Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
NA
Total Enrollment
304 participants
Study Classification
INTERVENTIONAL
Study Start Date
2016-05-31
Study Completion Date
2017-06-30
Brief Summary
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Babies born preterm (before completing 37 weeks in the womb) are at increased risk of long-term disability and death. The investigators do not fully understand the cause(s) of preterm birth but it occurs more frequently when the normal, healthy bacteria (called Lactobacilli) in a woman's birth canal are replaced with unhealthy bacteria. Previous attempts to get rid of the unhealthy bacteria with antibiotics have not shown to affect the risk of preterm birth. The reason for this may be that what is required is the replacement of Lactobacilli in the birth canal. This can be done by asking women to take capsules containing lactobacilli once daily. To study whether oral Lactobacilli capsules compared with dummy capsules can reduce the risk of preterm birth, a large study involving approximately 10,000 women would be required. But the investigators do not know whether women would agree to take part in and complete such a study, and this is what the investigators wish to study in the small, initial study described here. The results of this study will show whether probiotics produce the desired biological effects on vaginal bacteria, and whether it would be feasible to perform the larger, definitive study of their effectiveness in prevention of preterm birth.
Detailed Description
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Preterm birth (PTB) is defined as the birth of a baby before the completion of 37 weeks gestation in the womb. It is the major cause of infant mortality particularly during the first month of life. Approximately 75 per cent of babies who die during the first 28 days of life are born before 37 weeks gestation. Survivors of PTB are at increased risk of long-term disabilities such as cerebral palsy, sight and hearing impairment, learning and behavioural problems, epilepsy, and hospital readmissions. Even late preterm births, defined as PTB at 34--36 weeks gestation, which account for 70% of all preterm births in England and Wales, are at increased risk of death and disability compared with babies born at term. Although the prevalence of adverse long--term outcome is highest among children born at the earliest gestational ages, the much higher number of births at 34--36 weeks of gestation compared with earlier gestations means that this group of children makes a major contribution to the number of children adversely affected. PTB and its consequences can have negative emotional and psychosocial impacts on parents and families.
In addition to its impact on individuals and families, the financial consequences for the public sector of caring for children born preterm are significant. The cost of care up to the age of 18 for children born preterm has been estimated to exceed £3 billion per year in England and Wales at 2006 prices. It has been estimated that a hypothetical intervention that delayed PTB by 1 week across all gestational age categories would reduce the public sector cost of PTB by £1 billion annually.
About one third of PTBs occur because early delivery is indicated due to complications in the mother or the unborn baby (fetus); the remaining two thirds occur spontaneously. The rate of PTB has increased by 19% from 1990 to 2010 in developed countries. At the same time, there has been a marked improvement in the survival rates of PTBs but a similar reduction in adverse outcomes has not been seen. Thus, the absolute numbers of individuals adversely affected is increasing.
Infection within the womb (intrauterine infection) is strongly associated with spontaneous PTB. The commonest pathway for intrauterine infection is the ascent of unhealthy bacteria from the vagina and cervix into the womb. Bacterial vaginosis (BV), in which the normally dominant healthy bacteria in the vagina (lactobacilli) are replaced with unhealthy bacteria, is strongly associated with PTB. Lactobacilli, principally the strains that produce higher levels of the chemical hydrogen peroxide, appear to protect against BV and reduce the risk of PTB.
Despite substantial evidence linking BV with PTB, the results of trials of antibiotic treatment of BV in pregnancy have not produced clear evidence of benefit. The reason for this might be that it is not the eradication of unhealthy bacteria that is required but rather the replacement of unhealthy bacteria with the normally dominant lactobacilli. One way of achieving this could be by administering lactobacilli-containing capsules (probiotics) to pregnant women. Oral probiotics taken during pregnancy may directly alter the vaginal bacteria and in so doing protect the cervical opening from ascending infection.
The investigators have formally reviewed the medical literature on the use of probiotics to prevent PTB. There is some evidence from medical trials which suggests that probiotics taken during pregnancy can reduce the risk of PTB but the trials have either been too small or of poor quality for the results to be conclusive. The results of an observational study on nearly 19,000 pregnant women suggested that probiotic- containing foods reduced the risk of spontaneous PTB.
The best way to determine whether probiotics can reduce the risk of PTB is by performing a type of study called a double-blind, randomised controlled trial (RCT). In such a trial, the participants are allocated to receive either probiotic supplements or dummy (placebo) supplements. The allocation to a particular supplement is purely by chance (random) and neither the participants nor the researchers know the allocation of any participant until the end of the trial (double-blind). Then, by looking at the difference in the rate of PTB between the groups it would be possible to say whether probiotics can reduce the rate of PTB. The investigators have estimated that an RCT that could detect a useful difference in the rate of PTB between the two groups would require the participation of approximately 10,000 women and cost several million pounds. Given that approximately 20,000 deliveries occur annually in inner North East London alone, there are sufficient women in this region who would be eligible for participation in such a RCT. However, the willingness of women to participate in and complete such a trial is unknown.
A small, pilot trial is required to determine what proportion of pregnant women would participate in a probiotics and PTB trial and the proportion that would complete the study. The proposal here, the PrePro trial, is designed to gather these data which will inform the feasibility, planning and execution of a large RCT looking at the effects of probiotics on PTB.
Potential risks and benefits of probiotics The World Health Organisation defines probiotics as live micro-organisms that confer a health benefit on the host when administered in adequate amounts. They can displace and kill pathogens, and modulate the immune response by interfering with the inflammatory cascade that can cause preterm labour. Administration of probiotics by mouth or intravaginally is safe and effective in reducing the incidence of or treating urogenital infections. There is no evidence of adverse consequences for mothers or their infants as a result of probiotic exposure during pregnancy. Acceptability of and compliance with daily ingestion of probiotic or placebo for a few weeks during mid-pregnancy was found to be high. The particular probiotic strains proposed for this study have been shown to be acceptable to and safe in pregnant women, and can colonise the vagina within 4 weeks of commencing oral intake.
A large intervention trial of ingesting oral capsules from early pregnancy to the end of gestation has not been performed in the UK. For such a trial to be successful, it is essential to gather data that will inform its feasibility, planning and execution. PrePro is designed to provide these data. This trial will be conducted in compliance with the study protocol, relevant regulations, and the MRC Guidelines for Good Clinical Practice (GCP).
In addition to its impact on individuals and families, the financial consequences for the public sector of caring for children born preterm are significant. The cost of care up to the age of 18 for children born preterm has been estimated to exceed £3 billion per year in England and Wales at 2006 prices. It has been estimated that a hypothetical intervention that delayed PTB by 1 week across all gestational age categories would reduce the public sector cost of PTB by £1 billion annually.
About one third of PTBs occur because early delivery is indicated due to complications in the mother or the unborn baby (fetus); the remaining two thirds occur spontaneously. The rate of PTB has increased by 19% from 1990 to 2010 in developed countries. At the same time, there has been a marked improvement in the survival rates of PTBs but a similar reduction in adverse outcomes has not been seen. Thus, the absolute numbers of individuals adversely affected is increasing.
Infection within the womb (intrauterine infection) is strongly associated with spontaneous PTB. The commonest pathway for intrauterine infection is the ascent of unhealthy bacteria from the vagina and cervix into the womb. Bacterial vaginosis (BV), in which the normally dominant healthy bacteria in the vagina (lactobacilli) are replaced with unhealthy bacteria, is strongly associated with PTB. Lactobacilli, principally the strains that produce higher levels of the chemical hydrogen peroxide, appear to protect against BV and reduce the risk of PTB.
Despite substantial evidence linking BV with PTB, the results of trials of antibiotic treatment of BV in pregnancy have not produced clear evidence of benefit. The reason for this might be that it is not the eradication of unhealthy bacteria that is required but rather the replacement of unhealthy bacteria with the normally dominant lactobacilli. One way of achieving this could be by administering lactobacilli-containing capsules (probiotics) to pregnant women. Oral probiotics taken during pregnancy may directly alter the vaginal bacteria and in so doing protect the cervical opening from ascending infection.
The investigators have formally reviewed the medical literature on the use of probiotics to prevent PTB. There is some evidence from medical trials which suggests that probiotics taken during pregnancy can reduce the risk of PTB but the trials have either been too small or of poor quality for the results to be conclusive. The results of an observational study on nearly 19,000 pregnant women suggested that probiotic- containing foods reduced the risk of spontaneous PTB.
The best way to determine whether probiotics can reduce the risk of PTB is by performing a type of study called a double-blind, randomised controlled trial (RCT). In such a trial, the participants are allocated to receive either probiotic supplements or dummy (placebo) supplements. The allocation to a particular supplement is purely by chance (random) and neither the participants nor the researchers know the allocation of any participant until the end of the trial (double-blind). Then, by looking at the difference in the rate of PTB between the groups it would be possible to say whether probiotics can reduce the rate of PTB. The investigators have estimated that an RCT that could detect a useful difference in the rate of PTB between the two groups would require the participation of approximately 10,000 women and cost several million pounds. Given that approximately 20,000 deliveries occur annually in inner North East London alone, there are sufficient women in this region who would be eligible for participation in such a RCT. However, the willingness of women to participate in and complete such a trial is unknown.
A small, pilot trial is required to determine what proportion of pregnant women would participate in a probiotics and PTB trial and the proportion that would complete the study. The proposal here, the PrePro trial, is designed to gather these data which will inform the feasibility, planning and execution of a large RCT looking at the effects of probiotics on PTB.
Potential risks and benefits of probiotics The World Health Organisation defines probiotics as live micro-organisms that confer a health benefit on the host when administered in adequate amounts. They can displace and kill pathogens, and modulate the immune response by interfering with the inflammatory cascade that can cause preterm labour. Administration of probiotics by mouth or intravaginally is safe and effective in reducing the incidence of or treating urogenital infections. There is no evidence of adverse consequences for mothers or their infants as a result of probiotic exposure during pregnancy. Acceptability of and compliance with daily ingestion of probiotic or placebo for a few weeks during mid-pregnancy was found to be high. The particular probiotic strains proposed for this study have been shown to be acceptable to and safe in pregnant women, and can colonise the vagina within 4 weeks of commencing oral intake.
A large intervention trial of ingesting oral capsules from early pregnancy to the end of gestation has not been performed in the UK. For such a trial to be successful, it is essential to gather data that will inform its feasibility, planning and execution. PrePro is designed to provide these data. This trial will be conducted in compliance with the study protocol, relevant regulations, and the MRC Guidelines for Good Clinical Practice (GCP).
Conditions
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Preterm Birth
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
PREVENTION
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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Probiotic
Those who provide consent will be randomised to receive once daily for the remainder of their pregnancy capsules of probiotics (containing Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 (each at 2.5 x 109 colony forming units (CFUs)). The product contains freeze-dried bacteria and excipients in a gelatin capsule.
Group Type
EXPERIMENTAL
Probiotic
Intervention Type
DIETARY_SUPPLEMENT
The probiotic capsule contains the two probiotics Lactobacillus rhamnosus GR-1 (GR-1) and Lactobacillus reuteri RC-14 (RC-14). The product contains freeze-dried bacteria and excipients in a gelatin capsule;
Placebo
Those who provide consent will be randomised to receive once daily for the remainder of their pregnancy capsules of the placebo containing excipients alone in a gelatin capsule
Group Type
PLACEBO_COMPARATOR
Placebo Comparator
Intervention Type
OTHER
The placebo contains excipients alone in a gelatin capsule
Interventions
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Probiotic
The probiotic capsule contains the two probiotics Lactobacillus rhamnosus GR-1 (GR-1) and Lactobacillus reuteri RC-14 (RC-14). The product contains freeze-dried bacteria and excipients in a gelatin capsule;
Intervention Type
DIETARY_SUPPLEMENT
Placebo Comparator
The placebo contains excipients alone in a gelatin capsule
Intervention Type
OTHER
Eligibility Criteria
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Inclusion Criteria
* Women aged 16 years and over at the time of the booking appointment.
* Women who are between 9-14 weeks gestation at the time of the dating scan.
* Women who are between 9-14 weeks gestation at the time of the dating scan.
Exclusion Criteria
* Lack of informed, written consent
Minimum Eligible Age
16 Years
Eligible Sex
FEMALE
Accepts Healthy Volunteers
Yes
Sponsors
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Queen Mary University of London
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Khalid S Khan, Phd
Role: PRINCIPAL_INVESTIGATOR
Queen Mary University of London
Rehan Khan, MD
Role: PRINCIPAL_INVESTIGATOR
Barts Health NHS
Locations
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Barts Health NHS Trust
London, , United Kingdom
Site Status
Homerton University Hospital
London, , United Kingdom
Site Status
Countries
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United Kingdom
References
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Office for National Statistics, (2014a). Gestation-specific Infant Mortality in England and Wales, 2012 tables. [Internet] Available at: http://www.ons.gov.uk/ons/rel/child-health/gestation-specific-infant-mortality-in-england-and-wales/2012/rft-table-1.xls
Reference Type
BACKGROUND
Doyle LW, Ford G, Davis N. Health and hospitalistions after discharge in extremely low birth weight infants. Semin Neonatol. 2003 Apr;8(2):137-45. doi: 10.1016/S1084-2756(02)00221-X.
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BACKGROUND
Arpino C, Compagnone E, Montanaro ML, Cacciatore D, De Luca A, Cerulli A, Di Girolamo S, Curatolo P. Preterm birth and neurodevelopmental outcome: a review. Childs Nerv Syst. 2010 Sep;26(9):1139-49. doi: 10.1007/s00381-010-1125-y. Epub 2010 Mar 27.
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BACKGROUND
Boyle JD, Boyle EM. Born just a few weeks early: does it matter? Arch Dis Child Fetal Neonatal Ed. 2013 Jan;98(1):F85-8. doi: 10.1136/archdischild-2011-300535. Epub 2011 Aug 24.
Reference Type
BACKGROUND
Saigal S, Doyle LW. An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet. 2008 Jan 19;371(9608):261-9. doi: 10.1016/S0140-6736(08)60136-1.
Reference Type
BACKGROUND
Mangham LJ, Petrou S, Doyle LW, Draper ES, Marlow N. The cost of preterm birth throughout childhood in England and Wales. Pediatrics. 2009 Feb;123(2):e312-27. doi: 10.1542/peds.2008-1827.
Reference Type
BACKGROUND
Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med. 2000 May 18;342(20):1500-7. doi: 10.1056/NEJM200005183422007. No abstract available.
Reference Type
BACKGROUND
Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012 Jun 9;379(9832):2162-72. doi: 10.1016/S0140-6736(12)60820-4.
Reference Type
BACKGROUND
Office for National Statistics, (2014b). Childhood, Infant and Perinatal Mortality in England and Wales, 2012. [Internet] Available at: http://www.ons.gov.uk/ons/rel/vsob1/child-mortality-statistics--childhood--infant-and-perinatal/2012/rft-cms-2012.xls
Reference Type
BACKGROUND
Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, Draper ES. Short term outcomes after extreme preterm birth in England: comparison of two birth cohorts in 1995 and 2006 (the EPICure studies). BMJ. 2012 Dec 4;345:e7976. doi: 10.1136/bmj.e7976.
Reference Type
BACKGROUND
Guaschino S, De Seta F, Piccoli M, Maso G, Alberico S. Aetiology of preterm labour: bacterial vaginosis. BJOG. 2006 Dec;113 Suppl 3:46-51. doi: 10.1111/j.1471-0528.2006.01122.x.
Reference Type
BACKGROUND
Donders GG, Van Calsteren K, Bellen G, Reybrouck R, Van den Bosch T, Riphagen I, Van Lierde S. Predictive value for preterm birth of abnormal vaginal flora, bacterial vaginosis and aerobic vaginitis during the first trimester of pregnancy. BJOG. 2009 Sep;116(10):1315-24. doi: 10.1111/j.1471-0528.2009.02237.x. Epub 2009 Jun 17.
Reference Type
BACKGROUND
Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-Hanssen P, Holmes KK. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. J Infect Dis. 1996 Nov;174(5):1058-63. doi: 10.1093/infdis/174.5.1058.
Reference Type
BACKGROUND
Wilks M, Wiggins R, Whiley A, Hennessy E, Warwick S, Porter H, Corfield A, Millar M. Identification and H(2)O(2) production of vaginal lactobacilli from pregnant women at high risk of preterm birth and relation with outcome. J Clin Microbiol. 2004 Feb;42(2):713-7. doi: 10.1128/JCM.42.2.713-717.2004.
Reference Type
BACKGROUND
Mosbah A, Mesbah MR. (2009) A study of the role of hydrogen peroxide production by lactobacilli in preterm labor. Int J Med Med Sci, 1:388-95.
Reference Type
BACKGROUND
Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2013 Jan 31;2013(1):CD000262. doi: 10.1002/14651858.CD000262.pub4.
Reference Type
BACKGROUND
Cooper NA, Moores R; East London Preterm Prevention Collaboration. A review of the literature regarding nutritional supplements and their effect on vaginal flora and preterm birth. Curr Opin Obstet Gynecol. 2014 Dec;26(6):487-92. doi: 10.1097/GCO.0000000000000126.
Reference Type
BACKGROUND
Othman M, Neilson JP, Alfirevic Z. Probiotics for preventing preterm labour. Cochrane Database Syst Rev. 2007 Jan 24;2007(1):CD005941. doi: 10.1002/14651858.CD005941.pub2.
Reference Type
BACKGROUND
Unlu C, Donders G. Use of lactobacilli and estriol combination in the treatment of disturbed vaginal ecosystem: a review. J Turk Ger Gynecol Assoc. 2011 Dec 1;12(4):239-46. doi: 10.5152/jtgga.2011.57. eCollection 2011.
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BACKGROUND
Zhao T-F, Zhong L, Luo D.(2010) Living preparation of lactobacillus versus metronidazole for bacterial vaginosis in pregnancy: a systematic review. Chin J Evid-based Med, 10:1338-44.
Reference Type
BACKGROUND
Myhre R, Brantsaeter AL, Myking S, Gjessing HK, Sengpiel V, Meltzer HM, Haugen M, Jacobsson B. Intake of probiotic food and risk of spontaneous preterm delivery. Am J Clin Nutr. 2011 Jan;93(1):151-7. doi: 10.3945/ajcn.110.004085. Epub 2010 Oct 27.
Reference Type
BACKGROUND
Yeganegi M, Watson CS, Martins A, Kim SO, Reid G, Challis JR, Bocking AD. Effect of Lactobacillus rhamnosus GR-1 supernatant and fetal sex on lipopolysaccharide-induced cytokine and prostaglandin-regulating enzymes in human placental trophoblast cells: implications for treatment of bacterial vaginosis and prevention of preterm labor. Am J Obstet Gynecol. 2009 May;200(5):532.e1-8. doi: 10.1016/j.ajog.2008.12.032. Epub 2009 Mar 14.
Reference Type
BACKGROUND
Dugoua JJ, Machado M, Zhu X, Chen X, Koren G, Einarson TR. Probiotic safety in pregnancy: a systematic review and meta-analysis of randomized controlled trials of Lactobacillus, Bifidobacterium, and Saccharomyces spp. J Obstet Gynaecol Can. 2009 Jun;31(6):542-552. doi: 10.1016/S1701-2163(16)34218-9.
Reference Type
BACKGROUND
Lindsay KL, Brennan L, McAuliffe FM. Acceptability of and compliance with a probiotic capsule intervention in pregnancy. Int J Gynaecol Obstet. 2014 Jun;125(3):279-80. doi: 10.1016/j.ijgo.2014.01.004. Epub 2014 Feb 19. No abstract available.
Reference Type
BACKGROUND
Krauss-Silva L, Moreira ME, Alves MB, Braga A, Camacho KG, Batista MR, Almada-Horta A, Rebello MR, Guerra F. A randomised controlled trial of probiotics for the prevention of spontaneous preterm delivery associated with bacterial vaginosis: preliminary results. Trials. 2011 Nov 8;12:239. doi: 10.1186/1745-6215-12-239.
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BACKGROUND
Reid G, Charbonneau D, Erb J, Kochanowski B, Beuerman D, Poehner R, Bruce AW. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial in 64 healthy women. FEMS Immunol Med Microbiol. 2003 Mar 20;35(2):131-4. doi: 10.1016/S0928-8244(02)00465-0.
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BACKGROUND
Davidson SJ, Barrett HL, Price SA, Callaway LK, Dekker Nitert M. Probiotics for preventing gestational diabetes. Cochrane Database Syst Rev. 2021 Apr 19;4(4):CD009951. doi: 10.1002/14651858.CD009951.pub3.
Reference Type
DERIVED
Husain S, Allotey J, Drymoussi Z, Wilks M, Fernandez-Felix BM, Whiley A, Dodds J, Thangaratinam S, McCourt C, Prosdocimi EM, Wade WG, de Tejada BM, Zamora J, Khan K, Millar M. Effects of oral probiotic supplements on vaginal microbiota during pregnancy: a randomised, double-blind, placebo-controlled trial with microbiome analysis. BJOG. 2020 Jan;127(2):275-284. doi: 10.1111/1471-0528.15675. Epub 2019 Apr 1.
Reference Type
DERIVED
Other Identifiers
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010294QM
Identifier Type: -
Identifier Source: org_study_id