Intravaginal lactic acid gel versus oral metronidazole for treating women with recurrent bacterial vaginosis: the VITA randomised controlled trial.

BACKGROUND: Bacterial vaginosis is a common and distressing condition for women. Short-term antibiotic treatment is usually clinically effective, but recurrence is common. We assessed the effectiveness of intravaginal lactic acid gel versus oral metronidazole for treating recurrent bacterial vaginosis. METHODS: We undertook an open-label, multicentre, parallel group, randomised controlled trial in nineteen UK sexual health clinics and a university health centre. Women aged ≥ 16 years, with current bacterial vaginosis symptoms and a preceding history of bacterial vaginosis, were randomised in a 1:1 ratio using a web-based minimisation algorithm, to 400 mg twice daily oral metronidazole tablets or 5 ml once daily intravaginal lactic acid gel, for 7 days. Masking of participants was not possible. The primary outcome was participant-reported resolution of symptoms within 2 weeks. Secondary outcomes included time to first recurrence of symptoms, number of recurrences and repeat treatments over 6 months and side effects. RESULTS: Five hundred and eighteen participants were randomised before the trial was advised to stop recruiting by the Data Monitoring Committee. Primary outcome data were available for 79% (204/259) allocated to metronidazole and 79% (205/259) allocated to lactic acid gel. Resolution of bacterial vaginosis symptoms within 2 weeks was reported in 70% (143/204) receiving metronidazole versus 47% (97/205) receiving lactic acid gel (adjusted risk difference -23·2%; 95% confidence interval -32.3 to -14·0%). In those participants who had initial resolution and for whom 6 month data were available, 51 of 72 (71%) women in the metronidazole group and 32 of 46 women (70%) in the lactic acid gel group had recurrence of symptoms, with median times to first recurrence of 92 and 126 days, respectively. Reported side effects were more common following metronidazole than lactic acid gel (nausea 32% vs. 8%; taste changes 18% vs. 1%; diarrhoea 20% vs. 6%, respectively). CONCLUSIONS: Metronidazole was more effective than lactic acid gel for short-term resolution of bacterial vaginosis symptoms, but recurrence is common following both treatments. Lactic acid gel was associated with fewer reported side effects. TRIAL REGISTRATION: ISRCTN14161293 , prospectively registered on 18th September 2017.

Cord pilot trial, comparing alternative policies for timing of cord clamping before 32 weeks gestation: follow-up for women up to one year.

BACKGROUND: The Cord Pilot Trial compared two alternative policies for cord clamping at very preterm birth at eight UK maternity units: clamping after at least 2 min and immediate neonatal care (if needed) with cord intact, or clamping within 20 s and neonatal care after clamping. This paper reports follow-up of the women by two self-completed questionnaires up to one year after the birth. METHODS: Women were given or posted the first questionnaire between four and eight weeks after birth, usually before their baby was discharged, and were posted a second similar questionnaire at one year. The questionnaire included the Hospital Anxiety and Depression Scale; the Preterm Birth Experience and Satisfaction Scale (P-BESS) and questions about their baby's feeding. RESULTS: Of 261 women randomised (132 clamping ≥2 min, 129 clamping ≤20 s), six were excluded as birth was after 35+ 6 weeks (2, 4 in each group respectively). Six were not sent either questionnaire. The first questionnaire was given/sent to 244 and returned by 186 (76%) (79, 74%). The second, at one year, was sent to 242 and returned by 133 (55%) (66, 43%). On the first questionnaire, 89 (49%) had a score suggestive of an anxiety disorder, and 55 (30%) had a score suggestive of depression. Satisfaction with care at birth was high: median total P-BESS score 77 [interquartile range 68 to 84] (scale 17 to 85). There was no clear difference in anxiety, depression, or satisfaction with care between the two allocated groups. The median number of weeks after birth women breastfed/expressed was 16 (95% confidence interval (CI) 13 to 20, n = 119) for those allocated clamping ≥2 min and 12 (95% CI 11 to 16, n = 103) for those allocated clamping ≤20 s. CONCLUSIONS: The response rate was higher for the earlier questionnaire than at one year. A high proportion of women reported symptoms of anxiety or depression, however there were no clear differences between the allocated groups. Most women reported that they had breastfed or expressed milk and those allocated deferred cord clamping reported continuing this for slightly longer. TRIAL REGISTRATION: ISRCTN 21456601, registered 28th February 2013, http://www.isrctn.com/ISRCTN21456601.

Rapid respiratory microbiological point-of-care-testing and antibiotic prescribing in primary care: Protocol for the RAPID-TEST randomised controlled trial.

BACKGROUND: Antibiotics are prescribed for over 50% of respiratory tract infections in primary care, despite good evidence of there being no benefit to the patient, and evidence of over prescribing driving microbial resistance. The high treatment rates are attributed to uncertainty regarding microbiological cause and clinical prognosis. Point-of-care-tests have been proposed as potential antibiotic stewardship tools, with some providing microbiological results in 15 minutes. However, there is little research on their impact on antibiotic use and clinical outcomes in primary care. METHODS: This is a multi-centre, individually randomised controlled trial with mixed-methods investigation of microbial, behavioural and antibiotic mechanisms on outcomes in patients aged 12 months and over presenting to primary care in the UK with a suspected respiratory tract infection, where the clinician and/or patient thinks antibiotic treatment may be, or is, necessary. Once consented, all participants are asked to provide a combined nose and throat swab sample and randomised to have a rapid microbiological point-of-care-test or no point-of-care-test. For intervention patients, clinicians review the result of the test, before contacting the patient to finalise treatment. Treatment decisions are made as per usual care in control group patients. The primary outcome is whether an antibiotic is prescribed at this point. All swab samples are sent to the central laboratory for further testing. Patients are asked to complete a diary to record the severity and duration of symptoms until resolution or day 28, and questionnaires at 2 months about their beliefs and intention to consult for similar future illnesses. Primary care medical records are also reviewed at 6-months to collect further infection consultations, antibiotic prescribing and hospital admissions. The trial aims to recruit 514 patients to achieve 90% power with 5% significance to detect a 15% absolute reduction in antibiotic prescribing. Qualitative interviews are being conducted with approximately 20 clinicians and 30 participants to understand any changes in beliefs and behaviour resulting from the point-of-care-test and generate attributes for clinician and patient discrete choice experiments. DISCUSSION: This trial will provide evidence of efficacy, acceptability and mechanisms of action of a rapid microbiological point-of-care test on antibiotic prescribing and patient symptoms in primary care. TRIAL REGISTRATION: ISRCTN16039192, prospectively registered on 08/11/2022.

Lactic acid gel versus metronidazole for recurrent bacterial vaginosis in women aged 16 years and over: the VITA RCT.

BACKGROUND: Bacterial vaginosis is a common and distressing condition associated with serious comorbidities. Antibiotic treatment is usually clinically effective in the short term, but recurrence is common and side effects can occur. OBJECTIVES: The objective is to assess whether or not intravaginal lactic acid gel is clinically effective and cost-effective for treating recurrent bacterial vaginosis compared with oral metronidazole (Flagyl, Sanofi). DESIGN: This was an open-label, multicentre, parallel-arm, randomised (1 : 1) controlled trial. SETTING: This took place in one general practice and 19 sexual health centres in the UK. PARTICIPANTS: Women aged ≥ 16 years with bacterial vaginosis symptoms and one or more episode(s) within the past 2 years took part. INTERVENTIONS: The interventions were 5 ml of intravaginal lactic acid gel taken once daily for 7 days (intervention) or 400-mg oral metronidazole tablets taken twice daily for 7 days (control). MAIN OUTCOME MEASURES: The primary outcome was the resolution of bacterial vaginosis symptoms 14 days after randomisation. The secondary outcomes were time to first recurrence of symptoms; number of recurrences and treatment courses over 6 months; microbiological resolution on microscopy of vaginal smears at week 2; time to resolution of symptoms; tolerability, adherence and acceptability of the treatment; prevalence of concurrent sexually transmitted infections; quality of life; and cost-effectiveness. RESULTS: Recruitment stopped prior to reaching the target of 1900 participants on recommendation from the Data Monitoring Committee and Trial Steering Committee after a planned review of the results indicated that the research question had been answered. Overall, 518 participants were randomised and primary outcome data were available for 409 participants (79%; 204 in the metronidazole arm, 205 in the lactic acid gel arm). Participant-reported symptom resolution at week 2 was higher with metronidazole (143/204; 70%) than with lactic acid gel (97/205; 47%) (adjusted risk difference -23.2%, 95% confidence interval -32.3% to -14.0%). Recurrence in 6 months in a subset of participants who had initial resolution and were available for follow-up was similar across arms (metronidazole arm: 51/72, 71%; lactic acid gel arm: 32/46, 70%). A higher incidence of some side effects was reported with metronidazole than with lactic acid gel (nausea 32% vs. 8%; taste changes 18% vs. 1%; diarrhoea 20% vs. 6%, respectively). At week 2, the average cost per participant with resolved symptoms was £86.94 (metronidazole), compared with £147.00 (lactic acid gel). Some participants preferred using lactic acid gel even if they perceived it to be less effective than metronidazole. LIMITATIONS: Loss to follow-up for collection of the primary outcome data was 21% and was similar in both arms. There is a risk of bias owing to missing outcome data at 3 and 6 months post treatment. CONCLUSIONS: A higher initial response was seen with metronidazole than with lactic acid gel, but subsequent treatment failure was common with both. Lactic acid gel was less cost-effective than metronidazole. In general, women disliked taking repeated courses of metronidazole and preferred lactic acid gel, even when they were aware that it was less likely to provide symptom resolution. In the absence of effective curative therapy, further evaluation of non-antibiotic treatments to control the symptoms of recurrent bacterial vaginosis is required to improve quality of life for these patients. Further microbiological analysis of vaginal samples would be useful to identify additional factors affecting response to treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14161293. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 2. See the NIHR Journals Library website for further project information.

Bacterial vaginosis is a common cause of unpleasant vaginal discharge that is caused by an imbalance of vaginal bacteria. The usual treatment is an antibiotic called metronidazole (Flagyl, Sanofi). Although this generally works in the short term, symptoms often return, leading to the repeated use of antibiotics; this can cause side effects as well as increase the risk of antibiotic resistance. Lactic acid gel might be an alternative treatment, but previous studies have not confirmed how clinically effective it is. We wanted to find out if lactic acid gel was better than metronidazole for treating recurrent bacterial vaginosis. Women with typical symptoms and a history of bacterial vaginosis who were taking part in our trial were selected randomly to receive either 7 days of treatment with lactic acid gel inserted into the vagina once per day or 7 days of treatment with metronidazole tablets taken by mouth twice per day. Overall, 518 women took part in the trial. We originally intended to recruit 1900 women but the trial was stopped early because a planned review of the data showed which treatment was better. Most of the women took all of their treatment and 70% reported that symptoms had cleared 2 weeks after taking metronidazole, compared with 47% after using lactic acid gel. Less than half of the women stayed in the trial for the full 6 months; however, the data suggested that the majority of those whose symptoms cleared within 2 weeks with either treatment had symptoms return over the next 6 months. More side effects were reported for metronidazole than for lactic acid gel: nausea 32% compared with 8%, taste changes 18% compared with 1%, and diarrhoea 20% compared with 6%, respectively. Despite thinking that it was less effective, women preferred lactic acid gel because it avoided the need to take an antibiotic and had a soothing effect. The cost-effectiveness analysis found that lactic acid gel was less effective than metronidazole in clearing symptoms by 2 weeks and that the average costs for women whose symptoms resolved were higher (£86.94 with metronidazole vs. £147.00 with lactic acid gel).

Verification of placental growth factor and soluble-fms-like tyrosine kinase 1 assay performance in late pregnancy and their diagnostic test accuracy in women with reduced fetal movement.

BACKGROUND: Placental growth factor (PlGF) and soluble-fms-like tyrosine kinase 1 (sFlt-1) are biomarkers of placental function used to aid the diagnosis and prediction of pregnancy complications. This work verified the analytical performance of both biomarkers and provides preliminary diagnostic accuracy data to identify adverse pregnancy outcome in women with reduced fetal movement. METHODS: Verification of sFlt-1 and PlGF assays included a comparative accuracy assessment of 24 serum samples analysed at six different sites and laboratory-specific precision estimates. The sFlt-1/PlGF ratio was assessed in serum samples obtained prospectively from 295 women with reduced fetal movement ≥36 weeks' gestation; diagnostic accuracy was evaluated using 2 × 2 tables and area under the receiver operator characteristic (AUROC) curve. RESULTS: Regression analysis showed that performance between sites was good with Passing-Bablok slopes ranging from 0.96 to 1.05 (sFlt-1) and 0.93 to 1.08 (PlGF). All sites had a mean bias <15%, although there was poorer agreement at the lowest PlGF concentrations. All within- and between-batch coefficients of variation were <10%. In 289 women with an appropriately grown fetus, an sFlt-1/PlGF ratio ≥38 had a sensitivity of 0.20 (95% confidence interval [CI] 0.07, 0.41), specificity of 0.88 (95% CI 0.83, 0.92) and AUROC curve of 0.58 (95% CI 0.47, 0.68) to identify adverse pregnancy outcome. CONCLUSIONS: Analytical performance of the sFlt-1 and PlGF assays was comparable across different sites. The sensitivity of sFlt-1/PlGF to identify adverse pregnancy outcome in women with reduced fetal movement was considered acceptable, in the absence of other tests, to progress to a pilot randomized controlled trial.

Standard care informed by the result of a placental growth factor blood test versus standard care alone in women with reduced fetal movement at or after 36+0 weeks' gestation: a pilot randomised controlled trial.

BACKGROUND: Biomarkers of placental function can potentially aid the diagnosis and prediction of pregnancy complications. This randomised controlled pilot trial assessed whether for women with reduced fetal movement (RFM), intervention directed by the measurement of a placental biomarker in addition to standard care was feasible and improved pregnancy outcome compared with standard care alone. METHODS: Women aged 16-50 years presenting at eight UK maternity units with RFM between 36+0 and 41+0 weeks' gestation with a viable singleton pregnancy and no indication for immediate delivery were eligible. Participants were randomised 1:1 in an unblinded manner to standard care and a biomarker blood test result revealed and acted on (intervention arm) or standard care where the biomarker result was not available (control arm). The objectives were to determine the feasibility of a main trial by recruiting 175-225 participants over 9 months and to provide proof of concept that informing care by measurement of placental biomarkers may improve outcome. Feasibility was assessed via the number of potentially eligible women, number recruited, reasons for non-recruitment and compliance. Proof of concept outcomes included the rates of the induction of labour and caesarean birth, and a composite adverse pregnancy outcome. RESULTS: Overall, 2917 women presented with RFM ≥ 36 weeks, 352 were approached to participate and 216 (61%) were randomised (intervention n = 109, control n = 107). The main reason for not approaching women was resource/staff issues (n = 1510). Ninety-seven women declined the trial, mainly due to not liking blood tests (n = 24) or not wanting to be in a trial (n = 21). Compliance with the trial interventions was 100% in both arms. Labour was induced in 97 (45%) participants (intervention n = 49, control n = 48), while 17 (9%) had planned caesarean sections (intervention n = 9, control n = 8). Overall, 9 (8%) babies in the intervention arm had the composite adverse pregnancy outcome versus 4 (4%) in the control arm. CONCLUSIONS: A main trial using a placental biomarker in combination with delivery, as indicated by the biomarker, in women with RFM is feasible. The frequency of adverse outcomes in this population is low, hence, a large sample size would be required along with consideration of the most appropriate outcome measures. TRIAL REGISTRATION: ISRCTN, ISRCTN12067514; registered 8 September 2017.

Randomised trial of cord clamping at very preterm birth: outcomes at 2 years.

OBJECTIVE: To report outcomes at 2 years corrected age for children of women recruited to a trial comparing alternative policies for timing of cord clamping and immediate neonatal care at very preterm birth. DESIGN: Parallel group randomised (1:1) trial. SETTING: Eight UK tertiary maternity units. PARTICIPANTS: Two hundred and seventy-six babies born to 261 women expected to have a live birth before 32+0 weeks' gestation. INTERVENTIONS: Deferred cord clamping (≥2 min) and immediate neonatal care with cord intact or immediate (≤20 s) clamping and immediate neonatal care after clamping. MAIN OUTCOME MEASURE: Composite of death or adverse neurodevelopmental outcome at 2 years corrected age. RESULTS: Six babies born after 35+6 weeks were excluded. At 2 years corrected age, outcome data were not available for a further 52 children, leaving 218 for analysis (115 deferred clamping, 103 immediate clamping). Overall, 24/115 (21%) children allocated deferred clamping died or had an adverse neurodevelopmental outcome compared with 35/103 (34%) allocated immediate clamping; risk ratio (RR) 0.61 (95% CI 0.39 to 0.96); risk difference (RD) -13% (95% CI -25% to -1%). Multiple imputation for missing data gave an RR 0.69 (95% CI 0.44 to 1.09) and RD -9% (95% CI -21% to 2%). CONCLUSIONS: Deferred clamping and immediate neonatal care with cord intact may reduce the risk of death or adverse neurodevelopmental outcome at 2 years of age for children born very premature. Confirmation in larger studies is needed to determine the real benefits and harms. TRIAL REGISTRATION NUMBER: ISRCTN21456601.

Women's experiences of participating in a randomised trial comparing alternative policies for timing of cord clamping at very preterm birth: a questionnaire study.

BACKGROUND: The Cord Pilot Trial compared two alternative policies for cord-clamping at very preterm birth at eight UK tertiary maternity units: clamping after at least 2 min and immediate neonatal care with cord intact, or clamping within 20 s and neonatal care after clamping. This paper reports views and experiences of the women who participated in the trial (261 randomised), based on data from two self-completed questionnaires. METHODS: Women were given or posted the first questionnaire between 4 and 8 weeks after birth, and posted a second similar questionnaire at 1 year. Both questionnaires included three questions about experiences of participating in the trial: (1) If time suddenly went backwards and you had to do it all over again, would you agree to participate in the Cord Pilot Trial?; (2) Please tell us if there was anything about the Cord Pilot Trial that you think could have been done better; and (3) Please tell us if there was anything about the Cord Pilot Trial, or your experiences of joining the trial, that you think were particularly good. RESULTS: One hundred and eighty-six women completed the first questionnaire and 133 completed the second. At both time points, 90% responded 'probably' or 'definitely' to participating in the trial again. More women randomised to deferred clamping responded 'definitely yes' than those allocated immediate clamping (78% versus 67% first questionnaire). Women were positive about the level of information and explanations, the friendly and caring staff, and the benefits for their baby and others as a result of participating in the trial. Suggestions for how the trial could be done better included being approached earlier, better staff communication about the trial, more information overall, and better timing of follow-up. CONCLUSIONS: Women were largely positive about participating in the trial. Nevertheless, they had suggestions for how the study could have been improved. These suggestions have implications for the design of future trials. TRIAL REGISTRATION: ISRCTN21456601 . Registered on 28 February 2013.

Metronidazole versus lactic acid for treating bacterial vaginosis (VITA): protocol for a randomised controlled trial to assess the clinical and cost effectiveness of topical lactic acid gel for treating second and subsequent episodes of bacterial vaginosis.

BACKGROUND: Bacterial vaginosis (BV) affects 30-50% of women at some time in their lives and is an embarrassing and distressing condition which can be associated with potentially serious comorbidities. Current antibiotic treatments such as metronidazole are effective but can result in side effects, and recurrence is common. This trial aims to investigate whether lactic acid gel is clinically effective and cost effective in the treatment of recurrent BV compared with metronidazole. METHODS: VITA is an open-label, multicentre, parallel group randomised controlled trial for women with a clinical diagnosis of BV and at least one previous BV episode in the past 2 years. Participants will be randomised 1:1 to intravaginal lactic acid gel 5 ml once daily for 7 days or oral metronidazole tablets 400 mg twice daily for 7 days. All participants will be followed up for 6 months to assess health status and healthcare costs. A subgroup will be interviewed to further explore adherence, tolerability and acceptability of treatment. The estimated sample size is 1900 participants to detect a 6% absolute increase in response rate to 86% in those receiving lactic acid gel. The primary outcome is participant-reported resolution of BV at Week 2. DISCUSSION: Results from this trial will help inform UK treatment guidelines for BV and may provide an alternative effective treatment for recurrent episodes of this condition which avoids repeated exposure to antibiotics. TRIAL REGISTRATION: ISRCTN, ISRCTN14161293. Registered on 8 September 2017.

Reduced fetal movement intervention Trial-2 (ReMIT-2): protocol for a pilot randomised controlled trial of standard care informed by the result of a placental growth factor (PlGF) blood test versus standard care alone in women presenting with reduced fetal movement at or after 36+ 0 weeks gestation.

BACKGROUND: Forty percent of babies who are stillborn born die after 36 weeks gestation and have no lethal structural abnormality. Maternal perception of reduced fetal movement (RFM) is associated with stillbirth and is related to abnormal placental structure and function. The ultimate objective of this trial is to assess whether for women with RFM, intervention directed by measurement of placental biochemical factors in addition to standard care improves pregnancy outcome compared with standard care alone. This is the protocol for a pilot trial to determine the feasibility of a definitive trial and also provide proof of concept that informing care by measurement of placental factors improves neonatal outcomes. METHODS: ReMIT-2 is a multicentre, pilot randomised controlled trial of care informed by results of an additional placental factor blood test versus standard care alone for women presenting with RFM at or after 36+ 0 weeks gestation. Participants will be randomised 1:1 to the intervention arm where the blood test result is revealed and acted on, or to the control arm where the blood sample is not tested immediately and therefore the result cannot be acted on. All participants will be followed up six weeks after delivery to assess their health status and views of the trial, along with healthcare costs. A sub-group will be interviewed within 16 weeks after delivery to further explore their views of the trial. Outcomes to determine feasibility of a definitive trial include number of potentially eligible women, proportion lost to follow-up, clinical characteristics at randomisation, reasons for non-recruitment, compliance with the trial intervention and views of participants and clinicians about the trial. Proof of concept outcomes include: rates of induction of labour; Caesarean birth; and a composite neonatal outcome of stillbirths and deaths before discharge, 5-min Apgar score < 7, umbilical artery pH < 7.05 and admission to neonatal unit for > 48 h. DISCUSSION: Results from this pilot trial will help determine whether a large definitive trial is feasible. Such a study would provide evidence to guide management of women with RFM and reduce stillbirths. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN12067514 . Registered on 8 September 2017.