary and secondary endpoints. The Phase III study was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 320 patients with bacterial vaginosis (BV). After receiving seven days of oral metronidazole and vaginal LBP/placebo combination therapy, the cured patients were followed up for three months. The results from the treatment group were superior to the placebo group on the primary and secondary endpoints, with statistically significant differences between the two groups. In terms of safety, there was no difference in the incidence of adverse events or adverse reactions between the two groups. “The prevention of recurrent infection is critical in treating gynecological infections,” said Prof. Liu Zhaohui, MD, the principal investigator of the study and vice-chair of the Infection Working Group of the Chinese Medical Association's Department of Obstetrics and Gynecology, Capital Medical University Affiliated Beijing Obstetrics and Gynecology Hospital. “In China, more than 70 million BV cases are reported annually, with a 12-month recurrence rate of up to 60%. Currently, there are very limited effective treatments available. The positive results of this Phase III clinical trial have demonstrated the efficacy of L. crispatus in suppressing BV recurrence, providing patients with a new treatment option.” “Vaginal L. crispatus live bacteria capsule is a novel Live Biotherapeutic Product (LBP) that aims to restore healthy vaginal microbiota by using L. crispatus to prevent and reduce the recurrence of vaginal infections,” said Dr. Liu Yang, co-founder and chief scientific officer of Suzhou OSAI Biopharma. “This Phase III clinical trial is the first registrational Phase III clinical trial globally to evaluate the efficacy of L. crispatus in reducing BV recurrence under a rigorous clinical design. The observed data is encouraging, our team is committed to continuing to advance the program in regulatory registration and further expand our LBP pipeline.” About Vaginal L. crispatus Live Bacteria Capsule Vaginal L. crispatus live bacteria capsule is a first-in-class, innovative LBP developed by Suzhou OSAI Biopharma, utilizing live L. crispatus bacteria to restore the balance of the vaginal microbiome. L. crispatus is the most common and dominant bacteria in the vaginas of healthy Chinese women of childbearing age. The presence and enrichment of L. crispatus in the vaginal environment is considered a marker of healthy vaginal microbiota. L. crispatus can suppress the growth of other microorganisms through various mechanisms, such as maintaining a weakly acidic environment in the vagina by producing lactic acid, producing hydrogen peroxide, competing for nutrients (such as glycogen), occupying space (by competing for adhesion to vaginal epithelial cells) and stimulating local vaginal immunity. In recognition of the important role of L. crispatus in maintaining vaginal health, Suzhou OSAI Biopharma selected a strain of L. crispatus, Lc262-1, from the vaginal microbiota of healthy Chinese women. Leveraging its proprietary “Natural Microbiome Drug Development Platform,” the company developed a highly stable live bacteria capsule. About Bacterial Vaginosis Bacterial vaginosis (BV) is a common vaginal infection in women of childbearing age. It is caused by an overgrowth of anaerobic bacteria in the vagina. In China, there are over 70 million cases of BV each year. The recurrence rate of BV is high, roughly 20% within one month of treatment, 40% within three months of treatment, and 60% within 12 months of treatment. BV can also lead to pelvic inflammatory disease, post-surgical infections after gynecological surgery, and infertility. BV in pregnancy can lead to miscarriage, preterm birth, premature rupture of membranes, chorioamnionitis, neonatal infection, and postpartum infection. BV can also increase the risk of sexually transmitted infections (STIs), such as those caused by HPV, HIV, Neisseria gonorrhoeae, Chlamydia trachomatis, and herpes simplex virus type 2. About Suzhou OSAI Biopharma Founded in 2011, Suzhou OSAI Biopharma is a biopharmaceutical company focused on the research and development of LBPs. The company has built its own proprietary "Natural Microbiome Drug Development Platform" since its inception, with patents covering the Greater China Area, United States, Europe, Japan, South Korea, and Southeast Asia. OSAI Biopharma is committed to the research and development of LBPs to restore the healthy balance of human microbiome. Its lead asset, live L. crispatus capsule, has completed a Phase III clinical trial and demonstrated significant potential in the treatment and prevention of BV related to microbiota dysbiosis. OSAI Biopharma anticipates applying for Biologics License Applications (BLA) of its vaginal L. crispatus capsule to the China NMPA’s Center of Drug Evaluation (CDE) in the near future.

Phase 3Clinical ResultMicrobial therapy

21 Jul 2023

·www.sciencedaily.com

Probiotic combo stops bacteria that cause toxic shock syndrome

New findings suggest that a probiotic combination could reduce incidence of toxic shock syndrome. The widespread, pathogenic microbe Staphylococcus aureus can colonize the skin and mucous membranes throughout the body, particularly the vagina and gastrointestinal tract. A virulent strain of the bacterium produces proteins that trigger toxic shock syndrome (TSS), a disease characterized by the quick onset of fever, a telltale rash, and, without treatment, multi organ failure. In the vagina, TSS is associated with a life-threatening reaction from the immune system. Probiotics may help prevent the disease before the cytokine cascade ever begins. A study published in the American Society for Microbiology's journal Microbiology Spectrum reports that strains of 2 bacteria, Lactobacillus acidophilus and Lacticaseibacillus rhamnosus, successfully inhibited the production of the superantigens that cause TSS, in lab experiments. L. acidophilus, in addition, inhibited the growth of the S. aureus strains that produce the problematic proteins. A combination of the 2 could both prevent growth and inhibit the immune response. "It's kind of a double whammy against S. aureus," said microbiologist Patrick Schlievert, Ph.D., at the University of Iowa Carver College of Medicine, in Iowa City. "If any toxin is made, the probiotics still prevent inflammation." He noted that adding these probiotics to tampons or other menstrual products could reduce the risk -- and global incidence -- of TSS associated with menstruation. Such a preventive measure has the potential to benefit millions of vulnerable people, Schlievert said. "We know that 20% of people over age 12 cannot make antibodies and never will make antibodies against toxic shock syndrome," he said. Schlievert has been studying TSS -- and its prevention -- for decades. In the early 1980s, he was the first researcher to identify the toxin that triggers an overreaction of the immune system, and to show how high-absorbency tampons facilitated production of that toxin if S. aureus was present. The new work, he said, was motivated by observations made during an earlier study. A few years ago, he and his colleagues recruited 205 women to test whether a novel molecular mixture, when added to tampons, would inhibit pathogenic bacteria. That molecule proved effective against E. coli and other pathogens, but the researchers noticed an unexpected consequence. "Some of the women in the treatment group had this tremendous growth of Lactobacilli," Schlievert said. Further studies revealed that 9 of those women were colonized with only L. crispatus and no other bacteria. In microbiology research, Schlievert said, colonization by a single bacterium is often regarded as unhealthy. In this case, however, it offered an effective action against pathogenic S. aureus. Lactobacillus bacteria have already been shown to be safe, Schlievert said, and the new work suggests that treatment with L. crispatus alone, or L. acidophilus and L. rhamnosus in combination, could dramatically reduce the risk of TSS in vulnerable populations. Strains of S. aureus can also cause enterocolitis, a life-threatening immune response in the gut. Probiotics may also help reduce the production of dangerous proteins for that disease, said Schlievert. In ongoing and future work, Schlievert and his team are investigating how to use probiotics to prevent skin staph infections. The skin of people with atopic dermatitis, or with type 2 diabetes, is often colonized with the strains of S. aureus that produce superantigens, which are often resistant to treatment with standard antibiotics. In patients with type 2 diabetes, those superantigens could lead to foot ulcers that, if not treated successfully, could lead to amputation. Schlievert sees probiotics as a promising way to prevent those complications. "If we can improve their lives by using this approach, that would be wonderful."

Microbial therapy

03 Feb 2021

·www.biospace.com

Osel Obtains Exclusive License from Danish Research Consortia for IP Related to Osel’s LACTIN-V in Women Undergoing In-Vitro Fertilization

MOUNTAIN VIEW, Calif.--(BUSINESS WIRE)-- Osel, Inc., a company developing live biotherapeutic products (LBPs) for diseases linked to the disruption of the human microbiome, today announced that it has entered into a definitive agreement with a consortia comprising Aarhus University, Skive Hospital and Statens Serum Institut of Denmark, and obtained the exclusive worldwide license to inventions resulting from an investigator-initiated Phase 2 trial of Osel’s investigational LBP, LACTIN-V, in women undergoing in-vitro fertilization (IVF). Financial terms were not disclosed. Osel is developing LACTIN-V, a proprietary formulation of Lactobacillus crispatus being studied in IVF, in addition to bacterial vaginosis (BV) and pre-term birth. Last year, Osel and colleagues published data in The New England Journal of Medicine demonstrating that LACTIN-V significantly reduced the recurrence of BV versus placebo in a Phase 2b trial. “Dysbiosis, or disruption of the vaginal microbiome, can lead to many problems in women’s health including BV and decreasing the success rate of IVF,” said Peter P. Lee, MD, Founder and Executive Chairman of Osel. “LACTIN-V, which contains the protective vaginal bacterial strain L. crispatus CTV-05, could help promote a healthier vaginal microbiome for IVF.” Under the agreement, the ongoing Phase 2 IVF trial is being conducted at four fertility clinics in Denmark and led by Professor Peter Humaidan, MD, Aarhus University and Skive Regional Hospital. The primary endpoint of the trial is clinical pregnancy at seven weeks post-embryo transfer in women with documented abnormal vaginal microbiota, which lowers the probability of successful IVF. “The vaginal microbiome and its importance for fertility is an intriguing new field of research. In the near future we hope to be able to define the most optimal vaginal microbiome – and importantly, to be able to modify the abnormal to normal,” said Professor Humaidan. “The ultimate goal of our research is to improve success rates of not only IVF, but also spontaneous pregnancy.” “LACTIN-V holds promise as the first treatment to increase the possibility of pregnancy from IVF, especially in women with vaginal dysbiosis,” said Thomas Parks, PhD, Director of Product Development at Osel. “While the trial’s progress was impacted by COVID-19, we expect to complete enrollment by the end of 2021/early 2022.” About Osel, Inc. Osel, Inc., a privately held biopharmaceutical company based in Mountain View, California, is focused on the development and commercialization of a portfolio of live biotherapeutic products (LBPs) to prevent or treat medical conditions resulting from disruption of the human microbiome (dysbiosis). The company is a pioneer in the field of LBPs, with a primary focus in women’s health. While many current microbiome treatments involve microbial transplants that are collected and processed from donor pools, Osel focuses on rigorously selected single strain products that are highly reproducible, scalable, and safe. Visit oselinc.com to learn more.

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Vaginosis	Phase 3	US	Osel, Inc.	22 Jul 2022
Urinary Tract Infections	Phase 3	US	University of Washington	18 Aug 2015
Female genital tract infection	Phase 2	US	The Medicines Co.	17 Aug 2000
Obstetric Labor, Premature	Phase 1	US	Osel, Inc.	22 Jul 2022
Candidiasis	Preclinical	US	Osel, Inc.	31 Aug 2011

Clinical Result

Indication

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03151967 (CTgov)	Phase 2/3	Urinary Tract Infections	27	Lactobacillus crispatus CTV-05 (Applicator With LACTIN-V Treatment)	grxjfxyihx(jbejvdpnnu) = engzqeedze oamkidcdzr (pyphtcbsah, ykgkbwmswi - azfmtylonr) View more	-	01 Mar 2023
				Placebo (Applicator With Placebo)	grxjfxyihx(jbejvdpnnu) = pjuognvggv oamkidcdzr (pyphtcbsah, tpvdpoclbe - qcrhzezgau) View more
NCT02766023 (Pubmed) Manual	Phase 2	Bacterial Vaginosis	228	Lactin-V	vbmdtxytlm(xtmzuslkah) = reburmvriu nkmgrkotpv (qulfywqggf ) View more	Positive	14 May 2020
				Placebo	vbmdtxytlm(xtmzuslkah) = pccqvazkon nkmgrkotpv (qulfywqggf )
NCT02766023 (CTgov)	Phase 2	Bacterial Vaginosis	228	Metronidazole+Lactobacillus crispatus CTV-05 (LACTIN-V)	ogjyxllkzz(xthvhouxdf) = zbxsnbcnco fihfoaxivp (kfsrhsknql, odommrmzac - gxrinrcvep) View more	-	11 Feb 2020
				Placebo+Metronidazole (Placebo)	ogjyxllkzz(xthvhouxdf) = gvarragtmk fihfoaxivp (kfsrhsknql, jemchapoyo - vuodokfexq) View more
NCT00305227 (CTgov)	Phase 2	Urinary Tract Infections	100	Lactin-V (Lactin-V)	stzwwecbzm(hpxslomiye) = wcgrvxjxqg ctrsathrqs (aemabxcnwy, fsofpzjgot - pdlpyyywkv) View more	-	04 Jul 2014
				Placebo (Placebo)	stzwwecbzm(hpxslomiye) = jnewprzwan ctrsathrqs (aemabxcnwy, jyklpwrzaa - vdindfarjj) View more
NCT00305227 (Pubmed \| Clin Infect Dis)	Phase 2	Urinary Tract Infections	100	Lactin-V	xmwyfnulcl(fcggvfqzmv) = xzvplfxezx xefsiqmcfv (ljzqfenelf )	Positive	01 May 2011
				Lactobacillus crispatus probiotic (Placebo)	xmwyfnulcl(fcggvfqzmv) = pxsjjlzzob xefsiqmcfv (ljzqfenelf )

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